bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–01–16
133 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Targeting glucose metabolism to develop anticancer treatments and therapeutic patents.
  2. Iodinated cyanine dye-based nanosystem for synergistic phototherapy and hypoxia-activated bioreductive therapy.
  3. Cancer metabolism and intervention therapy.
  4. Mesoporous Silica Nanoprodrug Encapsulated with Near-Infrared Absorption Dye for Photothermal Therapy Combined with Chemotherapy.
  5. Tumor Acidity and Near-Infrared Light Responsive Drug Delivery MoS2-Based Nanoparticles for Chemo-Photothermal Therapy.
  6. Review of the Mechanism of Nanocarriers and Technological Developments in the Field of Nanoparticles for Applications in Cancer Theragnostics.
  7. Concise Nanoplatform of Phycocyanin Nanoparticle Loaded with Docetaxel for Synergetic Chemo-sonodynamic Antitumor Therapy.
  8. An Albumin-Based Therapeutic Nanosystem for Photosensitizer/Protein Co-Delivery to Realize Synergistic Cancer Therapy.
  9. Multifunctional inorganic nanomaterials for cancer photoimmunotherapy.
  10. Binary Prodrug of Dichloroacetic Acid and Doxorubicin with Enhanced Anticancer Activity.
  11. Therapeutic carrier based on solanesol and hyaluronate for synergistic tumor treatment.
  12. Expanding the Limits of Photodynamic Therapy: The Design of Organelles and Hypoxia-Targeting Nanomaterials for Enhanced Photokilling of Cancer.
  13. Metabolic adaptations in cancers expressing isocitrate dehydrogenase mutations.
  14. Tumor Microenvironment-Responsive and Catalytic Cascade-Enhanced Nanocomposite for Tumor Thermal Ablation Synergizing with Chemodynamic and Chemotherapy.
  15. Integration of Au Nanosheets and GdOF:Yb,Er for NIR-I and NIR-II Light-Activated Synergistic Theranostics.
  16. 808 nm NIR Laser-Excited Upconversion Nanoplatform for Combinatory Photodynamic and Chemotherapy with Deep Penetration and Acid Bursting Release Performance.
  17. Tumor-Targeting H2O2-Responsive Photosensitizing Nanoparticles with Antiangiogenic and Immunogenic Activities for Maximizing Anticancer Efficacy of Phototherapy.
  18. Stealth Polydopamine-Based Nanoparticles with Red Blood Cell Membrane for the Chemo-Photothermal Therapy of Cancer.
  19. Artesunate-Based Multifunctional Nanoplatform for Photothermal/Photoinduced Thermodynamic Synergistic Anticancer Therapy.
  20. NIR-/pH-Responsive Nanocarriers Based on Mesoporous Hollow Polydopamine for Codelivery of Hydrophilic/Hydrophobic Drugs and Photothermal Synergetic Therapy.
  21. NIR-Triggered Chemo-Photothermal Therapy by Thermosensitive Gold Nanostar@Mesoporous Silica@Liposome-Composited Drug Delivery Systems.
  22. Multifunctional Reduced Graphene Oxide-Based Nanoplatform for Synergistic Targeted Chemo-Photothermal Therapy.
  23. GSH-responsive poly-resveratrol based nanoparticles for effective drug delivery and reversing multidrug resistance.
  24. Mitochondrial Dysfunction and Antioxidation Dyshomeostasis-Enhanced Tumor Starvation Synergistic Chemotherapy Achieved using a Metal-Organic Framework-Based Nano-Enzyme Reactor.
  25. Biomimetic Nanoreactor for Cancer Eradication via Win-Win Cooperation between Starvation/Photo/Chemodynamic Therapies.
  26. Epigallocatechin‑3‑gallate hinders metabolic coupling to suppress colorectal cancer malignancy through targeting aerobic glycolysis in cancer‑associated fibroblasts.
  27. Glucose/Glutathione Co-triggered Tumor Hypoxia Relief and Chemodynamic Therapy to Enhance Photothermal Therapy in Bladder Cancer.
  28. Folic Acid Functionalized Carbon Dot/Polypyrrole Nanoparticles for Specific Bioimaging and Photothermal Therapy.
  29. Synthesis, Physicochemical Characterization and In vitro Evaluation of Biodegradable PLGA Nanoparticles entrapped to Folic acid for Targeted Delivery of Kaempferitrin.
  30. Polydopamine-Based Multifunctional Antitumor Nanoagent for Phototherapy and Photodiagnosis by Regulating Redox Balance.
  31. Near-Infrared Light-Initiated Upconversion Nanoplatform with Tumor Microenvironment Responsiveness for Improved Photodynamic Therapy.
  32. Antibacterial Activity of Porous Gold Nanocomposites via NIR Light-Triggered Photothermal and Photodynamic Effects.
  33. Tin-Doped Near-Infrared Persistent Luminescence Nanoparticles with Considerable Improvement of Biological Window Activation for Deep Tumor Photodynamic Therapy.
  34. Boronic acid derivative activates pyruvate kinase M2 indispensable for redox metabolism in oral cancer cells.
  35. Phenylthiourea-Conjugated BODIPY as an Efficient Photosensitizer for Tyrosinase-Positive Melanoma-Targeted Photodynamic Therapy.
  36. Antiproliferative and ROS Regulation Activity of Photoluminescent Curcumin-Derived Nanodots.
  37. Engineering Near-Infrared-Excitable Metal-Organic Framework for Tumor Microenvironment Responsive Therapy.
  38. Reduction-Responsive and Multidrug Deliverable Albumin Nanoparticles: An Antitumor Drug to Abraxane against Human Pancreatic Tumor-Bearing Mice.
  39. Oxidative stress in cancer therapy: Friend or enemy?
  40. Role of histone demethylases and histone methyltransferases in triple-negative breast cancer: Epigenetic mnemonics.
  41. Polymeric Micelles with Reduction-Responsive Function for Targeted Cancer Chemotherapy.
  42. Injectable Liquid Metal- and Methotrexate-Loaded Microsphere for Cancer Chemophotothermal Synergistic Therapy.
  43. Multifunctional Biodegradable Prussian Blue Analogue for Synergetic Photothermal/Photodynamic/Chemodynamic Therapy and Intrinsic Tumor Metastasis Inhibition.
  44. Near-Infrared Conjugated Oligomer for Effective Killing of Bacterial through Combination of Photodynamic and Photothermal Treatment.
  45. Reduced Graphene Oxide/Mesoporous Silica Nanocarriers for pH-Triggered Drug Release and Photothermal Therapy.
  46. A bone implant with NIR-responsiveness for eliminating osteosarcoma cells and promoting osteogenic differentiation of BMSCs.
  47. Construction of a Drug Delivery System and Photodynamic Therapy Reagent Based on the Biotin-HSA-DDA-TCPP Molecules and the Application of Synergistic Antitumor Effect.
  48. Eyeball-Like Yolk-Shell Bimetallic Nanoparticles for Synergistic Photodynamic-Photothermal Therapy.
  49. Iron-doxorubicin prodrug loaded liposome nanogenerator programs multimodal ferroptosis for efficient cancer therapy.
  50. Development of Nanocarrier-Based Mitochondrial Chaperone, TRAP-1 Inhibitor to Combat Cancer Metabolism.
  51. Combined effect of heat shock protein inhibitor geldanamycin and free radicals on photodynamic therapy of prostate cancer.
  52. Surface Chemistry- and Intracellular Trafficking-Dependent Autophagy Induction by Iron Oxide Nanoparticles.
  53. Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy.
  54. Identification of medicinal compounds as potential inhibitors for mutated isocitrate dehydrogenases against chondrosarcoma.
  55. Engineering a pH/Glutathione-Responsive Tea Polyphenol Nanodevice as an Apoptosis/Ferroptosis-Inducing Agent.
  56. A Review of Microbial Mediated Iron Nanoparticles (IONPs) and Its Biomedical Applications.
  57. Near-Infrared Thermally Activated Delayed Fluorescence Nanoparticle: A Metal-Free Photosensitizer for Two-Photon-Activated Photodynamic Therapy at the Cell and Small Animal Levels.
  58. Multifunctional liquid metal-based nanoparticles with glycolysis and mitochondrial metabolism inhibition for tumor photothermal therapy.
  59. Review on metal nanoparticles as nanocarriers: current challenges and perspectives in drug delivery systems.
  60. ROS-responsive dexamethasone micelles normalize the tumor microenvironment enhancing hypericin in cancer photodynamic therapy.
  61. Versatile Nanoplatform Loaded with Doxorubicin and Graphene Quantum Dots/Methylene Blue for Drug Delivery and Chemophotothermal/Photodynamic Synergetic Cancer Therapy.
  62. Sonodynamic Therapy (SDT) for Cancer Treatment: Advanced Sensitizers by Ultrasound Activation to Injury Tumor.
  63. Metal Complexes or Chelators with ROS Regulation Capacity: Promising Candidates for Cancer Treatment.
  64. Targeted Designing of Multimodal Tumor-Seeking Nanomedicine for Breast Cancer-Specific Triple-Therapeutic Effects.
  65. Fluorescent Carbon Dot-Curcumin Nanocomposites for Remarkable Antibacterial Activity with Synergistic Photodynamic and Photothermal Abilities.
  66. The Potential Mechanisms by which Artemisinin and Its Derivatives Induce Ferroptosis in the Treatment of Cancer.
  67. Injectable and Temperature-Sensitive Titanium Carbide-Loaded Hydrogel System for Photothermal Therapy of Breast Cancer.
  68. Polypyrrole-Coated Mesoporous TiO2 Nanocomposites Simultaneously Loading DOX and Aspirin Prodrugs for a Synergistic Theranostic and Anti-Inflammatory Effect.
  69. Upconversion Nanoparticle-Based Organosilica-Micellar Hybrid Nanoplatforms for Redox-Responsive Chemotherapy and NIR-Mediated Photodynamic Therapy.
  70. Tumor Microenvironment-Directed Multisensitive Nanorobotics for Synergistic Photothermal Therapy/Chemotherapy.
  71. Nanostructuring a Widely Used Antiworm Drug into the Lipid-Coated Calcium Phosphate Matrix for Enhanced Skin Tumor Treatment.
  72. A Strategy to Fight against Triple-Negative Breast Cancer: pH-Responsive Hexahistidine-Metal Assemblies with High-Payload Drugs.
  73. Polyphosphazene-Based Drug Self-Framed Delivery System as a Universal Intelligent Platform for Combination Therapy against Multidrug-Resistant Tumors.
  74. Reactive Oxygen Species Self-Sufficient Multifunctional Nanoplatform for Synergistic Chemo-Photodynamic Therapy with Red/Near-Infrared Dual-Imaging.
  75. Intelligent Size-Changeable Nanoparticles for Enhanced Tumor Accumulation and Deep Penetration.
  76. Smart Nanocarriers as an Emerging Platform for Cancer Therapy: A Review.
  77. Dandelion-Inspired Hierarchical Upconversion Nanoplatform for Synergistic Chemo-Photodynamic Therapy In Vitro.
  78. Synthesis of Gelatin-Based Dual-Targeted Nanoparticles of Betulinic Acid for Antitumor Therapy.
  79. Self-Adaptive Single-Atom Catalyst Boosting Selective Ferroptosis in Tumor Cells.
  80. In Situ Biosynthesized Superparamagnetic Iron Oxide Nanoparticles (SPIONS) Induce Efficient Hyperthermia in Cancer Cells.
  81. Injectable and pH-responsive self-assembled peptide hydrogel for promoted tumor cell uptake and enhanced cancer chemotherapy.
  82. Recent Trends in Assessment of Cellulose Derivatives in Designing Novel and Nanoparticulate-Based Drug Delivery Systems for Improvement of Oral Health.
  83. PEGylated Dimeric BODIPY Photosensitizers as Nanocarriers for Combined Chemotherapy and Cathepsin B-Activated Photodynamic Therapy in 3D Tumor Spheroids.
  84. RNA Hydrogel Combined with MnO2 Nanoparticles as a Nano-Vaccine to Treat Triple Negative Breast Cancer.
  85. Cannabinoids in Breast Cancer: Differential Susceptibility According to Subtype.
  86. Ru(II) Polypyridine Complex-Functionalized Mesoporous Silica Nanoparticles as Photosensitizers for Cancer Targeted Photodynamic Therapy.
  87. Synergistic Photodynamic and Photothermal Antibacterial Therapy Based on a Conjugated Polymer Nanoparticle-Doped Hydrogel.
  88. A possible theranostic approach of chitosan-coated iron oxide nanoparticles against human colorectal carcinoma (HCT-116) cell line.
  89. Charge reversal nano-systems for tumor therapy.
  90. Fibronectin-Coated Metal-Phenolic Networks for Cooperative Tumor Chemo-/Chemodynamic/Immune Therapy via Enhanced Ferroptosis-Mediated Immunogenic Cell Death.
  91. Design of Curcumin Loaded Carbon Nanodots Delivery System: Enhanced Bioavailability, Release Kinetics, and Anticancer Activity.
  92. A Novel Metabolic Reprogramming Strategy for the Treatment of Diabetes-Associated Breast Cancer.
  93. Paclitaxel-Loaded Biotinylated Fe2+-Doped Carbon Dot: Combination Therapy in Cancer Treatment.
  94. Aptamer-Functionalized Gold Nanostars for on-Demand Delivery of Anticancer Therapeutics.
  95. Mesoporous Doxorubicin-Loaded Polydopamine Nanoparticles Coated with a Platelet Membrane Suppress Tumor Growth in a Murine Model of Human Breast Cancer.
  96. Conjugated Polymer Nanoparticles Based on Copper Coordination for Real-Time Monitoring of pH-Responsive Drug Delivery.
  97. Targeting PGM3 as a Novel Therapeutic Strategy in KRAS/LKB1 Co-Mutant Lung Cancer.
  98. Promising Natural Products in New Drug Design, Development, and Therapy for Skin Disorders: An Overview of Scientific Evidence and Understanding Their Mechanism of Action.
  99. Lamellar Metal Oxide Based Nanoagent Realizing Intensive Interlamellar Ca2+ Release and Hypoxia Relief for Enhanced Synergistic Therapy.
  100. Phase-Change Nanotherapeutic Agents Based on Mesoporous Carbon for Multimodal Imaging and Tumor Therapy.
  101. Carrier-free prodrug nanoparticles based on dasatinib and cisplatin for efficient antitumor in vivo.
  102. Improved Photophysical Properties of Ionic Material-Based Combination Chemo/PDT Nanomedicine.
  103. Red-light-triggered self-destructive mesoporous silica nanoparticles for cascade-amplifying chemo-photodynamic therapy favoring antitumor immune responses.
  104. Biodegradable Hollow Manganese Silicate Nanocomposites to Alleviate Tumor Hypoxia toward Enhanced Photodynamic Therapy.
  105. Reprogramming Cancer Stem-like Cells with Nanoforskolin Enhances the Efficacy of Paclitaxel in Targeting Breast Cancer.
  106. Advances in Polyhydroxyalkanoate Nanocarriers for Effective Drug Delivery: An Overview and Challenges.
  107. Anti-lung Cancer Marine Compounds: A Review.
  108. Structural modification and strategies for the enhanced doxorubicin drug delivery.
  109. Reactive Oxygen Species-Sensitive Nanophotosensitizers of Methoxy Poly(ethylene glycol)-Chlorin e6/Phenyl Boronic Acid Pinacol Ester Conjugates Having Diselenide Linkages for Photodynamic Therapy of Cervical Cancer Cells.
  110. Fabrication of a pH/Redox-Triggered Mesoporous Silica-Based Nanoparticle with Microfluidics for Anticancer Drugs Doxorubicin and Paclitaxel Codelivery.
  111. Targeting PGC1α to wrestle cancer: a compelling therapeutic opportunity.
  112. Doxorubicin and Crocin Co-delivery by Polymeric Nanoparticles for Enhanced Anticancer Potential In Vitro and In Vivo.
  113. A medicinal chemist's perspective towards structure activity relationship of heterocycle based anti-cancer agents.
  114. Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer.
  115. Hyaluronic Acid-Conjugated Carbon Nanomaterials for Enhanced Tumour Targeting Ability.
  116. Folic Acid-Conjugated Gold Nanostars for Computed Tomography Imaging and Photothermal/Radiation Combined Therapy.
  117. Traceable Nanocluster-Prodrug Conjugate for Chemo-photodynamic Combinatorial Therapy of Non-small Cell Lung Cancer.
  118. Zeolitic Imidazolate Framework Platform for Combinational Starvation Therapy and Oxygen Self-Sufficient Photodynamic Therapy against a Hypoxia Tumor.
  119. Highly Efficient Near-Infrared Photosensitizers with Aggregation-Induced Emission Characteristics: Rational Molecular Design and Photodynamic Cancer Cell Ablation.
  120. Vitamin-H Channeled Self-Therapeutic P-gp Inhibitor Curcumin-Derived Nanomicelles for Targeting the Tumor Milieu by pH- and Enzyme-Triggered Hierarchical Disassembly.
  121. RNA-Seq Explores the Mechanism of Oxygen-Boosted Sonodynamic Therapy Based on All-in-One Nanobubbles to Enhance Ferroptosis for the Treatment of HCC.
  122. Synergistic antitumor efficacy of PD-1-conjugated PTX- and ZSQ-loaded nanoliposomes against multidrug-resistant liver cancers.
  123. Calorie restriction or dietary restriction: how far they can protect the brain against neurodegenerative diseases?
  124. Cancer-Targeted Chitosan-Biotin-Conjugated Mesoporous Silica Nanoparticles as Carriers of Zinc Complexes to Achieve Enhanced Chemotherapy In Vitro and In Vivo.
  125. Conjugated Polymer and Triphenylamine Derivative Codoped Nanoparticles for Photothermal and Photodynamic Antimicrobial Therapy.
  126. Folic Acid-Conjugated pH and Redox-Sensitive Ellipsoidal Hybrid Magnetic Nanoparticles for Dual-Triggered Drug Release.
  127. Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives.
  128. Enhanced Anti-Proliferative Effect of Carboplatin in Ovarian Cancer Cells Exploiting Chitosan - Poly (lactic glycolic acid) Nanoparticles.
  129. Self-Assembled Hybrid Nanogel as a Multifunctional Theranostic Probe for Enzyme-Regulated Ultrasound Imaging and Tumor Therapy.
  130. The Role of Bioactive Compounds from Dietary Spices in the Management of Metabolic Syndrome: An Overview.
  131. Nanoparticles use for Delivering Ursolic Acid in Cancer Therapy: A Scoping Review.
  132. Recent Advances on Stimuli-Responsive Combination Therapy against Multidrug-Resistant Bacteria and Biofilm.
  133. Orchestrated Yolk-Shell Nanohybrids Regulate Macrophage Polarization and Dendritic Cell Maturation for Oncotherapy with Augmented Antitumor Immunity.
  1. Expert Opin Ther Pat. 2022 Jan 09.
    Targeting glucose metabolism to develop anticancer treatments and therapeutic patents.
    Yan Zhou, Yizhen Guo, Kin Yip Tam.
       INTRODUCTION: One of the most distinctive hallmarks of cancer cells is increased glucose consumption for aerobic glycolysis which is named the Warburg effect. In recent decades, extensive research has been carried out to exploit this famous phenomenon, trying to detect promising targetable vulnerabilities in altered metabolism to fight cancer. Targeting aberrant glucose metabolism can perturb cancer malignant proliferation and even induce programmed cell death.
    AREAS COVERED: This review covered the recent patents which focused on targeting key glycolytic enzymes including hexokinase, pyruvate dehydrogenase kinases and lactate dehydrogenase for cancer treatment.
    EXPERT OPINION: Compared with the conventional cancer treatment, specifically targeting the well-known Achilles heel Warburg effect has attracted considerable attention. Although there is still no single glycolytic agent for clinical cancer treatment, the combination of glycolytic inhibitor with conventional anticancer drug or the combined use of multiple glycolytic inhibitors are being investigated extensively in recent years, which could emerge as attractive anticancer strategies.
    Keywords:  Warburg effect; cancer glucose metabolism; cancer treatment patent; glycolytic inhibitor; hexokinase 2 (HK2); lactate dehydrogenase A (LDHA); pyruvate dehydrogenase kinase (PDK)
    DOI:  https://doi.org/10.1080/13543776.2022.2027912
  2. Drug Deliv. 2022 Dec;29(1): 238-253
    Iodinated cyanine dye-based nanosystem for synergistic phototherapy and hypoxia-activated bioreductive therapy.
    Yunxia Dong, Ling Zhou, Zijun Shen, Qingming Ma, Yifan Zhao, Yong Sun, Jie Cao.
      Photodynamic therapy (PDT) has been applied in cancer treatment by utilizing reactive oxygen species (ROS) to kill cancer cells. However, the effectiveness of PDT is greatly reduced due to local hypoxia. Hypoxic activated chemotherapy combined with PDT is expected to be a novel strategy to enhance anti-cancer therapy. Herein, a novel liposome (LCT) incorporated with photosensitizer (PS) and bioreductive prodrugs was developed for PDT-activated chemotherapy. In the design, CyI, an iodinated cyanine dye, which could simultaneously generate enhanced ROS and heat than other commonly used cyanine dyes, was loaded into the lipid bilayer; while tirapazamine (TPZ), a hypoxia-activated prodrug was encapsulated in the hydrophilic nucleus. Upon appropriate near-infrared (NIR) irradiation, CyI could simultaneously produce ROS and heat for synergistic PDT and photothermal therapy (PTT), as well as provide fluorescence signals for precise real-time imaging. Meanwhile, the continuous consumption of oxygen would result in a hypoxia microenvironment, further activating TPZ free radicals for chemotherapy, which could induce DNA double-strand breakage and chromosome aberration. Moreover, the prepared LCT could stimulate acute immune response through PDT activation, leading to synergistic PDT/PTT/chemo/immunotherapy to kill cancer cells and reduce tumor metastasis. Both in vitro and in vivo results demonstrated improved anticancer efficacy of LCT compared with traditional PDT or chemotherapy. It is expected that these iodinated cyanine dyes-based liposomes will provide a powerful and versatile theranostic strategy for tumor target phototherapy and PDT-induced chemotherapy.
    Keywords:  Photodynamic therapy; hypoxia-activated chemotherapy; immune response; iodinated-cyanine dyes
    DOI:  https://doi.org/10.1080/10717544.2021.2023701
  3. Mol Biomed. 2021 Feb 20. 2(1): 5
    Cancer metabolism and intervention therapy.
    Huakan Zhao, Yongsheng Li.
      Metabolic reprogramming with heterogeneity is a hallmark of cancer and is at the basis of malignant behaviors. It supports the proliferation and metastasis of tumor cells according to the low nutrition and hypoxic microenvironment. Tumor cells frantically grab energy sources (such as glucose, fatty acids, and glutamine) from different pathways to produce a variety of biomass to meet their material needs via enhanced synthetic pathways, including aerobic glycolysis, glutaminolysis, fatty acid synthesis (FAS), and pentose phosphate pathway (PPP). To survive from stress conditions (e.g., metastasis, irradiation, or chemotherapy), tumor cells have to reprogram their metabolism from biomass production towards the generation of abundant adenosine triphosphate (ATP) and antioxidants. In addition, cancer cells remodel the microenvironment through metabolites, promoting an immunosuppressive microenvironment. Herein, we discuss how the metabolism is reprogrammed in cancer cells and how the tumor microenvironment is educated via the metabolic products. We also highlight potential metabolic targets for cancer therapies.
    Keywords:  Cancer; Heterogeneity; Metabolic reprogramming; Targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s43556-020-00012-1
  4. ACS Appl Bio Mater. 2021 Dec 20. 4(12): 8225-8235
    Mesoporous Silica Nanoprodrug Encapsulated with Near-Infrared Absorption Dye for Photothermal Therapy Combined with Chemotherapy.
    Shiyuan Peng, Fusheng Zhang, Baihao Huang, Jufang Wang, Lijuan Zhang.
      Based on the tumor microenvironment with weak acidic characteristics, a nano-drug delivery system that achieves controlled release of drugs through the pH response has been a popular strategy to improve the effectiveness of tumor therapy and reduce toxic side effects, and combining photothermal therapy (PTT) on this basis can help improve the antitumor effect. In this study, mesoporous silica nanoparticles (MSNs) were surface-modified with polymer poly(PEGMA-co-HEMA) via surface-initiated atom transfer radical polymerization, and a multifunctional nanoplatform MSN@poly(PEGMA-co-HEMA-g-doxorubicin (DOX)/indocyanine green (ICG) was designed for effective photothermal/chemotherapy combination therapy. The anticancer drug DOX was anchored to the polymer on the surface of MSN by reversible covalent bond cis-aconitic anhydride with a drug loading of 10%. Meanwhile, the small-molecule dye was loaded into the pores of MSN, and PTT mediated by near-infrared (NIR) radiation could further kill cancer cells. Under low-pH stimulation, the cis-aconitic anhydride bond breaks and DOX is released, with a 65% increase in cumulative drug release over 50 h compared to that at pH 7.4 (normal physiological environment). The high temperature induced by photothermal conversion accelerated the reversible covalent bond breakage, and the cumulative drug release at pH 5.0 for 3 h at elevated temperature up to 50 °C increased by 24.3% compared with that under normal physiological conditions (T = 37 °C), demonstrating that increasing the temperature can reduce the time required to reach blood drug concentration. In vitro cytotoxicity results revealed that the prodrug delivery system showed stronger cytotoxicity under NIR light irradiation compared with free DOX, with more than 90% of tumor cells killed after 48 h. Therefore, MSN@poly(PEGMA-co-HEMA-g-DOX)/ICG enhanced the synergistic effect of chemotherapy through photothermal action and accelerated reversible chemical bond cleavage, which has great potential in the combined therapy of cancer.
    Keywords:  accelerated release; mesoporous silica nanoparticles; photothermal therapy; reversible covalent bond; synergistic effect
    DOI:  https://doi.org/10.1021/acsabm.1c00751
  5. Photodiagnosis Photodyn Ther. 2022 Jan 09. pii: S1572-1000(22)00005-9. [Epub ahead of print] 102716
    Tumor Acidity and Near-Infrared Light Responsive Drug Delivery MoS2-Based Nanoparticles for Chemo-Photothermal Therapy.
    Wen Zhang, Meili Ding, Huilan Zhang, Hongyuan Shang, Aiping Zhang.
      The rational design of tumor microenvironment (TME)- multifunctional stimuli-responsive nanocomposites is appealing for effective cancer treatment. However, multidrug resistance remains the main obstacles to construct responsive oncotherapy. Herein, a novel MoS2/PDA-TPP nanocomposite loaded with chemotherapy drug of doxorubicin (DOX) is designed for TME dual-response and synergistically enhanced anti-tumor therapy based on the tumor-specific mitochondria accumulation ability and photothermal (PTT) therapy. In detail, the designed MoS2/PDA-TPP nanoplatform can act as a pH-responsive dissociation to endow fast release of DOX under an acidic TME and simultaneously improve the efficiency of PTT. Moreover, the mechanism shows that MoS2/PDA-TPP trigger mitochondrial-dependent apoptosis by producing reactive oxygen species (ROS) and reducing mitochondrial membrane potential (MMP). Most importantly, during PTT procedure, hyperthermia up to 50°C can effectively induce tumor cell death without causing severe inflammation to adjacent tissues. Tumor targeting double stimulation response of nanocomposites is a novel idea to overcome drug resistance, which will provide a more effective strategy for solving practical problems.
    Keywords:  Chemo-photothermal therapy; Mitochondrial targeting; MoS(2)-based nanoparticles; Multifunctional stimulus response; Tumor parallelcatalytic therapy
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.102716
  6. ACS Appl Bio Mater. 2021 Mar 15. 4(3): 2307-2334
    Review of the Mechanism of Nanocarriers and Technological Developments in the Field of Nanoparticles for Applications in Cancer Theragnostics.
    Nehil Shreyash, Muskan Sonker, Sushant Bajpai, Saurabh Kr Tiwary.
      Cancer cannot be controlled by the usage of drugs alone, and thus, nanotechnology is an important technique that can provide the drug with an impetus to act more effectively. There is adequate availability of anticancer drugs that are classified as alkylating agents, hormones, or antimetabolites. Nanoparticle (NP) carriers increase the residence time of the drug, thereby enhancing the survival rate of the drug, which otherwise gets washed off owing to the small size of the drug particles by the excretory system. For example, for enhancing the circulation, a coating of nonfouling polymers like PEG and dextran is done. Famous drugs such as doxorubicin (DOX) are commonly encapsulated inside the nanocomposite. The various classes of nanoparticles are used to enhance drug delivery by aiding it to fight against the tumor. Targeted therapy aims to attack the cells with features common to the cancer cells while minimizing damage to the normal cell, and these therapies work in one in four ways. Some block the cancer cells from reproducing newer cells, others release toxic substances to kill the cancer cells, some stimulate the immune system to destroy the cancer cells, and some block the growth of more blood vessels around cancer cells, which starve the cells of the nutrients, which is needed for their growth. This review aims to testify the advancements nanotechnology has brought in cancer therapy, and its statements are supported with recent research findings and clinical trial results.
    Keywords:  cancer treatment; doxorubicin; drug delivery; nanoparticles; polymeric nanoparticles; theragnostic
    DOI:  https://doi.org/10.1021/acsabm.1c00020
  7. ACS Appl Bio Mater. 2021 Sep 20. 4(9): 7176-7185
    Concise Nanoplatform of Phycocyanin Nanoparticle Loaded with Docetaxel for Synergetic Chemo-sonodynamic Antitumor Therapy.
    Jin Cao, Qiwen Pan, Shifang Bei, Mingxue Zheng, Zhenyan Sun, Xueyong Qi, Song Shen.
      Combined chemotherapy and sonodynamic therapy (chemo-SDT) based on the nanoplatform/nanocarrier is a potential antitumor strategy that has shown higher therapeutic efficacy than any monotherapy. Therefore, a safe and effective multifunctional system with a concise design and simple preparation process is urgently needed. In this work, by using a one-step cross-linking method, a multifunctional nanosystem, which employs phycocyanin nanoparticles (PCNPs) as a nanocarrier to deliver the chemotherapy drug docetaxel (DTX) and a nanosonosensitizer to generate reactive oxygen species (ROS), was prepared and evaluated (PCNP-DTX). Under low-intensity ultrasound irradiation, PCNP-DTX retained the ROS generation ability of phycocyanin and caused the destruction of mitochondrial potential. PCNP was also revealed to be an acidic and ultrasound-sensitive carrier with good biocompatibility. In addition to its cumulation behavior in tumors, PCNP can achieve tumor-targeted delivery and release of DTX. PCNP-DTX has also been proven to have a significant chemo-SDT synergy effect when low-intensity ultrasound was applied, showing enhanced antitumor activity both in vitro and in vivo. This study provides a concise yet promising nanoplatform based on the natural protein phycocyanin for achieving an effective, targeted, and synergetic chemo-SDT for antitumor therapy.
    Keywords:  chemo-sonodynamic therapy; docetaxel; drug delivery; phycocyanin; protein nanoparticle
    DOI:  https://doi.org/10.1021/acsabm.1c00745
  8. ACS Appl Bio Mater. 2021 Jun 21. 4(6): 4946-4952
    An Albumin-Based Therapeutic Nanosystem for Photosensitizer/Protein Co-Delivery to Realize Synergistic Cancer Therapy.
    Shu-Lun Ai, Cai-Xia Wang, Yan Peng, Yi Tu, Jin-Ju Lei, Chang Xu, Xiao-He Ren, Si-Xue Cheng.
      Oxygen-dependent photodynamic therapy (PDT) is hindered by the limited availability of endogenous oxygen in solid tumors and low tumor accumulation of photosensitizers. Herein, we developed a biocompatible cancer-targeted therapeutic nanosystem based on cRGD conjugated bovine serum albumin (CBSA) co-loaded with a photosensitizer (chlorin e6, Ce6) and a therapeutic protein (cytochrome c, Cytc) for synergistic photodynamic and protein therapy. The nanosystem (Ce6/Cytc@CBSA) can target αVβ3 integrin overexpressed cancer cells to improve tumor accumulation due to incorporation of cRGD. In the intracellular environment, Ce6 is released to produce toxic singlet oxygen upon near-infrared irradiation. At the same time, the therapeutic protein, Cytc, can induce programmed cell death by activating the downstream caspase pathway. Most importantly, Cytc with the catalase-like activity accelerates O2 generation by decomposing excess H2O2 in cancer cells, thereby relieving the PDT-induced hypoxia to enhance therapeutic efficacy. Both in vitro and in vivo studies reveal the significantly improved antitumor effects of the combined photodynamic/protein therapy, indicating that Ce6/Cytc@CBSA shows great potential in synergetic cancer treatments.
    Keywords:  albumin; drug delivery; photodynamic therapy; protein therapy; tumor targeting
    DOI:  https://doi.org/10.1021/acsabm.1c00233
  9. Cancer Commun (Lond). 2022 Jan 09.
    Multifunctional inorganic nanomaterials for cancer photoimmunotherapy.
    Lu Tang, Aining Zhang, Ziyao Zhang, Qingqing Zhao, Jing Li, Yijun Mei, Yue Yin, Wei Wang.
      Phototherapy and immunotherapy in combination is regarded as the ideal therapeutic modality to treat both primary and metastatic tumors. Immunotherapy uses different immunological approaches to stimulate the immune system to identify tumor cells for targeted elimination. Phototherapy destroys the primary tumors by light irradiation, which induces a series of immune responses through triggering immunogenic cancer cell death. Therefore, when integrating immunotherapy with phototherapy, a novel anti-cancer strategy called photoimmunotherapy (PIT) is emerging. This synergistic treatment modality can not only enhance the effectiveness of both therapies but also overcome their inherent limitations, opening a new era for the current anti-cancer therapy. Recently, the advancement of nanomaterials affords a platform for PIT. From all these nanomaterials, inorganic nanomaterials stand out as ideal mediators in PIT due to their unique physiochemical properties. Inorganic nanomaterials can not only serve as carriers to transport immunomodulatory agents in immunotherapy owing to their excellent drug-loading capacity but also function as photothermal agents or photosensitizers in phototherapy because of their great optical characteristics. In this review, the recent advances of multifunctional inorganic nanomaterial-mediated drug delivery and their contributions to cancer PIT will be highlighted.
    Keywords:  biodegradability; cancer photoimmunotherapy; immune stimulation; inorganic nanomaterial; nanoparticles; targeted drug delivery
    DOI:  https://doi.org/10.1002/cac2.12255
  10. ACS Appl Bio Mater. 2021 Mar 15. 4(3): 2026-2032
    Binary Prodrug of Dichloroacetic Acid and Doxorubicin with Enhanced Anticancer Activity.
    Amit Sharma, Jieun Chun, Myung Sun Ji, Sooyeon Lee, Chulhun Kang, Jong Seung Kim.
      The inevitable challenge in conventional chemotherapy is to deliver the anticancer drugs to the dense population of tumors cells while minimizing the drug-associated side effects on the normal cells. Cancer cells' preference for glycolysis for energy production is well recognized. Intuitively, taking advantage of such cancer-associated metabolism would be a promising strategy for anticancer drug delivery with minimal side effects. In this investigation, we have designed a binary prodrug PDOX as a sequential drug delivery regimens to realize the combination therapy for cancer. As cancer cells exhibit abrupt metabolism with elevated pyruvate dehydrogenase kinase (PDK) activity, dichloroacetic acid (DCA, a well-known PDK inhibitor) was used in combination with anticancer drug doxorubicin (DOX). The designed molecular prodrug was activated selectively by cancer-associated esterase to deliver DCA and DOX, respectively, and induced synergetic effects. Hence, sequential targeted delivery of molecular prodrug PDOX offers a promising approach to overcome the offside drug toxicity, pharmacokinetics, and biodistribution of individuals and provide an alternative option for cancer treatment.
    Keywords:  cancer; doxorubicin; drug delivery; esterase; fluorescence; theranostic
    DOI:  https://doi.org/10.1021/acsabm.0c00443
  11. Int J Biol Macromol. 2022 Jan 05. pii: S0141-8130(21)02840-3. [Epub ahead of print]201 20-28
    Therapeutic carrier based on solanesol and hyaluronate for synergistic tumor treatment.
    Mengying Zhang, Huimin Yu, Jinglu Hu, Zhengyu Zhao, Lei Liu, Gaomin Yang, Tingli Wang, Guang Han, Shiyong Song.
      The administration of nanodrugs can lead to metabolism related systemic toxicity due to the use of inert carriers in large quantities. Carrier materials that offer therapeutic effects are therefore a promising means of addressing this limitation. Herein, a hyaluronate-based nanocarrier was prepared from hyaluronic acid (HA) and solanesol. Solanesyl thiosalicylate (STS) derived from solanesol has certain antitumor effects and was used to modify HA. The conjugate (HA-STS) self-assembled into nanoparticles acting as a drug carrier. The synthesis of the conjugates was confirmed by 1H NMR spectroscopy. Doxorubicin (DOX) was loaded into the HA-STS nanoparticles with a relatively high content of 6.0%. pH-sensitive drug release behavior was achieved by introducing a hydroazone bond between STS and HA. A cytotoxicity assay indicated that the blank nanoparticles had an antitumor effect, which was enhanced by loading with an additional drug. Moreover, in vivo antitumor experiments indicated that the HA-STS-DOX showed superior tumor inhibition compared with free DOX, as well as lower cardiotoxicity and hepatotoxicity, demonstrating the advantages of the bioactive drug vehicles in cancer therapy.
    Keywords:  Hyaluronic acid; Nanoparticle; Tumor
    DOI:  https://doi.org/10.1016/j.ijbiomac.2021.12.194
  12. ACS Appl Bio Mater. 2021 Jan 18. 4(1): 195-228
    Expanding the Limits of Photodynamic Therapy: The Design of Organelles and Hypoxia-Targeting Nanomaterials for Enhanced Photokilling of Cancer.
    Italo Rodrigo Calori, Hong Bi, Antonio Claudio Tedesco.
      Photodynamic therapy (PDT) is a minimally invasive clinical protocol that combines a nontoxic photosensitizer (PS), appropriate visible light, and molecular oxygen for cancer treatment. This triad generates reactive oxygen species (ROS) in situ, leading to different cell death pathways and limiting the arrival of nutrients by irreversible destruction of the tumor vascular system. Despite the number of formulations and applications available, the advancement of therapy is hindered by some characteristics such as the hypoxic condition of solid tumors and the limited energy density (light fluence) that reaches the target. As a result, the use of PDT as a definitive monotherapy for cancer is generally restricted to pretumor lesions or neoplastic tissue of approximately 1 cm in size. To expand this limitation, researchers have synthesized functional nanoparticles (NPs) capable of carrying classical photosensitizers with self-supplying oxygen as well as targeting specific organelles such as mitochondria and lysosomes. This has improved outcomes in vitro and in vivo. This review highlights the basis of PDT, many of the most commonly used strategies of functionalization of smart NPs, and their potential to break the current limits of the classical protocol of PDT against cancer. The application and future perspectives of the multifunctional nanoparticles in PDT are also discussed in some detail.
    Keywords:  cell death pathway; hypoxia; lysosome; mitochondria; oxygen generator; photodynamic therapy
    DOI:  https://doi.org/10.1021/acsabm.0c00945
  13. Cell Rep Med. 2021 Dec 21. 2(12): 100469
    Metabolic adaptations in cancers expressing isocitrate dehydrogenase mutations.
    Ingvild Comfort Hvinden, Tom Cadoux-Hudson, Christopher J Schofield, James S O McCullagh.
      The most frequently mutated metabolic genes in human cancer are those encoding the enzymes isocitrate dehydrogenase 1 (IDH1) and IDH2; these mutations have so far been identified in more than 20 tumor types. Since IDH mutations were first reported in glioma over a decade ago, extensive research has revealed their association with altered cellular processes. Mutations in IDH lead to a change in enzyme function, enabling efficient conversion of 2-oxoglutarate to R-2-hydroxyglutarate (R-2-HG). It is proposed that elevated cellular R-2-HG inhibits enzymes that regulate transcription and metabolism, subsequently affecting nuclear, cytoplasmic, and mitochondrial biochemistry. The significance of these biochemical changes for tumorigenesis and potential for therapeutic exploitation remains unclear. Here we comprehensively review reported direct and indirect metabolic changes linked to IDH mutations and discuss their clinical significance. We also review the metabolic effects of first-generation mutant IDH inhibitors and highlight the potential for combination treatment strategies and new metabolic targets.
    Keywords:  2-oxoglutarate; IDH inhibition; R-2-HG; R-2-hydoxyglutarate; TCA cycle; cancer metabolism; chromatin modification; histone modification; metabolic target; mutant isocitrate dehydrogenase; redox metabolism
    DOI:  https://doi.org/10.1016/j.xcrm.2021.100469
  14. ACS Appl Bio Mater. 2020 Jun 15. 3(6): 3880-3893
    Tumor Microenvironment-Responsive and Catalytic Cascade-Enhanced Nanocomposite for Tumor Thermal Ablation Synergizing with Chemodynamic and Chemotherapy.
    Ye Zhang, Yi Cao, Tian Gao, Ye Kuang, Zhen An, Zheng Mao, Yilin He, Jincong Yan, Zhongzhong Lu, Renjun Pei.
      Chemodynamic therapy (CDT) is considered as a promising nanocatalytic therapeutic strategy for cancer because of its specific response toward the tumor microenvironment (TME). Improving the efficiency of this kind of reactive oxygen species (ROS)-mediated therapy is still a formidable challenge. Herein, we integrate CDT with other therapeutic methods together to enhance anticancer effects via overcoming robust ROS defensive mechanisms and hypoxia in cancer cells. The biocompatible and biodegraded nanoplatform (HMnO2-DOX-GOD-HA) has been constructed on the basis of hollow MnO2 nanoparticles loaded with chemotherapeutics doxorubicin (DOX) and glucose oxide (GOD) and further decorated with hyaluronic acid (HA) for targeting tumor cells. We demonstrated that HMnO2-DOX-GOD-HA is not only able to deplete glutathione (GSH) to disturb the redox balance but also release Mn2+ to initiate the magnetic resonance imaging signal and induce Fenton reaction happening. Meanwhile, GOD-induced glucose oxidation and HMnO2-catalyzed O2 generation facilitate hypoxia relief and enhance toxic hydroxyl radical (•OH) production for CDT efficiency promotion. Upon 808 nm laser irradiation, cancer-killing efficiency can be notably increased by photothermally enhanced ion and drug release and thermal ablation. This work offers a paradigm to design a TME-responsive and imaging-guided synergistic strategy for hypoxia tumors based on GSH depletion and catalytic cascade-enhanced CDT, thermal ablation, and chemotherapy.
    Keywords:  Fenton reaction; catalytic cascade; glutathione depletion; oxygen generation; thermal ablation
    DOI:  https://doi.org/10.1021/acsabm.0c00042
  15. ACS Appl Mater Interfaces. 2022 Jan 11.
    Integration of Au Nanosheets and GdOF:Yb,Er for NIR-I and NIR-II Light-Activated Synergistic Theranostics.
    Qi Cai, Chen Wang, Shili Gai, Piaoping Yang.
      The local hyperthermia (>41 °C) effect of photothermal therapy (PTT) is significantly limited by the efficiency of PTT agents to convert laser energy to heat, and such oncotherapy, similar to conventional chemotherapy, invariably encounters the challenge of nonspecific application. Undue reliance on oxygen sources still poses particular difficulties in photodynamic therapy (PDT) for deep-level clinical applications. Considering these therapeutic issues, in this study, we constructed a versatile but unique nanosystem by encapsulating Au nanosheets in codoped gadolinium oxyfluoride (GdOF):Yb,Er spheres, followed by decoration of a chemotherapeutic drug (doxorubicin), photosensitizer (rose Bengal, RB), and targeted agent (folic acid). This allowed the incorporation of cancer treatment and real-time curative efficacy monitoring into one single theranostic nanoplatform. Benefiting from the dual contribution of the strong absorptions in the NIR-I and NIR-II regions, relevant photothermal-conversion efficiency (η) values pertaining to that final product were 39.2% at 1064 nm irradiation and 35.7% at 980 nm illumination. The fluorescence resonance energy transfer that occurred in the up-converted GdOF:Yb,Er to RB contributed to the high PDT efficacy. Combined with a micromeric acid-responsive drug release in a targeted tumor microenvironment, high-performance synergistic therapy was realized. In addition, up-conversion fluorescence imaging and computed tomography imaging accompanied by multimodal magnetic resonance imaging were simultaneously achieved owing to the doped lanthanide ions and the encapsulated Au nanosheets. Our designed oncotherapy nanosystem provides an alternative strategy to acquire ideal theranostic effects.
    Keywords:  Au; NIR; photodynamic therapy; photothermal therapy; rare earth
    DOI:  https://doi.org/10.1021/acsami.1c21307
  16. ACS Appl Bio Mater. 2021 Mar 15. 4(3): 2639-2653
    808 nm NIR Laser-Excited Upconversion Nanoplatform for Combinatory Photodynamic and Chemotherapy with Deep Penetration and Acid Bursting Release Performance.
    Yingtao Zhong, Yun Dong, Tie Chen, Lingzhi Yang, Min Yao, Yunshi Zhi, Haoyi Yang, Jian Zhang, Wenchuan Bi.
      Combinatory photodynamic and chemotherapy have demonstrated superior performance in cancer ablation over singular therapeutics. However, photodynamic therapy (PDT) often exhibits suboptimal efficacy for deep-seated tumors, owing to the limited penetration depth of illumination light, while chemotherapy is generally accompanied by severe side effects. Therefore, it is imperative to develop a functional nanoplatform for combinatory PDT and chemotherapy, which could, for PDT, achieve enhanced light penetration and, for chemotherapy, realize reduced therapeutic threshold dosage and a controllable drug release profile (e.g., minimized release in blood circulation but bursting release in the tumor microenvironment). Herein, we demonstrate a therapeutic nanoplatform composed of poly(acrylic acid) (PAA)-modified silica-coated Nd3+-doped upconversion nanoparticles decorated with methylene blue (MB) and doxorubicin (DOX) in silica and a PAA layer, respectively. Notably, 808 nm light is used to excite upconversion nanoparticles and further trigger the photosensitization behavior of MB in PDT, while the quick acid response of the PAA layer in the tumor acid environment introduces DOX bursting for optimized chemotherapy with significantly decreased therapeutic threshold dosage and minimized side effects. Importantly, the anticancer efficiency of the nanoplatform in vitro and in vivo shows an IC50 and a tumor inhibition rate of 12.55 μg mL-1 and 89.81%, respectively. This study provides a strategy for combinatory cancer therapy.
    Keywords:  chemotherapy; combinatory therapy; pH responsive; photodynamic therapy; upconversion nanoparticles
    DOI:  https://doi.org/10.1021/acsabm.0c01607
  17. ACS Appl Bio Mater. 2021 May 17. 4(5): 4450-4461
    Tumor-Targeting H2O2-Responsive Photosensitizing Nanoparticles with Antiangiogenic and Immunogenic Activities for Maximizing Anticancer Efficacy of Phototherapy.
    Eunkyeong Jung, Jeonghun Lee, Yeongjong Lee, Semee Seon, Miran Park, Chulgyu Song, Dongwon Lee.
      Phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) uses photosensitizers and light to kill cancer cells and has become a promising therapeutic modality because of advantages such as minimal invasiveness and high cancer selectivity. However, PTT or PDT as a single treatment modality has insufficient therapeutic efficacy. Moreover, oxygen consumption by PDT activates angiogenic factors and leads to cancer recurrence and progression. Therefore, the therapeutic outcomes of phototherapy would be maximized by employing photosensitizers for concurrent PTT and PDT and suppressing angiogenic factors. Therefore, integrating photosensitive agents and antiangiogenic agents in a single nanoplatform would be a promising strategy to maximize the therapeutic efficacy of phototherapy. In this study, we developed hyaluronic acid-coated fluorescent boronated polysaccharide (HA-FBM) nanoparticles as a combination therapeutic agent for phototherapy and antiangiogenic therapy. Upon a single near-infrared laser irradiation, HA-FBM nanoparticles generated heat and singlet oxygen simultaneously to kill cancer cells and also induced immunogenic cancer cell death. Beside their fundamental roles as photosensitizers, HA-FBM nanoparticles exerted antiangiogenic effects by suppressing the vascular endothelial growth factor (VEGF) and cancer cell migration. In a mouse xenograft model, intravenously injected HA-FBM nanoparticles targeted tumors by binding CD44-overexpressing cancer cells and suppressed angiogenic VEGF expression. Upon laser irradiation, HA-FBM nanoparticles remarkably eradicated tumors and increased anticancer immunity. Given their synergistic effects of phototherapy and antiangiogenic therapy from tumor-targeting HA-FBM nanoparticles, we believe that integrating the photosensitizers and antiangiogenic agents into a single nanoplatform presents an attractive strategy to maximize the anticancer therapeutic efficacy of phototherapy.
    Keywords:  angiogenesis; cancer; photodynamic therapy; photosensitizers; photothermal therapy
    DOI:  https://doi.org/10.1021/acsabm.1c00210
  18. ACS Appl Bio Mater. 2020 Apr 20. 3(4): 2350-2359
    Stealth Polydopamine-Based Nanoparticles with Red Blood Cell Membrane for the Chemo-Photothermal Therapy of Cancer.
    Haijun Wang, Gareth R Williams, Xiaotian Xie, Meng Wu, Junzi Wu, Li-Min Zhu.
      Herein, we developed curcumin (Cur)-loaded porous poly(lactic-co-glycolic acid) (pPLGA) nanoparticles (NPs) by the nanoprecipitation method. Dopamine (DA) was then self-polymerized to form a polydopamine (PDA) layer on the surface of the NPs, yielding Cur@pPLGA/PDA NPs that are able to act as both chemotherapeutic and photothermal agents. These NPs were further camouflaged with the red blood cell membrane (RBCM) to construct RBCM-Cur@pPLGA/PDA NPs. The RBCM-pPLGA/PDA NPs were around 200 nm in size and demonstrated photothermal performance in the near-infrared (NIR) region, with a potent conversion efficiency (35.2%). The blank carrier has favorable cytocompatibility, but when drug loaded the NPs can efficiently induce the death of cancer cells (particularly when combined with NIR laser treatment). Cellular uptake results revealed greater in vitro uptake of RBCM-Cur@pPLGA/PDA NPs than bare Cur@pPLGA/PDA NPs in the case of cancer cells but reduced macrophage phagocytosis. In vivo studies in mice showed that the RBCM-Cur@pPLGA/PDA NPs exhibited prolonged blood circulation times and excellent photothermal properties, allowing tumor-specific chemo-photothermal therapy. The RBCM-Cur@pPLGA/PDA NP platform presents great potential for targeted synergistic cancer treatments.
    Keywords:  biomimetic; chemo-photothermal therapy; curcumin; polydopamine; red blood cell membrane
    DOI:  https://doi.org/10.1021/acsabm.0c00094
  19. ACS Appl Bio Mater. 2020 Nov 16. 3(11): 7876-7885
    Artesunate-Based Multifunctional Nanoplatform for Photothermal/Photoinduced Thermodynamic Synergistic Anticancer Therapy.
    Peng-Hui Zhao, Si-Tan Ma, Jia-Qian Hu, Bi-Yuan Zheng, Mei-Rong Ke, Jian-Dong Huang.
      Thermodynamic therapy (TDT), one that uses heat to activate thermosensitizers and produce reactive oxygen species (ROS), has recently emerged as an attractive approach for cancer therapy. However, the development of safe and efficient thermosensitizers for TDT remains a big challenge. Here, we have found that artesunate (ARS) could produce ROS upon heating. Based on this interesting result, we have designed and prepared a pH-sensitive liposomal nanoplatform (ICG-ARS@NPs) composed of indocyanine green (ICG) and ARS for photoinduced TDT as well as photothermal therapy (PTT). Under the slightly acidic conditions in tumor tissues, the pH-sensitive liposomal ICG-ARS@NPs were able to release their drug cargos. Upon near-infrared irradiation, the photothermal agent ICG generated in situ hyperthermia and triggered the thermal sensitizing activity of ARS to produce ROS, resulting in damage to cancer cells and tumor tissues. The heat-induced ROS generation of ARS was also confirmed both in vitro and in vivo. In addition, because of their specific tumor targeting and synergistic photothermal and thermodynamic effects, ICG-ARS@NPs exhibited highly efficient anticancer therapeutic efficacy in H22 tumor-bearing mice. We believe that this work will promote the exploration of TDT for cancer therapy as well as the application of the old drug, artemisinin.
    Keywords:  artesunate; liposomal nanoplatform; photohermal therapy; thermodynamic therapy; thermosensitizer
    DOI:  https://doi.org/10.1021/acsabm.0c01026
  20. ACS Appl Bio Mater. 2021 Feb 15. 4(2): 1605-1615
    NIR-/pH-Responsive Nanocarriers Based on Mesoporous Hollow Polydopamine for Codelivery of Hydrophilic/Hydrophobic Drugs and Photothermal Synergetic Therapy.
    Shanshan Li, Ying Gan, Chen Lin, Kunpeng Lin, Peng Hu, Lei Liu, Shuling Yu, Shuang Zhao, Jiahua Shi.
      Combined therapy system has become an efficient strategy to overcome drug resistance and strengthen therapeutic effects. Herein, an efficient NIR-/pH-triggered dual-drug-loaded nanoplatform was designed for combined chemo-photothermal therapy. The hydrophobic anticancer drug bortezomib (BTZ) was first loaded in mesoporous polydopamine nanospheres (MPDAs) through the acid-sensitive borate ester bond. Afterward, pH-responsive carboxymethyl chitosan (CMCS) conjugated on the surface of MPDA could capture another anticancer drug doxorubicin (DOX) and exhibited controlled release behavior in an acidic tumor microenvironment. Meanwhile, under NIR laser irradiation, hyperthermia produced by the photothermal conversion agent MPDA could efficiently ablate cancer cells and further promote drug release. In vitro and in vivo experiments emphasized that the synthesized MPDA-BTZ@CMCS-DOX nanostructure exhibited efficient accumulation in the tumor site, resulting in sustained release of BTZ and DOX and realizing NIR-/pH-triggered chemotherapy and photothermal synergistic ablation of cancer.
    Keywords:  NIR-/pH-responsive; controlled release; dual-drug delivery; mesoporous hollow polydopamine; photothermal therapy; synergistic therapy
    DOI:  https://doi.org/10.1021/acsabm.0c01451
  21. ACS Appl Bio Mater. 2020 Aug 17. 3(8): 5322-5330
    NIR-Triggered Chemo-Photothermal Therapy by Thermosensitive Gold Nanostar@Mesoporous Silica@Liposome-Composited Drug Delivery Systems.
    Zheng Cai, Yingwen Zhang, Zhimei He, Li-Ping Jiang, Jun-Jie Zhu.
      Multimodal therapeutic strategy that combines drug delivery with other treatments (e.g., photodynamic therapy) is highly desired for biomedical applications. Here, we engineer a promising versatile platform based on gold nanostar liposome-entrapped mesoporous silica core-shell nanostructure (GSMS@lip). This system not only served as a container for therapeutic drugs (hydrophilic doxorubicin and hydrophobic docetaxel), but also had high photothermal conversion efficiency. Specifically, the thermosensitive liposome wrapping around mesoporous silica acted as a gatekeeper to encapsulate the drug molecules within the GSMS/Dox/Doc@lip drug delivery system. After exposure to near-infrared (NIR) laser, gold nanostar significantly raised the ambient temperature via photothermal conversion, thereby rupturing the thermosensitive liposomes and subsequently triggering the drug release. Benefiting from the combined chemo-photothermal therapy, this composite system showed enhanced cytotoxicity to MDA-MB-231 and MCF-7 cells. Furthermore, effective drug release and synergistic inhibition of tumor growth were achieved after intratumoral injection of GSMS/Dox/Doc@lip followed by NIR laser irradiation. The proposed multifunctional drug delivery system is capable of codelivering hydrophilic-hydrophobic drugs, providing a potential strategy for multimodal tumor therapies.
    Keywords:  chemo-photothermal therapy; docetaxel; doxorubicin; gold nanostar; photothermal conversion; sensitive liposome
    DOI:  https://doi.org/10.1021/acsabm.0c00651
  22. ACS Appl Bio Mater. 2020 Aug 17. 3(8): 5213-5222
    Multifunctional Reduced Graphene Oxide-Based Nanoplatform for Synergistic Targeted Chemo-Photothermal Therapy.
    Liying Hao, Hongjie Song, Zixuan Zhan, Yi Lv.
      As for cancer treatments, synergistic therapy provides outstanding strategies to facilitate multiple anticancer pathways to induce improved therapeutic efficacy. Here, because of excellent physicochemical and biological properties, tea polyphenol-reduced and functionalized graphene oxide (TPG) was used to develop one single nanoplatform for synergistic targeted photo-chemotherapy. Specifically, a multifunctional nanoplatform with anti-PDL1-conjugated TPG (TPDL1) as a targeted therapy, loading the anticancer drug doxorubicin hydrochloride (DOX) on TPDL1 (TPD) as chemotherapy, and TPDL1 as a photothermal agent with near-infrared (NIR) irradiation as photothermal therapy (PTT) was constructed to reduce side effects and enhance the therapeutic efficacy. As expected, the nanoplatform showed NIR-enhanced, pH-responsive, and stable drug release behavior, targeting ability, and efficient photothermal conversion under NIR irradiation. Compared with pure DOX, TPD not only did protect normal cells from side effects but also efficiently enhanced the cytotoxicity in human tongue squamous cancer cells (CAL27) under NIR laser irradiation, which may be due to the synergistic effects between DOX-induced chemotherapy and TPDL1-elicited PTT. This study shows that the multifunctional reduced graphene oxide-based nanoplatform with combined targeted chemo-PTT has potential application values in cancer therapy.
    Keywords:  anti-PDL1; chemo-photothermal therapy; reduced graphene oxide; synergistic therapy; target
    DOI:  https://doi.org/10.1021/acsabm.0c00614
  23. Drug Deliv. 2022 Dec;29(1): 229-237
    GSH-responsive poly-resveratrol based nanoparticles for effective drug delivery and reversing multidrug resistance.
    Yang Liping, He Jian, Tao Zhenchao, Zhou Yan, Yang Jing, Zhang Yangyang, Gao Jing, Qian Liting.
      Cancer poses a serious threat to human health and is the most common cause of human death. Polymer-based nanomedicines are presently used to enhance the treatment effectiveness and decrease the systemic toxicity of chemotherapeutic agents. However, the disadvantage of currently polymeric carriers is without therapy procedure. Herein, for the first time, glutathione (GSH)-responsive polymer (PRES) with anti-cancer effect was synthesized following the condensation-polymerization method using resveratrol (RES) and 3,3'-dithiodipropionic acid. PRES can not only suppress the tumor cells growth but can also self-assemble into nanoparticles (∼93 nm) for delivering antitumor drugs, such as paclitaxel (PTX@PRES NPs). The system could achieve high drug loading (∼7%) and overcome multidrug resistance (MDR). The results from the in vitro studies revealed that the NPs formed of PRES were stable in the systemic circulation, while could be efficiently degraded in tumor cells high GSH environment. Results from cytotoxicity tests confirmed that PTX@PRES NPs could effectively suppress the growth of cancer cells (A549) and drug-resistant cells (A549/PTX). The NPs could also be used to significantly increase the therapeutic efficacy of the drugs in A549/PTX tumor-bearing mice. In vivo investigations also demonstrated that the PRES-based NPs exhibited tumor inhibition effects. In summary, we report that the GSH-responsive polymer synthesized by us exhibited multiple interesting functions and could be used for effective drug delivery. The polymer exhibited good therapeutic effects and could be used to overcome MDR. Thus, the synthesized system can be used to develop a new strategy for treating cancer.
    Keywords:  GSH-sensitive drug; Polymer-based nanomedicine; multidrug resistance; resveratrol
    DOI:  https://doi.org/10.1080/10717544.2021.2023700
  24. ACS Appl Mater Interfaces. 2022 Jan 12.
    Mitochondrial Dysfunction and Antioxidation Dyshomeostasis-Enhanced Tumor Starvation Synergistic Chemotherapy Achieved using a Metal-Organic Framework-Based Nano-Enzyme Reactor.
    Taotao Huo, Leilei Chen, Huifang Nie, Wenshuai Li, Chenteng Lin, Muhammad Akhtar, Rongqin Huang.
      Exploiting zeolitic imidazolate framework (ZIF)-based nanoparticles to synergistically enhance starvation-combined chemotherapy strategies remains an urgent demand. Herein, glucose oxidase (GOX) and doxorubicin (DOX) were facilely incorporated into ZIFs for starvation-combined chemotherapy. The as-prepared DOX/GOX-loaded ZIF (DGZ) exhibited uniform size with good dispersity, effective protection of the GOX activity, and stable delivery of the drugs into tumor. Correspondingly, it could achieve the glucose- and pH-responsive degradation and thus the controllable drug release. As a result, the acidification of glucose accompanied with reactive oxygen species (ROS) production was observed for the starvation-enhanced chemotherapy and the improved degradation. Most importantly, adjustable Zn2+ release was achieved with the biodegradation of DGZ, which thus contributed to an augmented therapeutic outcome via the Zn2+-induced mitochondrial dysfunction and antioxidation dyshomeostasis. These findings, synergized with the enhancement of starvation-combined chemotherapy by inhibiting the mitochondrial energy metabolism and boosting the ROS accumulation using pristine ZIF-based nanoparticles, provide a new insight into the metal-organic framework-based nanomedicine for further cancer treatments.
    Keywords:  antioxidation dyshomeostasis; glucose oxidase; mitochondrial dysfunction; starvation synergistic chemotherapy; zeolitic imidazolate framework
    DOI:  https://doi.org/10.1021/acsami.1c18654
  25. ACS Appl Bio Mater. 2021 Jul 19. 4(7): 5650-5660
    Biomimetic Nanoreactor for Cancer Eradication via Win-Win Cooperation between Starvation/Photo/Chemodynamic Therapies.
    Ting-Yi Ciou, Chiranjeevi Korupalli, Tzung-Han Chou, Chien-Hua Hsiao, Girum Getachew, Sintia Bela, Jia-Yaw Chang.
      Combining phototherapy with the cancer cell metabolic pathway altering strategies, that is, glucose starvation, would be a promising approach to accomplish high curative efficiency of cancer treatment. Accordingly, herein, we sought to construct a multifunctional biomimetic hybrid nanoreactor by fastening nanozyme AuNPs (glucose oxidase activity) and PtNPs (catalase and peroxidase activity) and photosensitizer Indocyanine green (ICG) onto the polydopamine (PDA) surface (ICG/Au/Pt@PDA-PEG) to attain superior cancer cell killing efficiency though win-win cooperation between starvation therapy, phototherapy, and chemodynamic therapy. The as-synthesized ICG/Au/Pt@PDA-PEG has shown excellent light-to-heat conversion (photothermal therapy) and reactive oxygen species generation (photodynamic therapy) properties upon laser irradiation and also red-shifted ICG absorption (from 780 to 800 nm) and enhanced its photostability. Further, the ICG/Au/Pt@PDA-PEG NRs have reduced the solution glucose concentration and slightly increased solution oxygen levels and also enhanced 3,3',5,5'-tetramethylbenzidine oxidation in the presence of glucose through a cascade of enzymatic activities. The in vitro results demonstrated that the ICG/Au/Pt@PDA-PEG NRs have superior therapeutic efficacy against cancer cells via the cooperative effect between starvation/photo/chemodynamic therapies and not much toxicity to normal cells.
    Keywords:  cancer; cascade nanoreactor; chemodynamic therapy; nanozymes; phototherapy; starvation therapy; win−win cooperation therapy
    DOI:  https://doi.org/10.1021/acsabm.1c00452
  26. Int J Oncol. 2022 Feb;pii: 19. [Epub ahead of print]60(2):
    Epigallocatechin‑3‑gallate hinders metabolic coupling to suppress colorectal cancer malignancy through targeting aerobic glycolysis in cancer‑associated fibroblasts.
    Shuhai Chen, Masaaki Nishi, Yuji Morine, Mitsuo Shimada, Takuya Tokunaga, Hideya Kashihara, Chie Takasu, Shinichiro Yamada, Yuma Wada.
      In recent times, researchers working on tumor metabolism have paid increasing attention to the tumor microenvironment. Emerging evidence has confirmed that epigenetic modifications of cancer‑associated fibroblasts (CAFs) alters the characteristics of glucose metabolism to achieve a symbiotic relationship with the cancer cells. Epigallocatechin‑3‑gallate (EGCG) exerts anti‑tumor effects via a variety of mechanisms, although the underlying mechanism that accounts for the effects of EGCG on glucose metabolic alterations of CAFs have yet to be elucidated. In the present study, through co‑culture with colorectal cancer (CRC) cells, human intestinal fibroblasts were transformed into CAFs, and exhibited enhanced aerobic glycolysis. Induced CAFs were able to enhance the proliferation, migration and invasion of CRC cells in vitro. EGCG treatment led to direct inhibition of the proliferation and migration of CRC cells; furthermore, EGCG treatment of CAFs suppressed their tumor‑promoting capabilities by inhibiting their glycolytic activity. Blocking the lactic acid efflux of CAFs with a monocarboxylate transporter 4 (MCT4) inhibitor or through silencing MCT4 could also suppress their tumor‑promoting capabilities, indicating that lactate fulfills an important role in the metabolic coupling that occurs between CAFs and cancer cells. Taken together, the results of the present study showed that EGCG targeting of the metabolism of tumor stromal cells provided a safe and effective strategy of anti‑cancer therapy.
    Keywords:  aerobic glycolysis; cancer‑associated fibroblasts; colorectal cancer; epigallocatechin‑3‑gallate; reverse Warburg effect
    DOI:  https://doi.org/10.3892/ijo.2022.5309
  27. ACS Appl Bio Mater. 2021 Oct 18. 4(10): 7485-7496
    Glucose/Glutathione Co-triggered Tumor Hypoxia Relief and Chemodynamic Therapy to Enhance Photothermal Therapy in Bladder Cancer.
    Wen-Hsuan Chen, Kai-Jie Yu, Jia-Wei Jhou, Hao-Han Pang, Wen-Hui Weng, Wen-Sou Lin, Hung-Wei Yang.
      Photothermal therapy (PTT) is a potential treatment for cancer that makes use of near-infrared (NIR) laser irradiation and is expected to assist traditional anti-cancer drug therapies; however, the therapeutic efficacy of PTT is restricted by thermal resistance due to the overexpression of heat shock proteins and insufficient penetration depth of lasers. Thus, PTT needs to be combined with additional therapeutic methods to obtain the optimal therapeutic efficacy for cancer. Herein, a multifunctional therapeutic platform combining PTT with glucose-triggered chemodynamic therapy (CDT) and glutathione (GSH)-triggered hypoxia relief was developed via GOx@MBSA-PPy-MnO2 NPs (GOx for glucose oxidase, M for Fe3O4, BSA for bovine serum albumin, and PPy for polypyrrole). GOx@MBSA-PPy-MnO2 NPs have excellent photothermal efficiency and can release Mn2+, which catalyzes the transformation of H2O2 into hydroxyl radicals (·OH) and O2 via a Fenton-like reaction, effectively destroying cancer cells and relieving tumor hypoxia. Meanwhile, a high content of H2O2 was produced via GOx catalysis of glucose, further enhancing the CDT efficiency. In addition, in vitro and in vivo experiments showed that the inhibition of cancer cell proliferation and effective inhibition of tumors could be caused by the combined PTT/glucose-triggered CDT effects and hypoxia relief of the GOx@MBSA-PPy-MnO2 NPs. Overall, this work provides evidence of a synergistic therapy that remarkably improves therapeutic efficacy and significantly prolongs the lifetime of mice compared with controls.
    Keywords:  bladder cancer; chemodynamic therapy; manganese dioxide (MnO2); photothermal therapy; tumor hypoxia
    DOI:  https://doi.org/10.1021/acsabm.1c00741
  28. ACS Appl Bio Mater. 2021 Apr 19. 4(4): 3453-3461
    Folic Acid Functionalized Carbon Dot/Polypyrrole Nanoparticles for Specific Bioimaging and Photothermal Therapy.
    Tae Eun Kim, Hyeon Jeong Jang, Seok Won Park, Jie Wei, Shinuk Cho, Woon Ik Park, Bo Ram Lee, Chang Duk Yang, Yun Kyung Jung.
      Polypyrrole nanoparticles (PPy-NPs) with excellent near-infrared absorption are commonly used as photothermal therapy (PTT) agents; however, PTT using PPy-NPs has a limitation in that it is difficult to maximize their therapeutic effect because of the lack of specific targeting. In this study, to overcome the difficulty of targeting, folic acid functionalized carbon dots (FA-CDs) with bright green fluorescence properties were combined with carboxylated PPy-NPs via the EDC/NHS coupling reaction to yield a PTT imaging agent. The synthesized FA-CD/PPy-NPs with excellent photostability performed folate receptor (FR) positive HeLa cancer cell imaging by green fluorescence signals of FA-CDs and exhibited high cell viability (above 90%) even at 500 μg/mL. The viability of HeLa cells incubated with 200 μg/mL FA-CD/PPy-NPs was dramatically decreased to 25.02 ± 1.85% by NIR laser irradiation, through photothermal therapeutic effects of FA-CD/PPy-NPs with high photothermal conversion efficiency (η = 40.80 ± 1.54%). The cancer cell death by FA-CD/PPy-NPs was confirmed by fluorescence imaging of FA-CDs as well as live/dead cell staining assay (calcein-AM/PI). These results demonstrate that the FA-CD/PPy-NPs can be utilized as multifunctional theranostic agents for specific bioimaging and treatment of FR-positive cancer cells.
    Keywords:  bioimaging; carbon dot; folate receptor; folic acid; photothermal therapy; polypyrrole nanoparticle
    DOI:  https://doi.org/10.1021/acsabm.1c00018
  29. Biotechnol Appl Biochem. 2022 Jan 12.
    Synthesis, Physicochemical Characterization and In vitro Evaluation of Biodegradable PLGA Nanoparticles entrapped to Folic acid for Targeted Delivery of Kaempferitrin.
    Mydhili Govindarasu, Pari Abirami, Salman S Alharthi, Muthu Thiruvengadam, Govindasamy Rajakumar, Manju Vaiyapuri.
      Polymeric nanoparticles are widely studied in the treatment of colorectal cancer. Kaempferitrin loaded non-toxic and biodegradable poly (D, L lactic-co-glycolic acid) PLGA nanoparticles (NPs) developed by solvent emulsion evaporation method by improving its solubility and bioavailability. In order to improve the delivery of kaempferitrin (KM) to cancerous cells, folic acid (FA) combined kaempfertrin PLGA NPs were prepared. The goal of the study was whether PLGA NPs with surface kaempferitrin and folic acid could help to prevent colorectal cancer. The synthesis of kaempferitrin with folic acid in nanomedicine could be crucial in the development of colon cancer chemotherapeutics. The physicochemical characteristics of synthesized kaempferitrin entrapped PLGA NPs were investigated by XRD, FTIR, zeta potential, and TEM. The KM+FA+PLGA NPs showed particle size with 132.9±1.4 nm, zeta potential -15.0±1.73mV, encapsulation efficiency (EE) 67.92±4.8 and drug loading capacity 0.463±0.173. In vitro cytotoxicity study on HT-29 cell lines using MTT assay, the apoptotic study revealed that KM+FA+PLGA NPs has an enhanced cytotoxic effect compared to KM+PLGA NPs drug solution. These findings suggested that KM+FA+PLGA NPs could be an effective chemotherapeutic drug delivery system in colon adenocarcinoma HT-29 cells. This article is protected by copyright. All rights reserved.
    Keywords:  PLGA; anticancer; cytotoxicity; folic acid; kaempferitrin; nanoparticle
    DOI:  https://doi.org/10.1002/bab.2290
  30. ACS Appl Bio Mater. 2020 Dec 21. 3(12): 8667-8675
    Polydopamine-Based Multifunctional Antitumor Nanoagent for Phototherapy and Photodiagnosis by Regulating Redox Balance.
    Jie Feng, Jia-Lin Gao, Ruo-Yu Zhang, Wen-Xiu Ren, Yu-Bin Dong.
      The development of multifunctional nanoagents for the simultaneous achievement of high diagnostic and therapeutic performances is significant for precise cancer treatment. Herein, we report on a polydopamine (PDA)-based multifunctional nanoagent, PML, in which the methylene blue (MB) photosensitizer (PS) and l-arginine (l-Arg) tumor-targeting species are equipped. After selectively accumulating in tumor sites, glutathione (GSH)-responsive PML degradation can controllably release loaded MB to produce singlet oxygen (1O2) under near-infrared (NIR) photoirradiation. This GSH-depleted PS release process can not only weaken the body's antioxidant defence ability but also synergistically increase the 1O2 concentration. Therefore, GSH depletion-enhanced photodynamic therapy (PDT) efficiency is logically achieved by regulating the intracellular redox balance. In addition, our nanoagent can guide photoacoustic/NIR thermal dual-modal imaging and convert light into heat for cooperative cancer phototherapy because of the inherent photothermal conversion nature of PDA. As a result, excellent in vivo antitumor phototherapy (PDT + PTT) is achieved under the precise guidance of dual-modal imaging. This work not only realizes the integration of cancer diagnosis and treatment through PDA-based nanocarriers but also delivers dimensions in designing the next generation of multifunctional antitumor nanoagents for enhanced phototherapy and photodiagnosis by regulating the redox balance.
    Keywords:  glutathione depletion; multifunctional nanoagent; photodiagnosis; phototherapy; polydopamine
    DOI:  https://doi.org/10.1021/acsabm.0c01057
  31. ACS Appl Bio Mater. 2020 Sep 21. 3(9): 5813-5823
    Near-Infrared Light-Initiated Upconversion Nanoplatform with Tumor Microenvironment Responsiveness for Improved Photodynamic Therapy.
    Xiaodan Wu, Ying Zhang, Zhiqiang Wang, Jingwan Wu, Rui Yan, Changhong Guo, Yingxue Jin.
      Photodynamic therapy (PDT) is inflowing the mainstream of the cancer treatments, yet the shallow light penetration, thermal damage to normal cells, poor tumor targeting, and skin phototoxicity compromised the PDT efficacy. This paper designed and prepared an upconversion nanoplatform that could effectively convert 808 nm NIR light to red and green light emission, both of which could excite photosensitizers and exert the PDT curative effects. A thin layer of mesoporous silica covering core-shell nanostructure NaGdF4:Yb,Er@NaGdF4:Yb,Nd upconversion nanoparticles was prepared as the carrier to load the photosensitizer pyropheophorbide-a (PPa), which could be excited by green and red light simultaneously and produce high singlet oxygen (1O2) quantum yield (79.1%). Meanwhile, the chemotherapy drug doxorubicin (DOX) was absorbed in the pores of the SiO2 layer to improve the therapeutic effect, and the folic acid-coupled chitosan (Cs-FA) was modified on the surface of the SiO2 layer to obtain the targeting and biocompatible UCNP@SiO2/PPa&DOX@Cs-FA nanoplatform. The physically adsorbed DOX in the pore channel could be released slowly under faintly acidic or GSH stimuli (84% release of DOX after 16 h), suggesting that the nanoplatform was responsive to the tumor microenvironment. In vitro experiments showed that the combined treatment of PDT and DOX was superior to that of PDT alone or DOX chemotherapy alone, implying a synergistic therapeutic effect. The morphological changes and dye staining research of HeLa cells were consistent with the MTT assay. Therefore, this research provided a strategy for the development of an efficient and safe multifunctional cancer treatment nanoplatform integrating low-intensity light excitation, slow release, targeting, photodynamic therapy, and chemotherapy.
    Keywords:  dual-fluorescence emission; near-infrared light; photodynamic therapy (PDT); tumor microenvironment responsiveness; upconversion nanoparticles (UCNPs)
    DOI:  https://doi.org/10.1021/acsabm.0c00545
  32. ACS Appl Bio Mater. 2021 Jun 21. 4(6): 5071-5079
    Antibacterial Activity of Porous Gold Nanocomposites via NIR Light-Triggered Photothermal and Photodynamic Effects.
    Qing Wu, Rui Peng, Yufeng Luo, Qianling Cui, Shuxian Zhu, Lidong Li.
      Phototherapeutic approaches, including photothermal therapy (PTT) and photodynamic therapy (PDT), have become a promising strategy to combat microbial pathogens and tackle the crisis brought about by antibiotic-resistant strains. Herein, porous gold nanoparticles (AuPNs) were synthesized as photothermal agents and loaded with indocyanine green (ICG), a common photosensitizer for PDT, to fabricate a nanosystem presenting near-infrared (NIR) light-triggered synchronous PTT and PDT effects. The AuPNs can not only convert NIR light into heat with a high photothermal conversion efficiency (50.6-68.5%), but also provide a porous structure to facilely load ICG molecules. The adsorption of ICG onto AuPNs was mainly driven by electrostatic and hydrophobic interactions with the surfactant layer of AuPNs, and the aggregate state of ICG significantly enhanced its generation of reactive oxygen species. Moreover, taking advantage of its synergistic PTT and PDT effect, the hybrid nanocomposites displayed a remarkable antibacterial effect to the gram-positive pathogen Staphylococcus aureus (S. aureus) upon 808 nm laser irradiation.
    Keywords:  antibacterial; gold nanocomposites; near-infrared light; photodynamic therapy; photothermal therapy
    DOI:  https://doi.org/10.1021/acsabm.1c00318
  33. ACS Appl Bio Mater. 2020 Sep 21. 3(9): 5995-6004
    Tin-Doped Near-Infrared Persistent Luminescence Nanoparticles with Considerable Improvement of Biological Window Activation for Deep Tumor Photodynamic Therapy.
    Junpeng Shi, Xia Sun, Shenghui Zheng, Liang Song, Fangrong Zhang, Tobias Madl, Yun Zhang, Hongwu Zhang, Maochun Hong.
      The photodynamic therapy (PDT) as a promising antitumor therapy technique is greatly hampered by the low tissue penetration of light and the photothermal effect of prolonged irradiation. Near-infrared (NIR) persistent luminescence nanoparticles (NPLNPs) possess the potential for application in next-generation PDT. However, owing to the low re-excitation efficiency of NPLNPs in deep tissue, the current PDT nanoplatform based on NPLNPs is faced with the disadvantage of decreased PDT efficiency induced by persistent luminescence (PersL) decay at the lesion site. Herein, NPLNPs, Zn1.3Ga1.4Sn0.3O4:Cr3+ (ZGS), with small particle sizes and excellent optical properties are synthesized via a simple acetylacetonate combustion method. The ZGS can be repeatedly excited by the biological window (659 nm) light to produce a strong NIR (700 nm) PersL. The response efficiency of ZGS to the wavelength in the biological window has been greatly improved by doping Sn4+ into the ZnGa2O4 matrix, which is 55 times higher than that of traditional ZnGa2O4:Cr3+. We further develop a PDT nanoplatform by modifying a photosensitizer on its surface. The PDT experiments show that the developed nanoplatform can achieve continuous and efficient tumor PDT with a depth of up to 3 cm by repeated excitation using a 659 nm LED. The NPLNPs largely solve the problem of the low re-excitation efficiency after NIR PersL decay of traditional NPLNPs in deep tissue applications and will further promote the application of NIR PLNPs in the biomedical field.
    Keywords:  nanoparticle; near-infrared; persistent luminescence; photodynamic therapy; tumor
    DOI:  https://doi.org/10.1021/acsabm.0c00644
  34. Bioorg Med Chem Lett. 2022 Jan 07. pii: S0960-894X(22)00015-4. [Epub ahead of print] 128539
    Boronic acid derivative activates pyruvate kinase M2 indispensable for redox metabolism in oral cancer cells.
    Mohd Rihan, Lakshmi Vineela Nalla, Anil Dharavath, Sagarkumar Patel, Amit Shard, Amit Khairnar.
      PKM2is considered a desirable target as its enzymatic activation is expected to cause a diminution in tumorigenesis and prevent limitless replication in cancerous cells. However, considering the functional consequences of kinase inhibitors, the design of PKM2 activators has been an attractive strategy that has yielded potent anticancer molecules like DASA-58. Therefore, a new class of boronic acid derivate was developed to elucidate the possible mechanistic link between PKM2 activation and TPI1 activity, which has a significant role in the redox balance in cancer. The present in vitro study revealed that treatment with boronic acid-based compound 1 and DASA-58 was found to activate PKM2 with an AC50 of 25 nM and 52 nM, respectively. Furthermore, at the AC50 concentration of compound 1, we found a significant increase in TPI1 activity and a decrease in GSH and NADP+/NADPH ratio. We also found increased ROS levels and decreased lactate secretion with treatment. Together with these findings, we can presume that compound 1 affects the redox balance by activating PKM2 and TPI1 activity. Implementation of this treatment strategy may improve the effect of chemotherapy in the conditions of ROS induced cancer drug resistance. This study for the first time supports the link between PKM2 and the TPI1 redox balance pathway in oral cancer. Collectively, the study findings provide a novel molecule for PKM2 activation for the therapeutic intervention in oral cancer.
    Keywords:  Boronic acid derivative; Lactate; Oral cancer; PKM2; Reactive oxygen species (ROS); TPI1; Warburg effect
    DOI:  https://doi.org/10.1016/j.bmcl.2022.128539
  35. ACS Appl Bio Mater. 2021 Mar 15. 4(3): 2120-2127
    Phenylthiourea-Conjugated BODIPY as an Efficient Photosensitizer for Tyrosinase-Positive Melanoma-Targeted Photodynamic Therapy.
    Eugeine Jung, Inseob Shim, Jusung An, Myung Sun Ji, Paramesh Jangili, Sung-Gil Chi, Jong Seung Kim.
      Melanoma is the most threatening form of metastatic skin cancer that develops from melanocytes and causes a large majority of deaths due to poor therapeutic prognosis. It has significant limitations in treatment because it shows great resistance to chemotherapy, radiotherapy, and other therapeutic methods. A noninvasive and clinically accepted therapeutic modality, photodynamic therapy (PDT), is a promising treatment option, but it is limitedly applied for melanoma skin cancer treatment. This is because most of the photosensitizers are unlikely to be expected to have a remarkable effect on melanoma due to drug efflux by melanin pigmentation and intrinsic antioxidant defense mechanisms. Moreover, melanin is a dominant absorber in the spectral region of 500-600 nm that can cause the decreased photoreaction efficiency of photosensitizers. Herein, to overcome these drawbacks, we have developed a phenylthiourea-conjugated BODIPY photosensitizer (PTUBDP) for tyrosinase-positive melanoma-targeted PDT. In light of our results, it exhibited an enhanced cytotoxic efficacy compared to BDP, a parallel PDT agent that absence of phenylthiourea unit. PTUBDP shows outstanding effects of increased oxidative stress by an enhanced cellular uptake of the tyrosinase positive melanoma cell line (B16F10). This work presents increased therapeutic efficacy through the combined therapeutic approach, enabling enhanced reactive oxygen species (ROS) generation as well as overcoming the critical limitations of melanoma.
    Keywords:  BODIPY; melanoma; phenylthiourea; photodynamic therapy; tyrosinase
    DOI:  https://doi.org/10.1021/acsabm.0c01322
  36. ACS Appl Bio Mater. 2021 Dec 20. 4(12): 8477-8486
    Antiproliferative and ROS Regulation Activity of Photoluminescent Curcumin-Derived Nanodots.
    Durga M Arvapalli, Alex T Sheardy, John J Bang, Jianjun Wei.
      Recently, various types of nanomaterials have been employed to design delivery vehicles for curcumin to address the problems of poor bioavailability, low aqueous solubility, and rapid metabolism. The present study focuses on a direct one-pot synthesis of curcumin-derived nanoparticles and exploits their potential therapeutic properties in cancer cells in vitro without additional delivery vehicles. The nanoparticles, named E-Curc-dots, are synthesized using three precursor molecules, ethylenediamine (EDA), curcumin, and citric acid. The structure, composition, and physichemical properties of the nanodots are characterized and identified by employing spectroscopic and microscopic techniques. The as-synthesized E-Curc-dots exhibit bright blue photoluminescence due to the incorporation of nitrogen from the EDA precursor molecule. The characterization studies show a uniform distribution of dots with an average size of 4.6 ± 1.7 nm and, notably, that the dots retain some of the major characteristics of native curcumin with much improved water solubility and bioavailability. The E-Curc-dots show antioxidation activity at low concentrations (<0.08 mg/mL) with low levels of reactive oxygen species (ROS) generation, i.e., 82% of the ROS level in cells without treatment for A549 cells; however, at high concentrations, the nanodots exhibit a pro-oxidant effect on both the cancer cells (A549) and normal cells (EA.hy926) by inducing more ROS generation and dose-dependent cytotoxicity. The E-Curc-dots demonstrate higher cytotoxicity toward cancer cells compared to native curcumin at a lower concentration. The results indicate the efficacy of E-Curc-dots as an antiproliferative and ROS regulator with the ability of cellular bioimaging.
    Keywords:  antioxidant; curcumin-derived nanodots; cytotoxicity; pro-oxidant; reactive oxygen species
    DOI:  https://doi.org/10.1021/acsabm.1c00991
  37. ACS Appl Bio Mater. 2021 Aug 16. 4(8): 6316-6325
    Engineering Near-Infrared-Excitable Metal-Organic Framework for Tumor Microenvironment Responsive Therapy.
    Jialin Lu, Xiaohui Zhu, Mingxia Li, Cuiping Fu, Yong Li, Jing Zhang, Jinliang Liu, Yong Zhang.
      Luminescent metal-organic frameworks (MOFs), which incorporate some guest luminescent molecules/ions into MOFs, have attracted extensive attention because of their exceptional optical properties. However, traditional luminescent MOFs are mainly responsive to ultraviolet (UV) or visible light, which has limited their bioapplications due to the restrained tissue penetration depths. In this study, we have constructed a diagnostic nanoplatform UCNP@MOF consisting of upconverting metal-organic frameworks, which combine the photo-upconverting characteristics of the upconversion nanoparticles (UCNPs) with the unique physicochemical properties of Al-MOFs. Specifically, the core-shell structured UCNP@MOF nanocomposites were prepared by poly(vinylpyrrolidone) (PVP)-regulated nucleation of Al-MOF layer on the UCNP surface. When excited by a 980 nm laser light, the green signal released from UCNPs can trigger the photosensitive Al-MOFs to produce a large amount of singlet oxygen (1O2) for photodynamic therapy (PDT). Meanwhile, the anticancer drug, doxorubicin hydrochloride (DOX), was further incorporated into the porous structures of Al-MOFs and demonstrated the pH-responsive drug release behavior. Our results show that the near-infrared (NIR) light-induced PDT with chemotherapy (CMT) exhibits excellent antitumor effects. It is believed that the present work highlights the potential of the combination of UCNPs and MOFs and holds great promise for biomedical applications.
    Keywords:  combination therapy; core−shell heterostructure; metal−organic frameworks (MOFs); pH-responsive; photodynamic therapy; upconversion nanoparticles (UCNPs)
    DOI:  https://doi.org/10.1021/acsabm.1c00573
  38. ACS Appl Bio Mater. 2021 May 17. 4(5): 4302-4309
    Reduction-Responsive and Multidrug Deliverable Albumin Nanoparticles: An Antitumor Drug to Abraxane against Human Pancreatic Tumor-Bearing Mice.
    Naoki Hirakawa, Yu Ishima, Ryo Kinoshita, Ryuto Nakano, Victor Tuan Giam Chuang, Hidenori Ando, Taro Shimizu, Keiichiro Okuhira, Toru Maruyama, Masaki Otagiri, Tatsuhiro Ishida.
      Many macromolecular antitumor drugs were developed based on the enhanced permeability and retention (EPR) effect, for example, albumin-bound paclitaxel nanoparticles (nab-PTX and Abraxane) and pegylated liposomal doxorubicin (Doxil). However, these EPR effect-based therapeutic systems are less effective in malignant tumors with low vascular permeability, such as pancreatic tumors. Because the EPR effect depends on nanoparticles' size, we first determined nanoparticles' size associated with a high tumor-targeting rate in a human pancreatic tumor xenograft model with low vascular permeability. Abraxane appears to behave as an albumin monomer (7 nm) in the blood circulation following intravenous injection. The in vitro and in vivo tumor-targeted delivery and antitumor activity of PTX-loaded albumin nanoparticles were significantly improved by optimizing the mean nanoparticle diameter to 30 nm. Furthermore, nitric oxide was added to 30 nm PTX-loaded albumin nanoparticles to examine the feasibility of albumin nanoparticles as a platform for multiple drug delivery. Their antitumor effect was evaluated in an orthotopic transplantation mouse model of a human pancreatic tumor. The nitric oxide PTX-loaded 30 nm albumin nanoparticle treatment on model mice achieved a significantly higher survival rate than Abraxane treatment. These findings suggest that 30 nm albumin nanoparticles have a high therapeutic effect as a useful platform for multiple drugs against human pancreatic tumors.
    Keywords:  EPR effect; antimetastatic effects; antitumor; human serum albumin nanoparticle; macromolecular drugs; pancreatic tumor
    DOI:  https://doi.org/10.1021/acsabm.1c00110
  39. Chembiochem. 2022 Jan 10.
    Oxidative stress in cancer therapy: Friend or enemy?
    Maria Azmanova, Anaïs Pitto-Barry.
      Excessive cellular oxidative stress is widely perceived as a key factor in pathophysiological conditions and cancer development. Healthy cells use several mechanisms to maintain intracellular levels of reactive oxygen species (ROS) and overall redox homeostasis to avoid damage to DNA, proteins, and lipids. Cancer cells, in contrast, exhibit elevated ROS levels and upregulated protective antioxidant pathways. Counterintuitively, such elevated oxidative stress and enhanced antioxidant defence mechanisms in cancer cells provide a therapeutic opportunity for the development of drugs with different anticancer mechanisms of action (MoA). In this review, oxidative stress and the role of ROS in cells are described. The tumour-suppressive and tumour-promotive functions of ROS are discussed to compare these two different therapeutic strategies (increasing or decreasing ROS to fight cancer). Clinically approved drugs with demonstrated oxidative stress anticancer MoAs are highlighted before describing examples of metal-based anticancer drug candidates causing oxidative stress in cancer cells via novel MoAs.
    Keywords:  ROS; antitumour agents; bioinorganic chemistry; metal complexes; redox chemistry
    DOI:  https://doi.org/10.1002/cbic.202100641
  40. Life Sci. 2022 Jan 11. pii: S0024-3205(22)00021-2. [Epub ahead of print] 120321
    Role of histone demethylases and histone methyltransferases in triple-negative breast cancer: Epigenetic mnemonics.
    Janice Jacson Mandumpala, Stephin Baby, Antriya Annie Tom, Chandraiah Godugu, Nagula Shankaraiah.
      Triple-negative breast cancer (TNBC) is a particularly lethal subtype of breast cancer owing to its heterogeneity, high drug resistance, poor prognosis and lack of therapeutic targets. Recent insights into the complexity of TNBC have been explained by epigenetic regulation and its ability to modulate certain oncogenes and tumour suppressor genes. This has opened an emerging area in anti-cancer therapy using epigenetic modulating drugs, highlighting the epigenetic reprogramming during tumorigenesis and tumour development. Histone methylation and demethylation are such dynamic epigenetic mechanisms mediated by histone methyltransferases (HMTs) and histone demethylases (HDMs), respectively. The interplay between HMTs and HDMs in histone methylation extrapolates their viability as druggable epigenetic targets in TNBC. In this review, we aim to summarize recent progress in the field of epigenetics focusing on HMTs and HDMs in TNBC development and their potential use in targeted therapy for TNBC management.
    Keywords:  Epi-drugs; Epigenetics; Histone demethylases inhibitors; Histone methyltransferase inhibitors; Triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.lfs.2022.120321
  41. ACS Appl Bio Mater. 2020 Feb 17. 3(2): 1139-1146
    Polymeric Micelles with Reduction-Responsive Function for Targeted Cancer Chemotherapy.
    Dong Wan, Chao Li, Jie Pan.
      In order to overcome the deficiencies of conventional nanotechnology-based drug delivery systems such as a short circulation time in blood, lack of tumor targeting, slow drug release in the interior of cancer cells, and so on, reduction-responsive polymeric micelles developed in this study with copolymers of TPGS3350-SS-DTX and TPGS3350-folate were triggered for cancer-targeted drug delivery. The layer of TPGS3350 in micelles was used to stabilize micelles and enhance the circulation period of micelles in blood. Once the micelles accumulated at the tumor region by EPR effect, tumor cells could ingest these micelles by the pathway of folate-receptor-mediated endocytosis. Next, fast drug release in cancer cells was achieved under the effect of high level of glutathione (GSH) inside cancer cells. The micelles invented in this study demonstrated various functions comprising active targeting, extended circulating life in blood, fast intracellular drug release, and so on. It can be noticed from findings in this research that these cooperative functions in micelles could significantly promote chemotherapeutic effectiveness and reduce their toxic side effects. Moreover, this work provides a drug delivery strategy to explore the feasibility of application reduction-responsive micelles for chemotherapy in clinic.
    Keywords:  cancer; chemotherapy; docetaxel; micelles; reduction-responsive
    DOI:  https://doi.org/10.1021/acsabm.9b01070
  42. ACS Appl Bio Mater. 2020 Jun 15. 3(6): 3553-3559
    Injectable Liquid Metal- and Methotrexate-Loaded Microsphere for Cancer Chemophotothermal Synergistic Therapy.
    Linlin Fan, Minghui Duan, Xuyang Sun, Hongzhang Wang, Jing Liu.
      With inherent fluidity and prominent photothermal conversion efficiency, multifunctional liquid metals (LMs) have been increasingly explored for various biomedical applications, especially as cancer therapeutic materials. Here, a series of LM- and/or methotrexate (MTX)-loaded microspheres, which are prepared by chitosan (CS) and formaldehyde, are employed to realize cancer chemophotothermal synergistic therapy under near-infrared (NIR) laser irradiation. The size of these microspheres is controllable and adjustable, and the preparation process is rather convenient. The LM- and MTX-loaded microspheres (CS/LM/MTX microspheres) are in the size range of 6-80 μm and exhibit an excellent photothermal effect of LM droplets, and MTX release, and thereby efficient in the inhibition of 4T1 cancer cell growth in vitro and in vivo. Further, the CS/LM/MTX microspheres were applied to tumor-bearing mice with intratumoral injection. The CS/LM/MTX microspheres can raise the local temperature of tumors to 60 °C in 1 min under NIR laser irradiation. Combined with the drug release of MTX, these microspheres showed better antitumor efficiency in vivo. Moreover, these microspheres display low toxicity and good biocompatibility, which are significant for practices in vivo. Hence, the demonstrated LM- and/or MTX-loaded microspheres reveal their superiority for cancer chemophotothermal synergistic therapy with NIR laser irradiation.
    Keywords:  chemophotothermal therapy; chitosan microsphere; controlled size; drug release; liquid metal
    DOI:  https://doi.org/10.1021/acsabm.0c00171
  43. ACS Appl Bio Mater. 2021 Sep 20. 4(9): 7081-7093
    Multifunctional Biodegradable Prussian Blue Analogue for Synergetic Photothermal/Photodynamic/Chemodynamic Therapy and Intrinsic Tumor Metastasis Inhibition.
    Yuting Hao, Lianzhi Mao, Rongjun Zhang, Xiaoshan Liao, Miaomiao Yuan, Wenzhen Liao.
      To date, various Prussian blue analogues (PBAs) have been prepared for biomedical applications due to their unique structural advantages. However, the safety and effectiveness of tumor treatment still need further exploration. This contribution reports a facile synthesis of PBA with superior tumor synergetic therapeutic effects and a detailed mechanistic evaluation of their intrinsic tumor metastasis inhibition activity. The as-synthesized PBA has a uniform cube structure with a diameter of approximately 220 nm and shows high near-infrared light (NIR) photoreactivity, photothermal conversion efficiency (41.44%), and photodynamic effect. Additionally, PBA could lead to a chemodynamic effect, which is caused by the Fenton reaction and ferroptosis. The combined therapy strategy of PBA exhibits notable tumor ablation properties due to photothermal therapy (PTT)/photodynamic therapy (PDT)/chemodynamic therapy (CDT) effects without obvious toxicity in vivo. The PBA has also shown potential as a contrast agent for magnetic resonance imaging (MRI) and photoacoustic (PA) imaging. More importantly, careful investigations reveal that PBA displays excellent biodegradation and anti-metastasis properties. Further exploration of the PBA implies that its underlying mechanism of intrinsic tumor metastasis inhibition activity can be attributed to the modulation of epithelial-mesenchymal transition (EMT) expression. The considerable potential exhibited by the as-synthesized PBA makes it an ideal candidate as a synergetic therapeutic agent for tumor treatment.
    Keywords:  Prussian blue analogues; anti-metastasis; chemodynamic therapy; ferroptosis; photodynamic therapy; photothermal therapy
    DOI:  https://doi.org/10.1021/acsabm.1c00694
  44. ACS Appl Bio Mater. 2020 Feb 17. 3(2): 1305-1311
    Near-Infrared Conjugated Oligomer for Effective Killing of Bacterial through Combination of Photodynamic and Photothermal Treatment.
    Rui Peng, Yufeng Luo, Qianling Cui, Jun Wang, Lidong Li.
      In recent years, phototherapeutic strategies including photodynamic therapy (PDT) and photothermal treatment (PTT) have attracted extensive interest in biological and medical applications. To achieve high efficiency in therapy, it is crucial to develop promising agents possessing synergistic PDT and PTT effects, especially those triggered by single-wavelength near-infrared (NIR) light. Herein, a low-bandgap fluorene-based conjugated oligomer OF-Green-N with a donor-acceptor-donor (D-A-D) structure was synthesized, which had a broad absorption in both the visible and NIR range. Upon irradiation by 808 nm laser, the oligomer displayed a good photothermal capacity with a conversion efficiency of 37.7%, together with simultaneous photodynamic behavior which produced reactive oxygen species. By incubation with Escherichia coli, OF-Green-N was demonstrated to possess outstanding antibacterial activity owing to the synergistic effects of PDT/PTT. Moreover, its green fluorescence excited by 420 nm light also provides an opportunity for imaging-guided treatment.
    Keywords:  NIR absorption; antibacterial; conjugated oligomer; photodynamic therapy; photothermal therapy
    DOI:  https://doi.org/10.1021/acsabm.9b01242
  45. ACS Appl Bio Mater. 2020 May 18. 3(5): 2577-2587
    Reduced Graphene Oxide/Mesoporous Silica Nanocarriers for pH-Triggered Drug Release and Photothermal Therapy.
    Xiao Liu, Xu Wu, Yuqian Xing, Ying Zhang, Xuefei Zhang, Qinqin Pu, Min Wu, Julia Xiaojun Zhao.
      A sandwich structured bifunctional nanocarrier (rGO@msilica) composed of an inner layer of reduced graphene oxide (rGO) and an outer layer of mesoporous silica (msilica) was developed for synergistic chemo-photothermal therapy. The rGO@msilica not only acted as a pH-triggered drug nanocarrier but also worked as a near-infrared (NIR) photothermal agent. The loaded drug, doxorubicin (DOX), in the rGO@msilica nanocarrier was controllably released in the acidic tumor microenvironment. Moreover, the cancer cells were ablated by laser irradiation (808 nm), contributing to the high photothermal conversion efficiency of the rGO core. With this two-in-one system, in vitro cancer cell experiments indicated that the synergistic therapeutic strategy was superior to those of single modality therapy. These findings imply that the bifunctional rGO@msilica nanocarrier could provide a powerful platform for cancer therapy.
    Keywords:  mesoporous silica; near-infrared; pH-triggered drug release; photothermal therapy; reduced graphene oxide
    DOI:  https://doi.org/10.1021/acsabm.9b01108
  46. Colloids Surf B Biointerfaces. 2021 Dec 18. pii: S0927-7765(21)00742-6. [Epub ahead of print]211 112296
    A bone implant with NIR-responsiveness for eliminating osteosarcoma cells and promoting osteogenic differentiation of BMSCs.
    Zhuangzhuang Wu, Qiaoqiao Tian, Jiani Wang, Yi Feng, Lizhi Li, Chaojian Xu, Jia Lv, Zhi Lv.
      Incomplete removal of tumor cells and insufficient osseointegration are the main causes of bone tumor recurrence and implantation failure. In the present study, a multifunctional titanium-based bioactive implant for near-infrared-triggered synergy therapy to overcome these hurdles is engineered, composed of titanium dioxide (TiO2) nanoparticles doped with fluorine (F)/dopamine (PDA)/collagen. The TiO2 nanoparticles designed in this work can simultaneously exhibit excellent near-infrared-activated photothermal and photocatalytic properties. Besides, the layer designed in this work show excellent anti-tumor activity under irradiation with 808 nm light due to the synergetic effect of hyperthermia and reactive oxygen species (ROS), and Saos-2 cells can be eradicated within 10 min. Moreover, modification of PDA and collagen endue the Ti alloy excellent osteogenic activity.
    Keywords:  Light-assisted therapy; Multifunctional coating; Osseointegration; Osteosarcoma cells
    DOI:  https://doi.org/10.1016/j.colsurfb.2021.112296
  47. ACS Appl Bio Mater. 2020 Sep 21. 3(9): 6237-6250
    Construction of a Drug Delivery System and Photodynamic Therapy Reagent Based on the Biotin-HSA-DDA-TCPP Molecules and the Application of Synergistic Antitumor Effect.
    Meixiu Xin, Hao Wang, Yehong Huo, Lei Wang, Liying Ma, Miaomiao Yan, Chunhua Wang, Guangcheng Wei.
      A biotin-HSA-DDA-TCPP molecule, which can be used as a photodynamic therapeutic agent and drug carrier, was synthesized. The molecule can self-assemble into spherical aggregates, which can be loaded with Dox to form biotin-HSA-DDA-TCPP-Dox nanoparticles in aqueous solution, and the Dox loading efficiency was 86.6 ± 1.76%. The Dox's release behavior was pH responsive and has a sustained release. Cell experiments showed that biotin-HSA-DDA-TCPP-Dox nanoparticles could effectively induce cancer cell apoptosis to exert anticancer and photodynamic therapy effects. The results of animal experiments, tissue sections, and blood biochemistry tests showed that the biotin-HSA-DDA-TCPP-Dox nanoparticles could exert the effect of photodynamic therapy and antitumor, which is similar to Dox after laser irradiation, and achieve a synergistic antitumor effect. The nanoparticles can significantly reduce the Dox toxicity and increase the circulation time of the drug in the body. In summary, the biotin-HSA-DDA-TCPP molecule, which combines the advantages of photodynamic therapy and drug carrier, has great potential in clinical application.
    Keywords:  HSA; anticancer; biotin; photodynamic therapy; porphyrin
    DOI:  https://doi.org/10.1021/acsabm.0c00756
  48. ACS Appl Bio Mater. 2020 Sep 21. 3(9): 5922-5929
    Eyeball-Like Yolk-Shell Bimetallic Nanoparticles for Synergistic Photodynamic-Photothermal Therapy.
    Xiaoli Cai, Shichao Ding, Qiurong Shi, Zhaoyuan Lyu, Dong Liu, Wen-Ji Dong, Min Du, Prashanta Dutta, Yang Song, Dan Du, Yuehe Lin.
      Noble metal-based nanomaterials offer great potential as cargoes for multifunctional cancer treatment. In this research, Au eyeball-like nanoparticles (NPs) with open-mouthed Pd shells were synthesized and their surface was functionalized with cell-targeting ligand folic acid (FA) and photodynamic agent Chlorin e6 (Ce6). Due to the broad near-infrared (NIR) absorption band of eyeball-like bimetallic Au and Pd, the photothermal therapy effects of this nanomaterial were studied in MCF-7 cancer cells. The anchored Ce6 not only addressed the hypoxia issue of tumor cells but also exhibited remarkable photodynamic efficacy upon irradiation. Results showed that the obtained Au@Pd-PEG-FA-Ce6 (APPFC) NPs were selectively accumulated at the tumor site and induced cell apoptosis effectively due to the target specificity and synergistic phototherapy effect. The high specificity, desirable biosafety, fast delivery, and drug functionalization demonstrated eyeball-like Au@Pd NPs are promising candidate for multifunctional therapy of breast cancer.
    Keywords:  Au@Pd nanoparticles; Chlorin e6; breast cancer; folic acid; multifunctional therapy
    DOI:  https://doi.org/10.1021/acsabm.0c00624
  49. Asian J Pharm Sci. 2021 Nov;16(6): 784-793
    Iron-doxorubicin prodrug loaded liposome nanogenerator programs multimodal ferroptosis for efficient cancer therapy.
    Yinxian Yang, Shiyi Zuo, Linxiao Li, Xiao Kuang, Jinbo Li, Bingjun Sun, Shujun Wang, Zhonggui He, Jin Sun.
      Ferroptosis is a new mode of cell death, which can be induced by Fenton reaction-mediated lipid peroxidation. However, the insufficient H2O2 and high GSH in tumor cells restrict the efficiency of Fenton reaction-dependent ferroptosis. Herein, a self-supplying lipid peroxide nanoreactor was developed to co-delivery of doxorubicin (DOX), iron and unsaturated lipid for efficient ferroptosis. By leveraging the coordination effect between DOX and Fe3+, trisulfide bond-bridged DOX dimeric prodrug was actively loaded into the core of the unsaturated lipids-rich liposome via iron ion gradient method. First, Fe3+could react with the overexpressed GSH in tumor cells, inducing the GSH depletion and Fe2+generation. Second, the cleavage of trisulfide bond could also consume GSH, and the released DOX induces the generation of H2O2, which would react with the generated Fe2+in step one to induce efficient Fenton reaction-dependent ferroptosis. Third, the formed Fe3+/Fe2+ couple could directly catalyze peroxidation of unsaturated lipids to boost Fenton reaction-independent ferroptosis. This iron-prodrug liposome nanoreactor precisely programs multimodal ferroptosis by integrating GSH depletion, ROS generation and lipid peroxidation, providing new sights for efficient cancer therapy.
    Keywords:  Ferroptosis; Iron; Liposome; Prodrug; Redox
    DOI:  https://doi.org/10.1016/j.ajps.2021.05.001
  50. ACS Appl Bio Mater. 2020 Jul 20. 3(7): 4188-4197
    Development of Nanocarrier-Based Mitochondrial Chaperone, TRAP-1 Inhibitor to Combat Cancer Metabolism.
    Vijayalakshmi Amash, Khanderao Paithankar, Shrikant Purushottam Dharaskar, Abirami Arunachalam, Sreedhar Amere Subbarao.
      Among human diseases, cancer has been in the frontlines of drug discovery and development. Despite having several decades of research efforts, therapeutic targeting of cancer is still challenging, which is due to the ability of cancer cells to adapt to the tumor microenvironment, exhibiting resistance to therapeutic drugs, and facilitated altered cancer metabolism. The small molecule inhibitors aimed at targeting a selective pathway are becoming void since cancer cells can activate alternate mechanisms. Despite broad acceptance of the Warburg effect, cellular energy metabolism, which determines the cell fate, is often overlooked for cancer treatment. We reported earlier that mitochondrial chaperone, TRAP-1 acts as a switch for activating the alternate cellular metabolism. Hence, we hypothesized that interfering with TRAP-1 inhibition can target the activation of alternative energy metabolism and sensitize tumor cells to existing chemotherapeutic drugs. We developed a nanocarrier where the iron oxide nanoparticles (IONs) were conjugated to Hsp90 inhibitor, geldanamycin (GA), and the mitochondria localization signal (MLS) peptide. We examined its effect against mitochondrial dynamics and metabolic status of human tumor cells. The synthesized nanocarrier exhibited both stability and target-specific activity and did not show nanoparticle-associated cytotoxicity. However, the nanocarrier treated cancer cells exhibited altered mitochondrial morphology and decreased cellular ATP levels suggesting that selective TRAP-1 targeting interferes with the altered energy metabolism. We present a nanoparticle-based TRAP-1 inhibitor to target tumor metabolism.
    Keywords:  MLS peptide; TRAP-1; cancer; geldanamycin; iron oxide nanoparticles; mitochondrion
    DOI:  https://doi.org/10.1021/acsabm.0c00268
  51. J Mater Chem B. 2022 Jan 13.
    Combined effect of heat shock protein inhibitor geldanamycin and free radicals on photodynamic therapy of prostate cancer.
    Qinyan Sun, Fengyu Liu, Zhenfu Wen, Jing Xia, Hongjuan Li, Yongqian Xu, Shiguo Sun.
      Prostate cancer is the most common malignancy and the second leading cause of cancer-induced death among men. Recently, photodynamic therapy (PDT) has attracted great attention in prostate cancer treatment because of its high accuracy and no trauma. However, the hypoxic microenvironment of the tumor severely reduces the therapeutic efficacy of oxygen-dependent PDT in prostate cancer, which hampers the generation of reactive oxygen species (ROS). In addition, the PDT process induces the overexpression of pro-survival and anti-apoptotic proteins, thereby reducing the efficacy of PDT. This study proposed a novel multifunctional nanosystem for the targeted delivery of indocyanine green (ICG), 2,2'-azobis[2-(2-imidazolinI-2-yl) propane] dihydrochloride (AIBI), and heat shock protein 90 (Hsp90) inhibitor geldanamycin (17-AAG). Under near-infrared light irradiation, the photothermal effect of ICG induces AIBI decomposition and releases oxygen-independent free radicals, which rescues the hindered ICG-mediated ROS generation. Moreover, 17-AAG reduces heat resistance by inhibiting Hsp90, thereby achieving mild hyperthermia. Simultaneously, the inhibition of Hsp90 can inhibit the overexpression of its client proteins such as anti-apoptotic proteins (survivin) and androgen receptor (AR), thereby improving the efficacy of PDT and inducing prostate cancer cell apoptosis. Results show that the nanosystem enhances PDT by combining free radicals and 17-AAG, exhibiting a good anticancer effect on prostate cancer cells but less toxicity on normal cells.
    DOI:  https://doi.org/10.1039/d1tb02219a
  52. ACS Appl Bio Mater. 2020 Sep 21. 3(9): 5974-5983
    Surface Chemistry- and Intracellular Trafficking-Dependent Autophagy Induction by Iron Oxide Nanoparticles.
    Prasanta Panja, Koushik Debnath, Nihar R Jana, Nikhil R Jana.
      Autophagy is a cellular self-clearance process for maintaining regular cytoplasmic function, and modulation of autophagy can influence cytotoxicity, apoptosis, and clearance of toxic amyloid fibril. In a recent work, functional nanoparticles are used to modulate autophagy. However, the role of nanoparticle uptake mechanisms and their intracellular processing on autophagy is vaguely understood. Here, we show that autophagy is influenced by nanoparticle surface chemistry-directed intracellular trafficking and localization. In particular, we have designed iron oxide nanoparticles functionalized with arginine/arginine methyl ester/octyl/oleyl/cholesterol with a high cell uptake property. We found that autophagy is induced by octyl/oleyl functionalization without appreciable cell death. Further study shows that enhanced cytosolic delivery over membrane localization and increased intracellular aggregation over homogeneous cytosolic distribution lead to autophagy induction via intracellular reactive oxygen species generation. The observed result can be used to design functional nanoparticles/nanodrugs for modulating cellular autophagy that can be used in various biomedical applications.
    Keywords:  autophagy; iron oxide; nanoparticle; reactive oxygen species; surface chemistry
    DOI:  https://doi.org/10.1021/acsabm.0c00640
  53. J Exp Clin Cancer Res. 2022 Jan 08. 41(1): 16
    Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy.
    Maria Saliakoura, Matteo Rossi Sebastiano, Ioanna Nikdima, Chiara Pozzato, Georgia Konstantinidou.
       BACKGROUND: KRAS is the predominant oncogene mutated in pancreatic ductal adenocarcinoma (PDAC), the fourth cause of cancer-related deaths worldwide. Mutant KRAS-driven tumors are metabolically programmed to support their growth and survival, which can be used to identify metabolic vulnerabilities. In the present study, we aimed to understand the role of extracellularly derived fatty acids in KRAS-driven pancreatic cancer.
    METHODS: To assess the dependence of PDAC cells on extracellular fatty acids we employed delipidated serum or RNAi-mediated suppression of ACSL3 (to inhibit the activation and cellular retention of extracellular fatty acids) followed by cell proliferation assays, qPCR, apoptosis assays, immunoblots and fluorescence microscopy experiments. To assess autophagy in vivo, we employed the KrasG12D/+;p53flox/flox;Pdx1-CreERT2 (KPC) mice crossed with Acsl3 knockout mice, and to assess the efficacy of the combination therapy of ACSL3 and autophagy inhibition we used xenografted human cancer cell-derived tumors in immunocompromised mice.
    RESULTS: Here we show that depletion of extracellularly derived lipids either by serum lipid restriction or suppression of ACSL3, triggers autophagy, a process that protects PDAC cells from the reduction of bioenergetic intermediates. Combined extracellular lipid deprivation and autophagy inhibition exhibits anti-proliferative and pro-apoptotic effects against PDAC cell lines in vitro and promotes suppression of xenografted human pancreatic cancer cell-derived tumors in mice. Therefore, we propose lipid deprivation and autophagy blockade as a potential co-targeting strategy for PDAC treatment.
    CONCLUSIONS: Our work unravels a central role of extracellular lipid supply in ensuring fatty acid provision in cancer cells, unmasking a previously unappreciated metabolic vulnerability of PDAC cells.
    Keywords:  Combination therapy; Extracellular lipids; Lipid metabolism; Pancreatic cancer; Tumor metabolic vulnerabilities
    DOI:  https://doi.org/10.1186/s13046-021-02231-y
  54. Saudi J Biol Sci. 2022 Jan;29(1): 161-167
    Identification of medicinal compounds as potential inhibitors for mutated isocitrate dehydrogenases against chondrosarcoma.
    Fahad Hassan Shah, Song Ja Kim.
      Chondrosarcoma is the third most common cartilaginous bone tumour that is insusceptible to radio- and chemotherapy and it is inclined to metastasis. These resistant qualities are facilitated by mutant variants of isocitrate dehydrogenases (IDH) 1-2 enzyme. These mutant enzymes promote oncogenesis of chondrocytes by changing their epigenetic wardrobe leading to tumour formation. Presently, there are lack of drugs available to be exploited as a remedy for this disease. On the other hand, majority of chemotherapeutic drugs induce cytotoxicity in the cancer cells at the cost of harming surrounding healthy cells, jeopardizing human life. The current study is focused on screening various medicinal compounds against IDH1 and IDH2 combined with insilico gene expression, cancer cells cytotoxicity and ADMET (absorption, distribution, metabolism, excretion and toxicity) studies to elucidate the molecular mechanism against chondrosarcoma and also to uncover pharmacokinetic profile of these compounds. Screening of 5000+ compounds filtered two efficacious compounds (Artocarpetin and 5-Galloylquinic acid) capable of establishing hydrogen bond connections with both IDH variants. Other studies showed that these compounds downregulate ITGAV, CARPIN1, CCL5 and COG5 and TNFRSF10B gene that reduces chondrogenesis and inflammation, Artocarpetin and 5-galloylquinic acid are TP53 expression enhancer and inhibit MM9 expression that promote immunomodulation and apoptosis in these cancers. These compounds are both active against CHSA8926 and CHSA011 cell line of chondrosarcoma. However, the ADME profile of 5-galloylquinic acid is slightly unsatisfactory based on druglikness and bioavailability score criteria as compared to artocarpetin. Both of these compounds are class-5 chemicals and require high doses to elicit adverse response. Our results suggest that artocarpetin and 5-galloylquinic acid are efficacious drug candidates and could be further exploited to validate these findings in vitro.
    Keywords:  Anti-cancer sensitivity prediction; Chondrosarcoma; Insilico Gene Expression; Isocitrate dehydrogenases; Medicinal compounds; Virtual Screening
    DOI:  https://doi.org/10.1016/j.sjbs.2021.08.077
  55. ACS Appl Bio Mater. 2020 Jul 20. 3(7): 4128-4138
    Engineering a pH/Glutathione-Responsive Tea Polyphenol Nanodevice as an Apoptosis/Ferroptosis-Inducing Agent.
    Min Mu, Yuelong Wang, Shasha Zhao, Xiaoling Li, Rangrang Fan, Lan Mei, Min Wu, Bingwen Zou, Na Zhao, Bo Han, Gang Guo.
      Chemotherapy works against tumors by inducing cell apoptosis; however, evasion of apoptosis is recognized to result in resistance to anticancer therapy. Ferroptosis is an iron-dependent cell death pathway that differs from apoptosis in morphological, biochemical, and genetic levels. Combined ferroptosis and apoptosis may shed light on strategies for cancer treatment. Therefore, we have designed a nanoparticle (NP) that can simultaneously cause tumor cell apoptosis and ferroptosis. This NP is composed of epigallocatechin gallate (EGCG) and Fe3+ through a simple and green process and can be used to deliver doxorubicin hydrochloride (DOX) and iron ions to the tumor site at the same time. DOX/Fe3+/EGCG (DF) NPs display a great resolubility and long-term storage stability, and efficient DOX and Fe3+ release is realized after cellular internalization under the high level of glutathione and acidic nature in tumor. EGCG is likely to chemically reduce the released Fe3+ to Fe2+. The generated Fe3+/Fe2+ converts intracellular H2O2 to hydroxyl radicals (•OH) via the Fenton reaction. In addition, the generated •OH subsequently induces lethal ferroptosis to improve DOX-induced apoptosis. In vitro and in vivo investigations indicate that a great therapeutic effect was achieved, suggesting that the formation of the DF NP delivery system is a promising strategy to fight against tumors by an apoptosis and ferroptosis combination modality.
    Keywords:  Fenton reaction; apoptosis; cancer therapy; ferroptosis; tea polyphenol
    DOI:  https://doi.org/10.1021/acsabm.0c00225
  56. Nanomaterials (Basel). 2021 Dec 31. pii: 130. [Epub ahead of print]12(1):
    A Review of Microbial Mediated Iron Nanoparticles (IONPs) and Its Biomedical Applications.
    Muhammad Nadeem, Rijma Khan, Nausheen Shah, Ishrat Rehman Bangash, Bilal Haider Abbasi, Christophe Hano, Chunzhao Liu, Sana Ullah, Syed Salman Hashmi, Akhtar Nadhman, Jonathan Celli.
      Nanotechnology is a booming avenue in science and has a multitude of applications in health, agriculture, and industry. It exploits materials' size at nanoscale (1-100 nm) known as nanoparticles (NPs). These nanoscale constituents are made via chemical, physical, and biological methods; however, the biological approach offers multiple benefits over the other counterparts. This method utilizes various biological resources for synthesis (microbes, plants, and others), which act as a reducing and capping agent. Among these sources, microbes provide an excellent platform for synthesis and have been recently exploited in the synthesis of various metallic NPs, in particular iron. Owing to their biocompatible nature, superparamagnetic properties, small size efficient, permeability, and absorption, they have become an integral part of biomedical research. This review focuses on microbial synthesis of iron oxide nanoparticles using various species of bacteria, fungi, and yeast. Possible applications and challenges that need to be addressed have also been discussed in the review; in particular, their antimicrobial and anticancer potentials are discussed in detail along with possible mechanisms. Moreover, some other possible biomedical applications are also highlighted. Although iron oxide nanoparticles have revolutionized biomedical research, issues such as cytotoxicity and biodegradability are still a major bottleneck in the commercialization of these nanoparticle-based products. Addressing these issues should be the topmost priority so that the biomedical industry can reap maximum benefit from iron oxide nanoparticle-based products.
    Keywords:  anticancer; antimicrobial; green synthesis; iron oxide; nanoparticles
    DOI:  https://doi.org/10.3390/nano12010130
  57. Small. 2022 Jan 12. e2106215
    Near-Infrared Thermally Activated Delayed Fluorescence Nanoparticle: A Metal-Free Photosensitizer for Two-Photon-Activated Photodynamic Therapy at the Cell and Small Animal Levels.
    Fang Fang, Yi Yuan, Yingpeng Wan, Jing Li, Yueyue Song, Wen-Cheng Chen, Dongxu Zhao, Yun Chi, Menglin Li, Chun-Sing Lee, Jinfeng Zhang.
      Thermally activated delayed fluorescence (TADF) materials with extremely small singlet-triplet energy offsets have opened new horizons for the development of metal-free photosensitizers for photodynamic therapy (PDT) in recent years. However, the exploration of near-infrared (NIR) TADF emitters for efficient two-photon-excited (TPE) PDT is still a formidable challenge, thus it has not been reported yet. In this study, purely organic photosensitizers (PSs) based on the TADF nanoparticles (NIR-TADF NPs) are designed for efficient TPE-PDT, which show excellent singlet oxygen generation ability. Thanks to the intrinsic two-photon excitation and NIR emission characteristics, the NIR-TADF NPs demonstrate promising potential in both single-photon-excited (SPE) and TPE NIR imaging. More importantly, the anti-tumor efficiency and biosafety of TADF-based PSs at the small animal level are confirmed in A549 tumor xenograft models under TPE laser irradiance, which will facilitate the practical biomedical applications of TADF materials. This work not only provides a promising strategy to develop metal-free PSs, but also expands the applied scope of TADF-based nanotherapeutics and advances their possible clinical translation in cancer therapy.
    Keywords:  metal-free photosensitizers; near-infrared emission; photodynamic therapy; thermally activated delayed fluorescence (TADF); two-photon activated photodynamic therapy
    DOI:  https://doi.org/10.1002/smll.202106215
  58. Biomaterials. 2022 Jan 07. pii: S0142-9612(22)00008-4. [Epub ahead of print]281 121369
    Multifunctional liquid metal-based nanoparticles with glycolysis and mitochondrial metabolism inhibition for tumor photothermal therapy.
    Xing-Lan Ding, Miao-Deng Liu, Qian Cheng, Wen-Hui Guo, Mei-Ting Niu, Qian-Xiao Huang, Xuan Zeng, Xian-Zheng Zhang.
      Tumor cells obtain energy supply from different metabolic pathways to maintain survival. In this study, a tumor acidity-responsive spherical nanoparticle (called as LMGC) was designed by attaching glucose oxidase (GOx) and mineralizing calcium carbonate on the surface of liquid metal nanoparticles to integrate the synergistic effect of adenosine triphosphate (ATP) generation inhibition and photothermal therapy (PTT) for enhanced tumor therapy. After GOx catalysis, the process of glycolysis was inhibited, and the increased H2O2 level enhanced the intratumoral oxidative stress. Besides, the gluconic acid production accelerated the degradation of LMGC and promoted Ca2+-mediated mitochondrial dysfunction. The inhibition of glycolysis and mitochondrial metabolism could significantly reduce ATP production and down-regulate heat shock protein (HSP) expression, which would reduce tumor cells heat resistance and improve PTT therapeutic effect. This liquid metal-based ATP inhibition system with enhanced therapeutic effect will find great potential for tumor treatment.
    Keywords:  Glycolysis; Liquid metal; Mitochondrial metabolism; Photothermal therapy; Tumor
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121369
  59. Emergent Mater. 2022 Jan 04. 1-23
    Review on metal nanoparticles as nanocarriers: current challenges and perspectives in drug delivery systems.
    V Chandrakala, Valmiki Aruna, Gangadhara Angajala.
      Over the past few years, nanotechnology has been attracting considerable research attention because of their outstanding mechanical, electromagnetic and optical properties. Nanotechnology is an interdisciplinary field comprising nanomaterials, nanoelectronics, and nanobiotechnology, as three areas which extensively overlap. The application of metal nanoparticles (MNPs) has drawn much attention offering significant advances, especially in the field of medicine by increasing the therapeutic index of drugs through site specificity preventing multidrug resistance and delivering therapeutic agents efficiently. Apart from drug delivery, some other applications of MNPs in medicine are also well known such as in vivo and in vitro diagnostics and production of enhanced biocompatible materials and nutraceuticals. The use of metallic nanoparticles for drug delivery systems has significant advantages, such as increased stability and half-life of drug carrier in circulation, required biodistribution, and passive or active targeting into the required target site. Green synthesis of MNPs is an emerging area in the field of bionanotechnology and provides economic and environmental benefits as an alternative to chemical and physical methods. Therefore, this review aims to provide up-to-date insights on the current challenges and perspectives of MNPs in drug delivery systems. The present review was mainly focused on the greener methods of metallic nanocarrier preparations and its surface modifications, applications of different MNPs like silver, gold, platinum, palladium, copper, zinc oxide, metal sulfide and nanometal organic frameworks in drug delivery systems.
    Keywords:  Drug carriers; Drug delivery; Metallic nanoparticles; Nanocarriers
    DOI:  https://doi.org/10.1007/s42247-021-00335-x
  60. Biomater Sci. 2022 Jan 13.
    ROS-responsive dexamethasone micelles normalize the tumor microenvironment enhancing hypericin in cancer photodynamic therapy.
    Ruifeng Liang, Ka Hong Wong, Yan Yang, Yourong Duan, Meiwan Chen.
      The efficacy of photodynamic therapy (PDT) for cancer is limited owing to the abnormality of the tumor microenvironment (TME), such as the dysfunctional tumor vascular system leading to restricted drug distribution in tumor lesions, and hypoxia resulting in hampering the application of the photosensitizer because of the shortage of oxygen. Therefore, normalizing the TME is a novel strategy for enhancing the therapeutic efficacy of PDT. Herein, we designed and fabricated reactive oxygen species (ROS)-responsive micelles with a self-circulating release manner to co-deliver a glucocorticoid steroid dexamethasone (DXM) and a photosensitizer hypericin (HYP) (denoted as HDTM). The current drug delivery system showed the following advantageous properties: (1) The DXM inhibited the migration, invasion and angiogenesis of vein endothelial cells by suppressing the function of vascular endothelial growth factor, thus promoting the delivery of oxygen and HDTM into the tumor site. (2) When the HDTM arrived at the tumor site, the endogenous ROS partially cleaved the outer shell of the micelle to release the HYP and DXM. With the use of an external light source with a wavelength of 590 nm, the in situ released HYP was excited, enabling ROS production, which resulted in effective cell apoptosis. Moreover, the upregulated ROS further cleaved the micelles, thus achieving the subsequent self-circulating burst release of HYP and DXM for PDT. Notably, real-time accumulation and elimination of drugs can be monitored owing to the red fluorescence property of HYP. This facile design not only provides a platform for cancer theranostics, but also offers a feasible strategy to combat cancer in an integral way.
    DOI:  https://doi.org/10.1039/d1bm01802g
  61. ACS Appl Bio Mater. 2020 Oct 19. 3(10): 7122-7132
    Versatile Nanoplatform Loaded with Doxorubicin and Graphene Quantum Dots/Methylene Blue for Drug Delivery and Chemophotothermal/Photodynamic Synergetic Cancer Therapy.
    Junlong Liang, Jianjun Liu, Xiaokang Jin, Shuting Yao, Biling Chen, Qianwei Huang, Jinhua Hu, Junmin Wan, Zhiwen Hu, Bing Wang.
      A versatile platform for nanodrug delivery and synergetic therapy is a promising therapeutic pattern for antitumor treatment in clinical biology. Here, we innovatively encapsulated graphene quantum dots (GQDs) or methylene blue (MB) together with doxorubicin (DOX) into the cores of poly lactic-co-glycolic acid (PLGA) nanoparticles coated with bovine serum albumin (BSA) based on the emulsion method to synthesize core-shell structure nanoparticles (GQDs@DOX/PB and MB@DOX/PB NPs). The GQDs@DOX/PB NPs exhibited excellent photothermal properties and stability under 808 nm laser irradiation. The in vitro chemophotothermal synergetic experiments manifested that the GQDs@DOX/PB NPs effectively cause the thermal ablation of tumor cells under NIR laser irradiation. Meanwhile, the in vitro chemophotodynamic synergetic experiments revealed that the MB@DOX/PB NPs could produce reactive oxygen species and showed outstanding antitumor efficacy under 660 nm laser irradiation. Consequently, the pH-responsive multifunctional nanoparticles prepared by a facile strategy have a high tumor cell-killing efficacy, manifesting excellent potential in synergistic therapy.
    Keywords:  core−shell structure; drug delivery; multifunctional nanoplatform; photodynamic effect; photothermal effect; synergetic therapy
    DOI:  https://doi.org/10.1021/acsabm.0c00942
  62. ACS Appl Bio Mater. 2020 Jun 15. 3(6): 3456-3475
    Sonodynamic Therapy (SDT) for Cancer Treatment: Advanced Sensitizers by Ultrasound Activation to Injury Tumor.
    Ping Yan, Li-Han Liu, Ping Wang.
      Because of its high tissue penetrative depth, high remote spatiotemporal selectivity, and noninvasive therapeutic features, sonodynamic therapy (SDT) has received much attention in recent years. In the SDT, a tumor-localizing sonosensitizing agent is activated by ultrasound and produces greatly reactive oxygen species (ROS) to kill tumor cells. Sonosensitizers, including some organic/inorganic compounds and micro/nanoscale sonosensitizers, are an important element in SDT. Herein, we will introduce the organic/inorganic sonosensitizers and advanced micro/nanosized sonosensitizers applied in SDT. At the same time, some perspectives and the future challenges of SDT will be discussed in this review.
    Keywords:  mechanism; reactive oxygen species; sonodynamic therapy; sonosensitizers; ultrasound
    DOI:  https://doi.org/10.1021/acsabm.0c00156
  63. Molecules. 2021 Dec 27. pii: 148. [Epub ahead of print]27(1):
    Metal Complexes or Chelators with ROS Regulation Capacity: Promising Candidates for Cancer Treatment.
    Xiang Li, Yuhui Wang, Man Li, Huipeng Wang, Xiongwei Dong.
      Reactive oxygen species (ROS) are rapidly eliminated and reproduced in organisms, and they always play important roles in various biological functions and abnormal pathological processes. Evaluated ROS have frequently been observed in various cancers to activate multiple pro-tumorigenic signaling pathways and induce the survival and proliferation of cancer cells. Hydrogen peroxide (H2O2) and superoxide anion (O2•-) are the most important redox signaling agents in cancer cells, the homeostasis of which is maintained by dozens of growth factors, cytokines, and antioxidant enzymes. Therefore, antioxidant enzymes tend to have higher activity levels to maintain the homeostasis of ROS in cancer cells. Effective intervention in the ROS homeostasis of cancer cells by chelating agents or metal complexes has already developed into an important anti-cancer strategy. We can inhibit the activity of antioxidant enzymes using chelators or metal complexes; on the other hand, we can also use metal complexes to directly regulate the level of ROS in cancer cells via mitochondria. In this review, metal complexes or chelators with ROS regulation capacity and with anti-cancer applications are collectively and comprehensively analyzed, which is beneficial for the development of the next generation of inorganic anti-cancer drugs based on ROS regulation. We expect that this review will provide a new perspective to develop novel inorganic reagents for killing cancer cells and, further, as candidates or clinical drugs.
    Keywords:  SOD1; TrxR; anti-cancer; antioxidant enzymes; chelators; metal complexes; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.3390/molecules27010148
  64. ACS Appl Bio Mater. 2021 Aug 16. 4(8): 6575-6588
    Targeted Designing of Multimodal Tumor-Seeking Nanomedicine for Breast Cancer-Specific Triple-Therapeutic Effects.
    Vellingiri Yasothamani, Laxmanan Karthikeyan, Namratha Partha Sarathy, Raju Vivek.
      Integrated tumor-seeking nanomedicine (TSN) is designed to achieve a high therapeutic anticancer effect that is highly desirable for effective cancer treatment to overcome the detrimental effects of conventional therapies. However, direct administration of drugs cannot achieve a high level of specificity, which remains a formidable challenge. To address the confines, incorporation of multifunctionalities to maximize the specificity of TSN must be performed; TSN picks up multiple cargoes that are initially arrested at the core location and delivers each type simultaneously to a specified destination. Here, we introduce a valuable approach of Her2/neu-rich tumor cell surface-receptor-targeting TSN, which was highly pH-responsive and significantly realized the selective triple-therapeutic effects of blocking Her2/neu functions, chemotherapy, and phototherapy (photodynamic therapy (PDT)/photothermal therapy (PTT)). Therefore, the unprecedented selectivity of TSN provides a triple-therapeutic effect to spread the repertoire of "TSN" targets for future clinically relevant translation in improving breast cancer therapy.
    Keywords:  cancer; chemotherapy; photodynamic therapy; photothermal therapy; tumor targeting; tumor-seeking nanomedicine
    DOI:  https://doi.org/10.1021/acsabm.1c00740
  65. ACS Appl Bio Mater. 2021 Sep 20. 4(9): 6703-6718
    Fluorescent Carbon Dot-Curcumin Nanocomposites for Remarkable Antibacterial Activity with Synergistic Photodynamic and Photothermal Abilities.
    Hongjun Yan, Baoqu Zhang, Ying Zhang, Rixiang Su, Peiyuan Li, Wei Su.
      Photosensitizer (PS)-mediated photodynamic therapy (PDT) has attracted more and more attention as an alternative to traditional antibiotic therapy. Nevertheless, the limitations of traditional photosensitizers seriously hinder their practical application, as a result, the methods to improve the antibacterial properties of traditional photosensitizers have become a hot topic in the field of photomedicine. Herein, a compound nano-PS system has been constructed with synergistic photodynamic and photothermal (PTT) antibacterial effects, triggered by a dual-wavelength illumination. Fluorescent carbon dots (CDs) were synthesized and employed as carriers for the delivery of curcumin (Cur) to obtain CDs/Cur. Upon combined near-infrared and 405 nm visible dual-wavelength irradiation, CDs/Cur could simultaneously generate ROS and a moderate temperature increase, triggering synergistic antibacterial effects against both Gram-positive and Gram-negative bacteria. The results of scanning electron microscopy and fluorescence confocal imaging showed that the combined effect of CDs/Cur with PDT and PTT caused more serious damage to the cell membrane. In addition, CDs/Cur exhibited low cytotoxicity and negligible hemolytic activity, showing great biocompatibility. Therefore, the construction of CDs/Cur by employing CDs as photosensitizer delivery carriers provides a strategy for the improvement of the antibacterial effect of the photosensitizer and the design of next-generation antibacterial agents in photomedicine.
    Keywords:  antibacterial; carbon dots; nanocomposite; photodynamic therapy; photothermal therapy; synergistic effects
    DOI:  https://doi.org/10.1021/acsabm.1c00377
  66. Oxid Med Cell Longev. 2022 ;2022 1458143
    The Potential Mechanisms by which Artemisinin and Its Derivatives Induce Ferroptosis in the Treatment of Cancer.
    Yingying Hu, Nan Guo, Ting Yang, Jianghong Yan, Wenjun Wang, Xiang Li.
      Artemisinin (ART) is a bioactive molecule derived from the Chinese medicinal plant Artemisia annua (Asteraceae). ART and artemisinin derivatives (ARTs) have been effectively used for antimalaria treatment. The structure of ART is composed of a sesquiterpene lactone, including a peroxide internal bridge that is essential for its activity. In addition to their well-known antimalarial effects, ARTs have been shown recently to resist a wide range of tumors. The antineoplastic mechanisms of ART mainly include cell cycle inhibition, inhibition of tumor angiogenesis, DNA damage, and ferroptosis. In particular, ferroptosis is a novel nonapoptotic type of programmed cell death. However, the antitumor mechanisms of ARTs by regulating ferroptosis remain unclear. Through this review, we focus on the potential antitumor function of ARTs by acting on ferroptosis, including the regulation of iron metabolism, generation of reactive oxygen species (ROS), and activation of endoplasmic reticulum stress (ERS). This article systematically reviews the recent progress in ferroptosis research and provides a basis for ARTs as an anticancer drug in clinical practice.
    DOI:  https://doi.org/10.1155/2022/1458143
  67. Front Bioeng Biotechnol. 2021 ;9 791891
    Injectable and Temperature-Sensitive Titanium Carbide-Loaded Hydrogel System for Photothermal Therapy of Breast Cancer.
    Jun Yao, Chuanda Zhu, Tianjiao Peng, Qiang Ma, Shegan Gao.
      Recently, organic-inorganic hybrid materials have gained much attention as effective photothermal agents for cancer treatment. In this study, Pluronic F127 hydrogel-coated titanium carbide (Ti3C2) nanoparticles were utilized as an injectable photothermal agent. The advantages of these nanoparticles are their green synthesis and excellent photothermal efficiency. In this system, lasers were mainly used to irradiate Ti3C2 nanoparticles to produce a constant high temperature, which damaged cancer cells. The nanoparticles were found to be stable during storage at low temperatures for at least 2 weeks. The Ti3C2 nanoparticles exhibited a shuttle-shaped structure, and the hydrogels presented a loosely meshed structure. In addition, Ti3C2 nanoparticles did not affect the reversible temperature sensitivity of the gel, and the hydrogel did not affect the photothermal properties of Ti3C2 nanoparticles. The in vitro and in vivo results show that this hydrogel system can effectively inhibit tumor growth upon exposure to near-infrared irradiation with excellent biocompatibility and biosafety. The photothermal agent-embedded hydrogel is a promising photothermal therapeutic strategy for cancer treatment by enhancing the retention in vivo and elevating the local temperature in tumors.
    Keywords:  Ti3C2 nanoparticles; anti-cancer; photothermal therapy; pluronic F127 hydrogel; thermosensitive
    DOI:  https://doi.org/10.3389/fbioe.2021.791891
  68. ACS Appl Bio Mater. 2021 Feb 15. 4(2): 1483-1492
    Polypyrrole-Coated Mesoporous TiO2 Nanocomposites Simultaneously Loading DOX and Aspirin Prodrugs for a Synergistic Theranostic and Anti-Inflammatory Effect.
    Weijian Chen, Jing Wang, Liang Cheng, Wenxiang Du, Jingwen Wang, Wanwan Pan, Shuilai Qiu, Lei Song, Xiaopeng Ma, Yuan Hu.
      Although a number of therapeutic strategies have been applied in cancer therapy, treatment for cancer metastasis is challenging due to unsatisfactory cure rate and easy cancer recurrence. In our work, nanocomposites (NCs) based on polypyrrole-coated mesoporous TiO2 with a suitable size are prepared through a modified soft-templating strategy, which integrates double prodrugs (doxorubicin (DOX) prodrug and aspirin prodrug) with superior drug loading capacity. Under external stimulation of near-infrared (NIR) and ultrasound (US), the prepared nanocomposites have an excellent photothermal conversion efficiency (over 50.8%) and a satisfactory sonodynamic therapeutic effect, and simultaneous prodrug activation and drug release occur rapidly under external stimulation. Through intravenous injection, the tumor area can be clearly seen through thermal imaging, benefiting from the enhanced permeability and retention (EPR) effect. Through synergistic therapy, cancer cell toxicity and the tumor inhibition effect are significantly enhanced. Moreover, downregulated inflammatory factors also reduce the risk of cancer recurrence. In general, the designed NCs provide a potential alternative for synergistic therapy as well as downregulation of inflammatory cytokines.
    Keywords:  anti-inflammatory effect; cancer imaging; mesoporous TiO2 (mTiO2); polypyrrole (PPy); synergistic therapy
    DOI:  https://doi.org/10.1021/acsabm.0c01370
  69. ACS Appl Bio Mater. 2020 Jul 20. 3(7): 4655-4664
    Upconversion Nanoparticle-Based Organosilica-Micellar Hybrid Nanoplatforms for Redox-Responsive Chemotherapy and NIR-Mediated Photodynamic Therapy.
    Zhenyang Wei, Xiaohang Liu, Dechao Niu, Limei Qin, Yongsheng Li.
      Upconversion nanoparticles (UCNPs) can convert near-infrared light (NIR, 980 or 808 nm) to ultraviolet (UV) or visible light, which can be widely used to improve tissue penetration depth in photodynamic therapy (PDT). Herein, we develop a kind of UCNP-based organosilica-micellar hybrid nanoplatform for redox-responsive chemotherapy and NIR-mediated PDT. The nanoplatform was constructed by the self-assembly of block copolymers polystyrene-b-poly (acrylic acid) and oil-soluble UCNPs in the oil/water system and the subsequent organosilica coating with 3-mercaptopropyltrimethoxysilane molecules. To endow the nanosystem with more stability in biological media, polyethylene glycol molecules were further modified via the Michael addition reaction. As a promising nanocarrier, chlorin e6 (Ce6) and doxorubicin (DOX) molecules were loaded into the hydrophobic core and the disulfide-doped organosilica shell, respectively. With endocytosis by SMMC-7721 tumor cells, the Ce6 and DOX coloaded nanosystem was activated by UCNPs through luminescence resonance energy transfer under the irradiation of 808 nm laser, thus generating cytotoxic 1O2 for NIR-mediated PDT. Meanwhile, DOX was selectively released because of the redox-responsive biodegradation of the disulfide-doped organosilica shell in the glutathione over-expressed SMMC-7721 tumor cells. Based on these, the chemotherapy/PDT combination toxic feature of the multifunctional nanosystem was further demonstrated in the DOX-resistant MCF-7 tumor cells. On the other hand, the Ce6 and DOX coloaded nanosystem exhibited negligible toxicity to the normal 3T3 cell because of the protective effects of organosilica coating. We envision that the resultant hybrid nanoplatform provides us a promising nanocarrier for the combination therapy of redox-responsive safe chemotherapy and efficient NIR-mediated PDT.
    Keywords:  block copolymers; organosilica coating; photodynamic therapy; redox-responsive chemotherapy; upconversion nanoparticles
    DOI:  https://doi.org/10.1021/acsabm.0c00524
  70. ACS Appl Bio Mater. 2020 May 18. 3(5): 3345-3353
    Tumor Microenvironment-Directed Multisensitive Nanorobotics for Synergistic Photothermal Therapy/Chemotherapy.
    Yang Zhang, Lu Yang, Wentong Li, Chengcheng Gai, Bo Hu, Aihua Liu.
      It is of great significance to design a multifunctional nanotherapeutic agent with flexible and intelligent response performance for a tumor microenvironment. Herein, hollow-structured hCu2-xS@Au derivatives were synthesized for multiswitchable drug release and synergistic photothermal therapy/chemotherapy. The remarkably improved release ratio (over 90%) under higher glutathione concentration and lower pH conditions could be ascribed to the fracture of the disulfide bond and the reduction of force between the drug and nanovehicles. In addition, the shrinking of tetradecanol molecules anchored on the surface of hCu2-xS@Au by near-infrared (NIR) photo-activation could also enhance the release of drugs in the cavity of hCu2-xS@Au. After decorating with Au nanoparticles, the favorable electron transitions endowed hCu2-xS@Au nanoparticles with a high photothermal conversion efficiency, which reaches 36.4% under a NIR laser irradiation of 808 nm. Compared to conventional single/double stimuli-responsive delivery, the proposed multimodal release pattern powerfully overcomes the limitation of insufficient dose as a single/double release unit for a tumor microenvironment was unable to meet the release requirements. After phagocytosis by tumor cells, the continuous release of anticancer drugs facilitated a substantial improvement in the antitumor therapy efficacy by combining chemo- and photothermal therapy in vivo. This design platform can provide a promising strategy for continuous and synergistic tumor therapy.
    Keywords:  drug delivery; multi-stimuli response; nanorobotics; synergistic therapy; tumor microenvironment
    DOI:  https://doi.org/10.1021/acsabm.0c00265
  71. ACS Appl Bio Mater. 2020 Jul 20. 3(7): 4230-4238
    Nanostructuring a Widely Used Antiworm Drug into the Lipid-Coated Calcium Phosphate Matrix for Enhanced Skin Tumor Treatment.
    Fatemeh Movahedi, Yilun Wu, Wenyi Gu, Zhi Ping Xu.
      Recently, a widely used antiworm drug albendazole (ABZ) has been recognized as an anticancer drug, while being safe for healthy cells. However, its clinical application is limited due to low water solubility. In this work, we incorporated ABZ into pH-responsive lipid-coated calcium phosphate (LCP) nanoparticles to enhance anticancer efficacy. LCP-ABZ nanoparticles doubled the ABZ solubility with a much quicker release rate in the slightly acidic environment. LCP-ABZ significantly improved cytotoxicity to B16F0 cells and reduced their migration probably through enhanced apoptosis induction via reactive oxygen species overproduction. In a B16F0-bearing mouse models, LCP-ABZ nanoparticles reduced the tumor size by 50-60% at the total dose of only 15 mg (ABZ)/kg, more effective than commercial albendazole and other ABZ nanoparticles. Overall, this research demonstrated LCP nanoparticle as an effective platform to deliver ABZ for cancer therapy, with safety to healthy tissues and the potential to inhibit metastasis.
    Keywords:  acid-triggered release; antiworm albendazole; enhanced anticancer activity; enhanced solubility of the hydrophobic drug; lipid-coated calcium phosphate nanoparticles; skin cancer therapy
    DOI:  https://doi.org/10.1021/acsabm.0c00313
  72. ACS Appl Bio Mater. 2020 Aug 17. 3(8): 5331-5341
    A Strategy to Fight against Triple-Negative Breast Cancer: pH-Responsive Hexahistidine-Metal Assemblies with High-Payload Drugs.
    Long Zhang, Hongyan Xu, Xiaoxiao Wu, Wenjuan Huang, Tinghong Zhang, Pengyan Hao, Bo Peng, Xingjie Zan.
      Triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer, is difficult to be targeted therapeutically due to negative expression of the bioreceptor, which leads to the poorest overall four-year survival rate among all cancer subtypes. We proposed that the nanomedicine featuring high payload and pH-responsive release of the loaded drugs could assist the TNBC treatment. In the present study, the His6-metal assemblies (HmA) were employed to encapsulate the doxorubicin (Dox), and the effect of HmA loaded with Dox (HmA@Dox) on treating TNBC was evaluated in vitro and in vivo. We found that the participation of Dox in the formation of HmA leads to high loading efficiency (99.4% for concentration ≤ 1 mg/mL) and the loading capacity (50.7% for concentration ≥ 10 mg/mL) of Dox encapsulated into HmA. HmA@Dox exhibited a narrow size distribution on the nanoscale, a pH-responsive release of loaded Dox, a quick endocytosis process, and fast lysosome escape. Most importantly, the HmA@Dox showed high efficacy in killing various breast cancer cells (MCF-7, MDA-MB-231, and MDA-MB-453) in vitro and depressing the development of TNBC in vivo. Our results demonstrated that such a strategy for designing a nanomedicine with high payload and responsive release of drugs to the environment around the tumor was of great importance to treat TNBC.
    Keywords:  Triple-negative breast cancer; hexahistidine-metal assemblies; high payload; nanomedicine; responsive release
    DOI:  https://doi.org/10.1021/acsabm.0c00653
  73. ACS Appl Bio Mater. 2020 Apr 20. 3(4): 2284-2294
    Polyphosphazene-Based Drug Self-Framed Delivery System as a Universal Intelligent Platform for Combination Therapy against Multidrug-Resistant Tumors.
    Shenglei Hou, Shiliu Zhou, Shuangshuang Chen, Qinghua Lu.
      Combination therapy is a burgeoning research field due to the advantages of the synergistic contributions from incorporating drugs and promising potentials in the therapy of aggressive tumors with multidrug resistance (MDR). Given the great efforts, it is extremely difficult to coordinate pharmacokinetics between drugs and elucidate the mechanism of synergistic effects. Additionally, limited by the inherent solubility of anticancer drugs, a common strategy for simultaneously delivering various drugs is yet a challenging target. To overcome these, we develop a drug self-framed delivery system (DSFDS) via treating multiple drugs as monomers to constructing cyclomatrix polyphosphazene nanoparticles (CPPZ NPs). Notably, it is a superflexible common platform to realize the rational design of combination therapy, which is verified by delivering doxorubicin (DOX) with mitoxantrone (Mit), resveratrol (RES), curcumin (Cur), and porphyrin (TPP). As a proof of concept, DOX-RES-CysM-CPPZ NP was selected to evaluate the therapeutic feasibility of DSFDSs. Obvious improvement in killing MDR tumors indicated an efficient combination therapy. The corresponding synergistic mechanism of DOX and RES was also addressed in this work. Throughout cutting-edge research, the drug self-framed delivery system is drawing promising blueprint for combination therapy.
    Keywords:  MDR cancer; combination therapy; drug self-framed delivery system; polyphosphazene; synergistic effect
    DOI:  https://doi.org/10.1021/acsabm.0c00072
  74. ACS Appl Bio Mater. 2020 Dec 21. 3(12): 9135-9144
    Reactive Oxygen Species Self-Sufficient Multifunctional Nanoplatform for Synergistic Chemo-Photodynamic Therapy with Red/Near-Infrared Dual-Imaging.
    Yongkang Huang, De-E Liu, Jinxia An, Bingqing Liu, Liya Sun, Hao Fu, Shuzhen Yan, Wenfang Sun, Hui Gao.
      Developing multifunctional nanoplatforms that combine controlled drug release, therapy, and real-time monitoring of intracellular distribution of therapeutic agents can provide a solution for practical precision cancer therapy. Herein, a daylight activatable and red to near-infrared (NIR) dual-imaging guided multifunctional anticancer nanoplatform based on diselenium-conjugated and aggregation-induced emission fluorogen (AIEgen)-cross-linked oligoethylenimine polymer loaded with cisplatin (Pt) and biscyclometalated iridium(III) (Ir(III)) complex (Pt&Ir@P NPs) is reported. Upon short-time daylight irradiation, the nanoplatform generates reactive oxygen species (ROS), which help them to escape from endo/lysosomes via enhanced lysosomal membrane permeability. Meanwhile, the chemotherapeutic drug cisplatin and the photosensitizer (PS) Ir(III) complex are released via breaking the ROS-labile diselenium bond. The released PS, together with AIEgen, respond to the continuous long-time daylight irradiation and produce more ROS, inducing photodynamic therapy (PDT) and damaging the nucleus. Along with PDT, selenium liberates cisplatin and exerts chemotherapy in the presence of endogenous spermine. In addition, the red/NIR emitting Ir(III) complex and the engineered AIEgen act as dual-imaging agents for real-time monitoring the distribution of PS and polymer. This daylight responsive multifunctional nanoplatform for efficient anticancer therapy and imaging could provide an intriguing strategy for developing theranostic antitumor platforms.
    Keywords:  aggregation-induced emission; antitumor; biscyclometalated iridium(III) complex; daylight-responsive; reactive oxygen species
    DOI:  https://doi.org/10.1021/acsabm.0c01419
  75. ACS Appl Bio Mater. 2020 Sep 21. 3(9): 5455-5462
    Intelligent Size-Changeable Nanoparticles for Enhanced Tumor Accumulation and Deep Penetration.
    Wenqi Yu, Chuan Hu, Huile Gao.
      Nanoparticles have shown great potential in tumor drug delivery. However, the accumulation and deep penetration behaviors of nanoparticles still need to be improved because of the barrier of tumor microenvironment. Recent days, intelligent aggregatable or shrinkable nanoparticles exhibit both good accumulation and deep penetration, providing the prospect for improved antitumor efficacy. This Spotlight first gives a concise introduction of the "size dilemma" in tumor accumulation and deep penetration and then goes in detail on our own contribution to the field of size aggregation and size shrinkage strategies. Also, we introduce the combination therapy of the size change strategy and other treatments, and the synergistic effect significantly improves the antitumor efficacy. In the end, we discuss the future directions for the potential applications.
    Keywords:  aggregation; drug delivery; nanoparticles; shrinkage; tumor
    DOI:  https://doi.org/10.1021/acsabm.0c00917
  76. Molecules. 2021 Dec 27. pii: 146. [Epub ahead of print]27(1):
    Smart Nanocarriers as an Emerging Platform for Cancer Therapy: A Review.
    Madhuchandra Kenchegowda, Mohamed Rahamathulla, Umme Hani, Mohammed Y Begum, Sagar Guruswamy, Riyaz Ali M Osmani, Mysore P Gowrav, Sultan Alshehri, Mohammed M Ghoneim, Areej Alshlowi, Devegowda V Gowda.
      Cancer is a group of disorders characterized by uncontrolled cell growth that affects around 11 million people each year globally. Nanocarrier-based systems are extensively used in cancer imaging, diagnostics as well as therapeutics; owing to their promising features and potential to augment therapeutic efficacy. The focal point of research remains to develop new-fangled smart nanocarriers that can selectively respond to cancer-specific conditions and deliver medications to target cells efficiently. Nanocarriers deliver loaded therapeutic cargos to the tumour site either in a passive or active mode, with the least drug elimination from the drug delivery systems. This review chiefly focuses on current advances allied to smart nanocarriers such as dendrimers, liposomes, mesoporous silica nanoparticles, quantum dots, micelles, superparamagnetic iron-oxide nanoparticles, gold nanoparticles and carbon nanotubes, to list a few. Exhaustive discussion on crucial topics like drug targeting, surface decorated smart-nanocarriers and stimuli-responsive cancer nanotherapeutics responding to temperature, enzyme, pH and redox stimuli have been covered.
    Keywords:  cancer; drug targeting; nanoparticles; smart nanocarriers; stimulus for drug release
    DOI:  https://doi.org/10.3390/molecules27010146
  77. ACS Appl Bio Mater. 2020 Sep 21. 3(9): 6015-6024
    Dandelion-Inspired Hierarchical Upconversion Nanoplatform for Synergistic Chemo-Photodynamic Therapy In Vitro.
    Qiang Zhang, Songqiang Sun, Zhuo Wang, Jiabei Li, Yao Xie, Liyi Shi, Lining Sun.
      Herein, inspired by the structure of a dandelion, we develop a fresh preparation of an upconversion nanoplatform (UCNPs@C60-DOX-FA). The target part folic acid (FA) modified with β-CD-NH2 can enhance dispersibility and afford the nanoplatform to arrive at the tumor and enter cancer cells easily. After the mouse breast cancer (4T1) cell incubation with the nanoplatform, the abundant glutathione (GSH) in cells cuts the -S-S- bonds like scissors, just as dandelion encountering wind, and the drug doxorubicin (DOX) flows into the nucleus for chemotherapy. Meanwhile, the photodynamic therapy (PDT) effect is enhanced with the decrease content of GSH, which promotes the reactive oxygen species to accumulation. The synergistic chemotherapy and PDT are outstanding in killing 4T1 cells. The rest part UCNPs@C60 possesses excellent biocompatibility and low cytotoxicity. As for cancer diagnosis, UCNPs can be used as a visual imaging agent. Benefited by the delicate structure, all of the functional parts of the nanoplatform go and coordinate well. On account of an FA ligand and the -S-S- bond, the nanoplatform works very well in 4T1 cells while it is able to avoid damage to normal cells since the FA receptors and GSH have overexpression in the 4T1 cells. Thus, this work shows an accessible strategy to design a dandelion-like hierarchical nanoplatform for potential bioimaging-guided synergistic chemo-photodynamic therapy.
    Keywords:  PDT; biocompatibility; bioimaging; drug release; synergy; upconversion nanoplatform
    DOI:  https://doi.org/10.1021/acsabm.0c00645
  78. ACS Appl Bio Mater. 2020 Jun 15. 3(6): 3518-3525
    Synthesis of Gelatin-Based Dual-Targeted Nanoparticles of Betulinic Acid for Antitumor Therapy.
    Shuting Lu, Xiaocheng Fan, Henan Wang, Yuliang Zhao, Wancheng Zhao, Mengzhu Li, Rongyao Lv, Ting Wang, Tiedong Sun.
      Betulinic acid (BA) is a natural antitumor agent and has biological activity against multiple human tumor cell lines with low cytotoxicity to normal cells, while the high hydrophobicity and the short half-life of this compound limit its clinical application. Here, gelatin-based dual-targeted nanoparticles of BA are promising to solve this problem. Hydrophobic BA is loaded in cyclodextrin to increase its solubility and prolong the circulation time in vivo. The nanoscale drug delivery systems can further enhance the bioavailability and the antitumor effect of BA and are passively targeted to the tumor tissue sites by enhanced permeability and retention effect. The RGD sequence of gelatin specifically recognizes tumor cells and brings agents into tumor cells. The nanoparticles were characterized by transmission electron microscopy, Fourier transform infrared, nuclear magnetic resonance, etc. In addition, we observed antitumor activity of the nanoparticles using both cell-based assays and mouse xenograft tumors, which proved that betulinic acid/gelatin-γ-cyclodextrin nanoparticles had a better tumor inhibition effect than betulinic acid/γ-cyclodextrin inclusion compound.
    Keywords:  betulinic acid; cyclodextrin; gelatin; hydrogel; tumor
    DOI:  https://doi.org/10.1021/acsabm.9b01204
  79. ACS Nano. 2022 Jan 13.
    Self-Adaptive Single-Atom Catalyst Boosting Selective Ferroptosis in Tumor Cells.
    Fangfang Cao, Yanjuan Sang, Chaoying Liu, Fuquan Bai, Lirong Zheng, Jinsong Ren, Xiaogang Qu.
      Ferroptosis, resulting from the catastrophic accumulation of lipid reactive oxygen species (ROS) and the inactivation of glutathione (GSH)-dependent peroxidase 4 (GPX4), has emerged as a form of regulated cell death for cancer therapy. Despite progress made with current ferroptosis inducers, efficient systems to trigger ferroptosis remain challenging, owing largely to their low activity, uncontrollable behavior, and even nonselective interactions. Here, we report a self-adaptive ferroptosis platform by engineering a DNA modulator onto the surface of single-atom nanozymes (SAzymes). The modulator could not only specifically intensify the ROS-generating activity but also endow the SAzymes with on-demand GSH-consuming ability in tumor cells, accelerating selective and safe ferroptosis. The self-adaptive antitumor response has been demonstrated in colon cancer and breast cancer, promoting the development of selective cancer therapy.
    Keywords:  DNA modulation; ROS regulation; activated GSH-consuming; selective ferroptosis; self-adaptive; single-atom catalysis
    DOI:  https://doi.org/10.1021/acsnano.1c08464
  80. ACS Appl Bio Mater. 2020 Feb 17. 3(2): 779-788
    In Situ Biosynthesized Superparamagnetic Iron Oxide Nanoparticles (SPIONS) Induce Efficient Hyperthermia in Cancer Cells.
    Swati Kaushik, Jijo Thomas, Vineeta Panwar, Hasan Ali, Vianni Chopra, Anjana Sharma, Ruchi Tomar, Deepa Ghosh.
      Despite the promising role of magnetic hyperthermia in cancer therapy, its use in patients has been restricted by hurdles that include inefficient targeting of magnetic particles to the tumor site, limited bioavailability, and high toxicity, etc. Taking advantage of the unique metabolic property of cancer cells, we explored the potential of these cells to biosynthesize magnetic nanoparticles for potential hyperthermia applications. Treatment of cancer cells with a mixture of FeCl2 and zinc gluconate resulted in a significant increase in intracellular Fe and Zn content in these cells. Exposure of these cells to an alternating magnetic field (AMF) for 30 min resulted in a substantial temperature rise of 5-6 °C. The in situ formed particles were identified as iron oxide and ZnO nanoparticles. Based on the magnetic property and size, the iron oxide nanoparticles were classified as superparamagnetic iron oxide nanoparticles (SPIONS) comprising a mixture of magnetite (Fe3-δO4) and maghemite (γ-Fe2O3). The role of reactive oxygen species (H2O2) and the involvement of the glycolytic pathway in the biosynthesis of the nanoparticles were confirmed using appropriate in vitro studies. The simplicity of treatment, the specificity of cells capable of synthesis of SPIONS, and the hyperthermia response observed in cancer cells indicate a promising strategy to achieve effective magnetic hyperthermia for cancer therapy.
    Keywords:  SPIONS; cancer therapy; in situ biosynthesis; magnetic hyperthermia; magnetic nanoparticles
    DOI:  https://doi.org/10.1021/acsabm.9b00720
  81. Biomater Sci. 2022 Jan 10.
    Injectable and pH-responsive self-assembled peptide hydrogel for promoted tumor cell uptake and enhanced cancer chemotherapy.
    Jiamin Zhang, Wenjing Lin, Lijun Yang, Aijie Zhang, Yumin Zhang, Jinjian Liu, Jianfeng Liu.
      Chemotherapy is the main treatment for cancer therapy. However, its anti-tumor efficiency is always impaired by the poor bioavailability and low tumor accumulation of chemotherapeutic drugs. The variation between the tumor microenvironment and normal tissue has been recognized as an effective tool to improve drug anti-tumor efficiency. Herein, we developed an injectable, pH-responsive, in situ self-assembled drug-peptide hydrogel (MTX-KKFKFEFEF(DA)) for highly efficient local tumor chemotherapy with few side effects. The small molecule drug, methotrexate (MTX), and pH-responsive linker, 2,3-dimethylmaleic anhydride (DA), were facilely conjugated onto the chain of the KKFKFEFEF peptide via an amidation reaction. The negatively charged drug-peptide (pH 7.4) can be activated to be positive and achieve a sol-gel phase transition under an acidic microenvironment (pH 6.5) both in vitro and in vivo, resulting in highly efficient cellular uptake and endocytosis capacities. Moreover, the in vivo anti-tumor therapeutic effect revealed that the MTX-KKFKFEFEF(DA) hydrogel exhibits long-term tumor retention time, much better tumor inhibition rate and negligible side effects after intratumoral injection into breast tumor-bearing mice. Therefore, this study reveals a versatile strategy for fabricating a pH-responsive drug-peptide hydrogel to improve the chemotherapeutic efficacy of drugs in cancer treatment.
    DOI:  https://doi.org/10.1039/d1bm01788h
  82. Polymers (Basel). 2021 Dec 27. pii: 92. [Epub ahead of print]14(1):
    Recent Trends in Assessment of Cellulose Derivatives in Designing Novel and Nanoparticulate-Based Drug Delivery Systems for Improvement of Oral Health.
    Khaled M Hosny, Hala M Alkhalidi, Waleed S Alharbi, Shadab Md, Amal M Sindi, Sarah A Ali, Rana B Bakhaidar, Alshaimaa M Almehmady, Eman Alfayez, Mallesh Kurakula.
      Natural polymers are revolutionizing current pharmaceutical dosage forms design as excipient and gained huge importance because of significant influence in formulation development and drug delivery. Oral health refers to the health of the teeth, gums, and the entire oral-facial system that allows us to smile, speak, and chew. Since years, biopolymers stand out due to their biocompatibility, biodegradability, low toxicity, and stability. Polysaccharides such as cellulose and their derivatives possess properties like novel mechanical robustness and hydrophilicity that can be easily fabricated into controlled-release dosage forms. Cellulose attracts the dosage design attention because of constant drug release rate from the precursor nanoparticles. This review discusses the origin, extraction, preparation of cellulose derivatives and their use in formulation development of nanoparticles having multidisciplinary applications as pharmaceutical excipient and in drug delivery, as bacterial and plant cellulose have great potential for application in the biomedical area, including dentistry, protein and peptide delivery, colorectal cancer treatment, and in 3D printable dosage forms.
    Keywords:  biopolymers; cellulose derivatives; controlled release; drug delivery; excipient; nanoparticles
    DOI:  https://doi.org/10.3390/polym14010092
  83. ACS Appl Bio Mater. 2020 Jun 15. 3(6): 3835-3845
    PEGylated Dimeric BODIPY Photosensitizers as Nanocarriers for Combined Chemotherapy and Cathepsin B-Activated Photodynamic Therapy in 3D Tumor Spheroids.
    Sheng Lu, Xiang Lei, Hao Ren, Shiyue Zheng, Jian Qiang, Zhijie Zhang, Yahui Chen, Tingwen Wei, Fang Wang, Xiaoqiang Chen.
      The development of enzyme-activatable photosensitizers and their combination with conventional chemodrugs for antitumor therapy are of great interest. In this work, we reported a strategy of constructing activatable photosensitizers by interfering with the intramolecular charge transfer (ICT) state of an orthogonal boron dipyrromethene (BODIPY) chromophore. By conjugating a cathepsin B substrate peptide with a photosensitizer, BDP-BDP-NH2, the reactive oxygen species (ROS) generation of the product (ABP) was significantly suppressed due to the blockage of the electron-donating amino group. In vitro experiments proved the recovery of ROS generation under laser irradiation after the peptide linker was cleaved by cathepsin B. The ABP was then PEGylated and modified with a cRGD peptide (RNC) to encapsulate a hydrophobic anticancer drug, 10-hydroxycamptothecin (HCPT). The formed RNC/HCPT nanoparticles had good stability in serum-containing solutions with a hydrodynamic size of around 200 nm. The combination of cathepsin B-activated PDT and chemotherapy exhibited a strong ability to inhibit the growth of 4T1 breast cancer cells while promoting the induction of cell apoptosis. The RNC/HCPT nanoparticles also showed the ability to penetrate the 4T1 three-dimensional (3D) tumor spheroids and effectively shrunk the size of the spheroids. Taken together, our strategy offers a platform for antitumor drug delivery with an activatable PDT effect and combined therapy.
    Keywords:  BODIPY; activatable photodynamic therapy; cathepsin B; drug delivery; tumor spheroid
    DOI:  https://doi.org/10.1021/acsabm.0c00394
  84. Front Chem. 2021 ;9 797094
    RNA Hydrogel Combined with MnO2 Nanoparticles as a Nano-Vaccine to Treat Triple Negative Breast Cancer.
    Weicai Wang, Xiaofan Liu, Lairong Ding, Hyung Jong Jin, Xuemei Li.
      Hypoxia is not only the reason of tumor metastasis but also enhances the spread of cancer cells from the original tumor site, which results in cancer recurrence. Herein, we developed a self-assembled RNA hydrogel that efficiently delivered synergistic DNA CpG and short hairpin RNA (shRNA) adjuvants, as well as MnO2 loaded-photodynamic agent chlorine e6 (MnO2@Ce6), and a chemotherapy drug doxorubicin (DOX) into MDA-MB-231cells. The RNA hydrogel consists of one tumour suppressor miRNA (miRNA-205) and one anti-metastatic miRNA (miRNA-182), both of which showed an outstanding effect in synergistically abrogating tumours. The hydrogel would be dissociated by endogenous Dicer enzyme to release loaded therapeutic molecules, and in the meantime induce decomposition of tumor endogenous H2O2 to relieve tumor hypoxia. As a result, a remarkable synergistic therapeutic effect is achieved through the combined chemo-photodynamic therapy, which simultaneously triggers a series of anti-tumor immune responses. Besides, the hydrogel as the carrier which modified aptamer to targeted MDA-MB-231 has the advantages of good biocompatibility and low cytotoxicity. This strategy could be implemented to design any other microRNA (miRNA) as the carrier, combined with other treatment methods to treat human cancer, thereby overcoming the limitations of current cancer therapies.
    Keywords:  RNA hydrogel; gene therapy; nano-vaccine; photodynamic therapy; triple negative breast cancer
    DOI:  https://doi.org/10.3389/fchem.2021.797094
  85. Molecules. 2021 Dec 28. pii: 156. [Epub ahead of print]27(1):
    Cannabinoids in Breast Cancer: Differential Susceptibility According to Subtype.
    Cristina Ferreira Almeida, Natércia Teixeira, Georgina Correia-da-Silva, Cristina Amaral.
      Although cannabinoids have been used for centuries for diverse pathological conditions, recently, their clinical interest and application have emerged due to their diverse pharmacological properties. Indeed, it is well established that cannabinoids exert important actions on multiple sclerosis, epilepsy and pain relief. Regarding cancer, cannabinoids were first introduced to manage chemotherapy-related side effects, though several studies demonstrated that they could modulate the proliferation and death of different cancer cells, as well as angiogenesis, making them attractive agents for cancer treatment. In relation to breast cancer, it has been suggested that estrogen receptor-negative (ER-) cells are more sensitive to cannabinoids than estrogen receptor-positive (ER+) cells. In fact, most of the studies regarding their effects on breast tumors have been conducted on triple-negative breast cancer (TNBC). Nonetheless, the number of studies on human epidermal growth factor receptor 2-positive (HER2+) and ER+ breast tumors has been rising in recent years. However, besides the optimistic results obtained thus far, there is still a long way to go to fully understand the role of these molecules. This review intends to help clarify the clinical potential of cannabinoids for each breast cancer subtype.
    Keywords:  Cannabis sativa; anandamide; breast cancer; cannabidiol; cannabidivarin; cannabigerol; cannabinoids; cannabinol; Δ9-tetrahydrocannabinol
    DOI:  https://doi.org/10.3390/molecules27010156
  86. ACS Appl Bio Mater. 2021 May 17. 4(5): 4394-4405
    Ru(II) Polypyridine Complex-Functionalized Mesoporous Silica Nanoparticles as Photosensitizers for Cancer Targeted Photodynamic Therapy.
    Johannes Karges, Diana Díaz-García, Sanjiv Prashar, Santiago Gómez-Ruiz, Gilles Gasser.
      Cancer is the leading cause of death in the developed world. In the last few decades, photodynamic therapy (PDT) has augmented the number of medical techniques to treat this disease in the clinics. As the pharmacological active species to kill cancer cells are only generated upon light irradiation, PDT is associated with an intrinsic first level of selectivity. However, since PDT agents also accumulate in the surrounding, healthy tissue and since it is practically very challenging to only expose the tumor site to light, some side effects can be observed. Consequently, there is a need for a selective drug delivery system, which would give a second level of selectivity. In this work, a dual tumor targeting approach is presented based on mesoporous silica nanoparticles, which act by the enhanced permeability and retention effect, and the conjugation to folic acid, which acts as a targeting moiety for folate receptor-overexpressed cancer cells. The conjugates were found to be nontoxic in noncancerous human normal lung fibroblast cells while showing a phototoxic effect upon irradiation at 480 or 540 nm in the low nanomolar range in folate receptor overexpressing cancerous human ovarian carcinoma cells, demonstrating their potential for cancer targeted treatment.
    Keywords:  anticancer; bioinorganic chemistry; medicinal inorganic chemistry; mesoporous silica nanoparticles; metals in medicine; photodynamic therapy
    DOI:  https://doi.org/10.1021/acsabm.1c00151
  87. ACS Appl Bio Mater. 2020 Jul 20. 3(7): 4436-4443
    Synergistic Photodynamic and Photothermal Antibacterial Therapy Based on a Conjugated Polymer Nanoparticle-Doped Hydrogel.
    Qifan Cui, Hongbo Yuan, Xueying Bao, Gang Ma, Manman Wu, Chengfen Xing.
      Herein, we have developed a composite antibacterial hydrogel with photodynamic therapy (PDT) and photothermal therapy (PTT) antibacterial capabilities, triggered by white light and NIR light irradiation. A water-insoluble conjugated polymer (PDPP) with photothermal ability was prepared into nanoparticles by the nanoprecipitation method, and the cell-penetrating peptide TAT was grafted on the surface of the nanoparticles. Based on our previous work that developed a hybrid hydrogel with an enhanced PDT effect from polyisocyanide (PIC) hydrogel and cationic conjugated polythiophene (PMNT), PDPP nanoparticles (CPNs-TAT) with photothermal ability are introduced to realize the synergistic antibacterial effect of PDT and PTT. Using the PIC hydrogel to combine PIC and CPNs-TAT has the following advantages. First, the PIC hydrogel can regulate the aggregation state of PMNT, making it better dispersed and improving its capacity of reactive oxygen species (ROS) production. Second, CPNs-TAT can be uniformly dispersed in the PIC hybrid, thereby avoiding the toxicity caused by too high local concentration, achieving a uniform increase in system temperature, and enhancing the therapeutic effect of PTT. Third, the PIC hybrid has the synergistic treatment effect of PDT and PTT. The PIC hybrid intelligently regulates its antibacterial ability through white light and NIR light, which can be used in the white light and NIR light areas. When irradiated with white light and NIR light sequentially, synergistic PDT and PTT exhibit stronger antibacterial ability than PDT or PTT alone. The combination of two antibacterial methods realizes the dual-control antibacterial hydrogel of PDT and PTT and provides an antibacterial mode based on PIC hybrids. Therefore, the PIC hybrids are promising as an antibacterial excipient for clinical wounds.
    Keywords:  antibacterial; conjugated polymer; hydrogel; nanoparticle; photodynamic; photothermal
    DOI:  https://doi.org/10.1021/acsabm.0c00423
  88. Saudi J Biol Sci. 2022 Jan;29(1): 154-160
    A possible theranostic approach of chitosan-coated iron oxide nanoparticles against human colorectal carcinoma (HCT-116) cell line.
    Abdullah A Alkahtane, Hamzah A Alghamdi, Alanoud T Aljasham, Saad Alkahtani.
      Iron oxides have become increasingly popular for their use as a diagnostic and therapeutic tool in oncology. This study aimed to improve pharmacological valuable of Fe3O4, which may be use to diagnosis colorectal cancers (CRC). Here, we have developed chitosan (CS) coated Fe3O4 through a cost-effective procedure. First, we determined the characterization of OA-C-Fe3O4 by FTIR, UV-Vis spectra, and TEM. Then, we evaluated the photodynamic therapeutic (PDT) activity of OA-C-Fe3O4 in human colorectal carcinoma cell lines (HCT 116). Current results revealed that the light-induced enhanced reactive oxygen species (ROS) activity of the nanoparticles (NPs) and caused cell death via the activity of caspase 9/3. The in vitro magnetic resonance imaging (MRI) experiments in (HCT 116) and human embryonic kidney cells (HEK 293) illustrated that nanohybrid is an effective MRI contrasting agents for the diagnosis of colorectal cancer.
    Keywords:  Colorectal cancer; MRI; Metallic nanoparticles; Photodynamic therapy; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.sjbs.2021.08.078
  89. J Nanobiotechnology. 2022 Jan 10. 20(1): 31
    Charge reversal nano-systems for tumor therapy.
    Peng Zhang, Daoyuan Chen, Lin Li, Kaoxiang Sun.
      Surface charge of biological and medical nanocarriers has been demonstrated to play an important role in cellular uptake. Owing to the unique physicochemical properties, charge-reversal delivery strategy has rapidly developed as a promising approach for drug delivery application, especially for cancer treatment. Charge-reversal nanocarriers are neutral/negatively charged at physiological conditions while could be triggered to positively charged by specific stimuli (i.e., pH, redox, ROS, enzyme, light or temperature) to achieve the prolonged blood circulation and enhanced tumor cellular uptake, thus to potentiate the antitumor effects of delivered therapeutic agents. In this review, we comprehensively summarized the recent advances of charge-reversal nanocarriers, including: (i) the effect of surface charge on cellular uptake; (ii) charge-conversion mechanisms responding to several specific stimuli; (iii) relation between the chemical structure and charge reversal activity; and (iv) polymeric materials that are commonly applied in the charge-reversal delivery systems.
    Keywords:  Antitumor therapy; Charge reversal; Nano systems; Stimuli-responsive; Surface charge
    DOI:  https://doi.org/10.1186/s12951-021-01221-8
  90. ACS Nano. 2022 Jan 13.
    Fibronectin-Coated Metal-Phenolic Networks for Cooperative Tumor Chemo-/Chemodynamic/Immune Therapy via Enhanced Ferroptosis-Mediated Immunogenic Cell Death.
    Yao Xu, Yunqi Guo, Changchang Zhang, Mengsi Zhan, Liang Jia, Shaoli Song, Chunjuan Jiang, Mingwu Shen, Xiangyang Shi.
      The development of nanomedicine formulations to overcome the disadvantages of traditional chemotherapeutic drugs and integrate cooperative theranostic modes still remains challenging. Herein, we report the facile construction of a multifunctional theranostic nanoplatform based on doxorubicin (DOX)-loaded tannic acid (TA)-iron (Fe) networks (for short, TAF) coated with fibronectin (FN) for combination tumor chemo-/chemodynamic/immune therapy under the guidance of magnetic resonance (MR) imaging. We show that the DOX-TAF@FN nanocomplexes created through in situ coordination of TA and Fe(III) and physical coating with FN have a mean particle size of 45.0 nm, are stable, and can release both DOX and Fe in a pH-dependent manner. Due to the coexistence of the TAF network and DOX, significant immunogenic cell death can be caused through enhanced ferroptosis of cancer cells via cooperative Fe-based chemodynamic therapy and DOX chemotherapy. Through further treatment with programmed cell death ligand 1 antibody for an immune checkpoint blockade, the tumor treatment efficacy and the associated immune response can be further enhanced. Meanwhile, with FN-mediated targeting, the DOX-TAF@FN platform can specifically target tumor cells with high expression of αvβ3 integrin. Finally, the TAF network also enables the DOX-TAF@FN to have an r1 relaxivity of 6.1 mM-1 s-1 for T1-weighted MR imaging of tumors. The developed DOX-TAF@FN nanocomplexes may represent an updated multifunctional nanosystem with simple compositions for cooperative MR imaging-guided targeted chemo-/chemodynamic/immune therapy of tumors.
    Keywords:  cooperative chemo-/chemodynamic therapy; fibronectin; immune checkpoint blockade therapy; immunogenic cell death; metal−phenolic networks
    DOI:  https://doi.org/10.1021/acsnano.1c08585
  91. ACS Appl Bio Mater. 2020 Dec 21. 3(12): 8776-8785
    Design of Curcumin Loaded Carbon Nanodots Delivery System: Enhanced Bioavailability, Release Kinetics, and Anticancer Activity.
    Durga M Arvapalli, Alex T Sheardy, Kokougan Allado, Harish Chevva, Ziyu Yin, Jianjun Wei.
      Despite the potential health benefits of curcumin, such as antioxidant, anticancer, anti-inflammatory, and antimicrobial properties, its usage is limited by poor bioavailability and low aqueous solubility. Nano-formulations of curcumin have gained a lot of attention due to their increased bioavailability, solubility, circulation times, targeted specificity, decreased biodegradation, better stability, and improved cellular uptake. The current study aimed to enhance the bioavailability of curcumin using carbon nanodots (CNDs) as loading vehicles to deliver curcumin due to their excellent biocompatibility, aqueous solubility, and photoluminescence properties. Two types of CNDs (E-CNDs and U-CNDs) were used for curcumin loading and characterized for particle size, morphology, loading capability (measured as adsorption efficiency and loading capacity), stability, photoluminescence properties, in vitro drug release studies, cellular uptake, and anticancer activity. The prepared curcumin-loading CNDs (Curc-CNDs) displayed sizes around or below 10 nm with good stability. The Curc-E-CNDs demonstrated a curcumin adsorption efficiency of 91% in solution, while the Curc-U-CNDs have an adsorption efficiency of 82%. Both have a loading capacity of 3.4-3.8% with respect to the weight of the CNDs. Curcumin release followed a controlled sustained pattern that a total of 60% and 74% of curcumin was released at 72 h from Curc-E-CNDs and Curc-U-CNDs, respectively, in pH 5 buffer, and almost 90% was released in culture media within 96 h. Both of the Curc-CNDs were uptaken by cells and exhibited prominent cytotoxicity toward cancer cells. The results clearly depict the role of CNDs as efficient carriers for curcumin delivery with prolonged release and enhanced bioavailability, thereby improving the overall antitumor activity.
    Keywords:  anticancer; carbon nanodots; cellular uptake; curcumin; cytotoxicity; nano−formulations
    DOI:  https://doi.org/10.1021/acsabm.0c01144
  92. Adv Sci (Weinh). 2022 Jan 12. e2102303
    A Novel Metabolic Reprogramming Strategy for the Treatment of Diabetes-Associated Breast Cancer.
    Qiongyu Hao, Zhimin Huang, Qun Li, Dingxie Liu, Piwen Wang, Kun Wang, Jieqing Li, Wei Cao, Wenhong Deng, Ke Wu, Rui Su, Zhongmin Liu, Jay Vadgama, Yong Wu.
      Diabetes is directly related to the risk of breast cancer (BC) occurrence and worsened BC prognosis. Currently, there are no specific treatments for diabetes-associated BC. This paper aims to understand the fundamental mechanisms of diabetes-induced BC progression and to develop personalized treatments. It reports a metabolic reprogramming strategy (MRS) that pharmaceutical induction of glucose import and glycolysis with metformin and NF-κB inhibitor (NF-κBi) while blocking the export of excessive lactate via inhibiting monocarboxylate transporter 4 (MCT4) leads to a metabolic crisis within the cancer cells. It demonstrates that the MRS shifts the metabolism of BC cells toward higher production of lactate, blocks lactate secretion, prompts intracellular acidification and induces significant cytotoxicity. Moreover, a novel MCT4 inhibitor CB-2 has been identified by structure-based virtual screening. A triple combination of metformin, CB-2, and trabectedin, a drug that impedes NF-κB signaling, strongly inhibits BC cells. Compared to normal glucose condition, MRS elicits more potent cancer cell-killing effects under high glucose condition. Animal model studies show that diabetic conditions promote the proliferation and progression of BC xenografts in nude mice and that MRS treatment significantly inhibits HG-induced BC progression. Therefore, inhibition of MCT4 combined with metformin/NF-κBi is a promising cancer therapy, especially for diabetes-associated BC.
    Keywords:  MCT4; breast cancer; diabetes; lactate; metabolic reprogramming; metformin
    DOI:  https://doi.org/10.1002/advs.202102303
  93. ACS Appl Bio Mater. 2021 Jun 21. 4(6): 5132-5144
    Paclitaxel-Loaded Biotinylated Fe2+-Doped Carbon Dot: Combination Therapy in Cancer Treatment.
    Monalisa Chowdhury, Prasanta Kumar Das.
      The present research work delineates the design and preparation of covalently tailored biotinylated Fe2+-doped carbon dots (FCDb). The FCDb was successfully used as a pro-drug activator, diagnostic probe, and target-specific delivery vehicle for anticancer drug paclitaxel in pro-drug-free drug combination therapy of cancer treatment. Fe2+-doped carbon dot was synthesized via the hydrothermal method (FCD). The surface of FCD was covalently modified with cancer cell targeting ligand biotin (FCDb). Microscopic and spectroscopic methods were used to characterize aqueous soluble FCD and FCDb. Both FCD and FCDb emit blue fluorescence under UV light irradiation. FCD and FCDb can effectively sense H2O2 by fluorescence quenching as well as activate H2O2 (pro-drug), which oxidatively damage the DNA through the generation of reactive oxygen species (ROS: superoxide (O2•-), hydroxyl radical (•OH), etc). Both FCD and FCDb were utilized as selective cellular markers for cancer cell B16F10 owing to their high H2O2 content, which was more distinct in the case of FCDb due to the overexpression of biotin receptor in cancer cell. Anticancer drug paclitaxel (PTX)-loaded FCDb (FCDb-PTX) was employed for the selective killing of B16F10 cancer cells. This pro-drug-free drug formulation (FCDb-PTX) exhibited ∼2.7- to 3.5-fold higher killing of B16F10 cells mostly via early as well as late apoptotic path in comparison to noncancer NIH3T3 cells through the synergistic action of ROS (generated from H2O2 in the presence of FCDb) and anticancer effect of PTX. Hence, this newly developed FCDb-PTX can act as a potential theranostic agent in the domain of combination therapy of cancer treatment.
    Keywords:  Fe2+-doped carbon dots; combination therapy; hydrogen peroxide; oxidative DNA damage; paclitaxel; pro-drug−free drug; selective killing of cancer cells
    DOI:  https://doi.org/10.1021/acsabm.1c00348
  94. ACS Appl Bio Mater. 2020 Jul 20. 3(7): 4590-4599
    Aptamer-Functionalized Gold Nanostars for on-Demand Delivery of Anticancer Therapeutics.
    Dalin Wu, Pei Zhao, Lei Wu, Lihua Lin, Guoyi Yu, Linlin Xu, Jun Yue.
      Gold nanostars (AuNS) are promising carriers for targeted delivery of therapeutic oligonucleotides, but their potential in fabricating an on-demand drug release system in a facile and robust way remains to be explored. In this paper, we used a model aptamer (HApt), acting not only as a target ligand but also as a natural thermal-responsive material, to decorate AuNS. The prepared gold nanoconstruct, HApt@AuNS, displayed stoichiometric loading capacity of the anthracycline drug doxorubicin (Dox). The on-demand drug release was realized by illuminating nanoconstructs with near-infrared (NIR) light. Furthermore, a higher degree of Dox release from the nanoconstructs was achieved in an acidic environment, compared to neutral conditions. The in vitro experiments showed that Dox-intercalation did not affect the cell uptake efficiency of HApt@AuNS, which could enter cells through clathrin-mediated endocytosis and microtubule-dependent active transport to lysosomes. Dox-loaded HApt@AuNS exhibited intracellular on-demand drug release and enhanced toxicity against cancer cells by NIR-irradiation.
    Keywords:  aptamers; gold nanostars; on-demand drug release; photothermal effect; targeting delivery
    DOI:  https://doi.org/10.1021/acsabm.0c00499
  95. ACS Appl Bio Mater. 2021 Dec 20.
    Mesoporous Doxorubicin-Loaded Polydopamine Nanoparticles Coated with a Platelet Membrane Suppress Tumor Growth in a Murine Model of Human Breast Cancer.
    Dandan Ren, Gareth R Williams, Yanyan Zhang, Rong Ren, Jiadong Lou, Li-Min Zhu.
      Bringing together photothermal therapy and chemotherapy (photothermal-chemotherapy, PT-CT) is a highly promising clinical approach but requires the development of intelligent multifunctional delivery vectors. In this work, we prepared mesoporous polydopamine nanoparticles (MPDA NPs) loaded with the chemotherapeutic drug doxorubicin (DOX). These NPs were then coated with the platelet membrane (PLTM). The coated MPDA NPs are spherical and clearly mesoporous in structure. They have a particle size of approximately 184 nm and pore size of ca. 45 nm. The NPs are potent photothermal agents and efficient DOX carriers, with increased rates of drug release observed in vitro in conditions representative of the tumor microenvironment. The NPs are preferentially taken up by cancer cells but not by macrophage cells, and while cytocompatible with healthy cells are highly toxic to cancer cells. An in vivo murine model of human breast cancer revealed that the NPs can markedly slow the growth of a tumor (ca. 9-fold smaller after 14 days' treatment), have extended pharmacokinetics compared to free DOX (with DOX still detectable in the bloodstream after 24 h when the NPs are applied), and are highly targeted with minimal off-site effects on the heart, liver, spleen, kidney, and lungs.
    Keywords:  cancer therapy; combination therapy; drug delivery system; mesoporous polydopamine; platelet membrane
    DOI:  https://doi.org/10.1021/acsabm.1c00926
  96. ACS Appl Bio Mater. 2021 Mar 15. 4(3): 2583-2590
    Conjugated Polymer Nanoparticles Based on Copper Coordination for Real-Time Monitoring of pH-Responsive Drug Delivery.
    Jiatong Li, Nan Du, Ying Tan, Hsien-Yi Hsu, Chunyan Tan, Yuyang Jiang.
      Metal coordination-driven composite systems have excellent stability and pH-responsive ability, making them suitable for specific drug delivery in physiological conditions. In this study, an anionic conjugated polymer PPEIDA with a poly(p-phenylene ethynylene) backbone and iminodiacetic acid (IDA) side chains is used as a drug carrier to construct a class of pH-responsive nanoparticles, PPEIDA-Cu-DOX conjugated polymer nanoparticles (CPNs), by taking advantage of the metal coordination interaction of Cu2+ with PPEIDA and the drug doxorubicin (DOX). PPEIDA-Cu-DOX CPNs have high drug loading and encapsulation efficiency (EE), calculated to be 54.30 ± 1.10 and 95.80 ± 0.84%, respectively. Due to the good spectral overlap, Förster resonance energy transfer (FRET) takes place between PPEIDA and the drug DOX, which enables the observation of the loading and the release of DOX from CPNs in an acidic environment by monitoring fluorescence emission changes. Therefore, PPEIDA-Cu-DOX CPNs can also be used in real-time cell imaging to monitor drug release in addition to delivering DOX targeting tumor cells. Compared with free DOX, PPEIDA-Cu-DOX CPNs show a similar inhibition to tumor cells and lower toxicity to normal cells. Our results demonstrate the feasibility and potential of constructing pH-responsive CPNs via metal-ligand coordination interactions for cancer treatment.
    Keywords:  FRET; cell imaging; conjugated polymer nanoparticles; coordination interaction; doxorubicin; pH-responsive drug release
    DOI:  https://doi.org/10.1021/acsabm.0c01564
  97. Cells. 2022 Jan 05. pii: 176. [Epub ahead of print]11(1):
    Targeting PGM3 as a Novel Therapeutic Strategy in KRAS/LKB1 Co-Mutant Lung Cancer.
    Hyunmin Lee, Feng Cai, Neil Kelekar, Nipun K Velupally, Jiyeon Kim.
      In non-small-cell lung cancer (NSCLC), concurrent mutations in the oncogene KRAS and tumor suppressor STK11 (also known as LKB1) confer an aggressive malignant phenotype, an unfavourability towards immunotherapy, and overall poor prognoses in patients. In a previous study, we showed that murine KRAS/LKB1 co-mutant tumors and human co-mutant cancer cells have an enhanced dependence on glutamine-fructose-6-phosphate transaminase 2 (GFPT2), a rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP), which could be targeted to reduce survival of KRAS/LKB1 co-mutants. Here, we found that KRAS/LKB1 co-mutant cells also exhibit an increased dependence on N-acetylglucosamine-phosphate mutase 3 (PGM3), an enzyme downstream of GFPT2. Genetic or pharmacologic suppression of PGM3 reduced KRAS/LKB1 co-mutant tumor growth in both in vitro and in vivo settings. Our results define an additional metabolic vulnerability in KRAS/LKB1 co-mutant tumors to the HBP and provide a rationale for targeting PGM3 in this aggressive subtype of NSCLC.
    Keywords:  KRAS and LKB1 co-mutations; O-GlcNAcylation; cancer metabolism; glycosylation; metabolic vulnerability; non-small cell lung cancer; the hexosamine biosynthesis pathway
    DOI:  https://doi.org/10.3390/cells11010176
  98. Drug Des Devel Ther. 2022 ;16 23-66
    Promising Natural Products in New Drug Design, Development, and Therapy for Skin Disorders: An Overview of Scientific Evidence and Understanding Their Mechanism of Action.
    Nurul Amirah Mohd Zaid, Mahendran Sekar, Srinivasa Reddy Bonam, Siew Hua Gan, Pei Teng Lum, M Yasmin Begum, Nur Najihah Izzati Mat Rani, Jaishree Vaijanathappa, Yuan Seng Wu, Vetriselvan Subramaniyan, Neeraj Kumar Fuloria, Shivkanya Fuloria.
      The skin is the largest organ in the human body, composed of the epidermis and the dermis. It provides protection and acts as a barrier against external menaces like allergens, chemicals, systemic toxicity, and infectious organisms. Skin disorders like cancer, dermatitis, psoriasis, wounds, skin aging, acne, and skin infection occur frequently and can impact human life. According to a growing body of evidence, several studies have reported that natural products have the potential for treating skin disorders. Building on this information, this review provides brief information about the action of the most important in vitro and in vivo research on the use of ten selected natural products in inflammatory, neoplastic, and infectious skin disorders and their mechanisms that have been reported to date. The related studies and articles were searched from several databases, including PubMed, Google, Google Scholar, and ScienceDirect. Ten natural products that have been reported widely on skin disorders were reviewed in this study, with most showing anti-inflammatory, antioxidant, anti-microbial, and anti-cancer effects as the main therapeutic actions. Overall, most of the natural products reported in this review can reduce and suppress inflammatory markers, like tumor necrosis factor-alpha (TNF-α), scavenge reactive oxygen species (ROS), induce cancer cell death through apoptosis, and prevent bacteria, fungal, and virus infections indicating their potentials. This review also highlighted the challenges and opportunities of natural products in transdermal/topical delivery systems and their safety considerations for skin disorders. Our findings indicated that natural products might be a low-cost, well-tolerated, and safe treatment for skin diseases. However, a larger number of clinical trials are required to validate these findings. Natural products in combination with modern drugs, as well as the development of novel delivery mechanisms, represent a very promising area for future drug discovery of these natural leads against skin disorders.
    Keywords:  anti-inflammatory; dermatitis; drug delivery; natural products; psoriasis; skin cancer; skin disorder
    DOI:  https://doi.org/10.2147/DDDT.S326332
  99. ACS Appl Bio Mater. 2021 Nov 15. 4(11): 7993-8003
    Lamellar Metal Oxide Based Nanoagent Realizing Intensive Interlamellar Ca2+ Release and Hypoxia Relief for Enhanced Synergistic Therapy.
    Xiaoqin Chen, Tianren Xu, Xiaojiao Zhu, Lei Chen, Li Yang, Shengnan Wang, Zhipeng Yu, Lianke Wang, Jie Zhang, Hongping Zhou.
      As an emerging cancer treatment, Ca2+-loaded nanoagents can disorder intracellular calcium homeostasis to induce cancer cell death. However, the developed Ca2+ nanocarriers are very limited in variety. Herein, we developed a metal oxide based nanoagent, Ca0.35CoO2@ss-SiO2-Ce6 (denoted as CCO@ss-SiO2-Ce6), which not only intensively released Ca2+ but also realized enhanced photothermal and photodynamic therapy. The excellent photothermal conversion efficacy (48.01% at 808 nm laser illumination, 1 W/cm2), high heat-enhanced release rate of Ca2+ (50.09% at pH 4.5), and catalase-mimic activity to generate oxygen as well as the facilitated production of the singlet oxygen all contributed to the enhanced synergistic cancer therapy efficacy. The in vitro and in vivo experiments displayed that CCO@ss-SiO2-Ce6 demonstrated superior biocompatibility and remarkable suppressive tumor growth. This work opens a pathway for fabricating synergistic therapeutic nanoplatforms.
    Keywords:  Ca2+ nanocarriers; enhanced photodynamic therapy; heat-enhanced interlayer Ca2+ release; photothermal performance; synergistic therapeutic nanoplatforms
    DOI:  https://doi.org/10.1021/acsabm.1c00894
  100. ACS Appl Bio Mater. 2020 Dec 21. 3(12): 8705-8713
    Phase-Change Nanotherapeutic Agents Based on Mesoporous Carbon for Multimodal Imaging and Tumor Therapy.
    Yong Li, Jialin Lu, Jing Zhang, Xiaohui Zhu, Jinliang Liu, Yong Zhang.
      A multifunctional nanotherapeutic agent based on mesoporous carbon is reported for multimodal imaging and cancer therapy. The nanoplatform consists of oxidized mesoporous carbon nanoparticles (OMCNs) as a near-infrared (NIR) photoresponse carrier and perfluoropentane (PFP) as a phase-change agent. OMCNs can absorb the NIR excitation light and convert it into heat, which not only triggers the thermal ablation of cancer cells but also promotes liquid-gas phase change for gasification of PFP to enhance the in site tumor ultrasound (US) and photoacoustic (PA) imaging signals. This nanoplatform demonstrates good biocompatibility, attractive ability to US/PA imaging, and excellent photothermal therapy efficiency.
    Keywords:  US/PA imaging; mesoporous carbon; microbubbles; perfluoropentane; photothermal therapy
    DOI:  https://doi.org/10.1021/acsabm.0c01102
  101. Asian J Pharm Sci. 2021 Nov;16(6): 762-771
    Carrier-free prodrug nanoparticles based on dasatinib and cisplatin for efficient antitumor in vivo.
    Lu Yang, Jiaxi Xu, Zheng Xie, Faquan Song, Xin Wang, Rupei Tang.
      Carrier-free drug self-delivery systems consisting of amphiphilic drug-drug conjugate (ADDC) with well-defined structure and nanoscale features have drawn much attention in tumor drug delivery. Herein, we report a simple and effective strategy to prepare ADDC using derivatives of cisplatin (CP) and dasatinib (DAS), which further self-assembled to form reduction-responsive nanoparticles (CP-DDA NPs). DAS was modified with succinic anhydride and then connected with CP derivative by ester bonds. The size, micromorphology and in vitro drug release of CP-DDA NPs were characterized. The biocompatibility and bioactivity of these carrier-free nanoparticles were then investigated by HepG2 cells and H22-tumor bearing mice. In vitro and in vivo experiments proved that CP-DDA NPs had excellent anti-tumor activity and significantly reduced toxicities. This study provides a new strategy to design the carrier-free nanomedicine composed of CP and DAS for synergistic tumor treatment.
    Keywords:  Cisplatin; Dasatinib; Nanoparticle; Prodrug
    DOI:  https://doi.org/10.1016/j.ajps.2021.08.001
  102. ACS Appl Bio Mater. 2021 Oct 18. 4(10): 7708-7718
    Improved Photophysical Properties of Ionic Material-Based Combination Chemo/PDT Nanomedicine.
    Samantha Macchi, Mohd Zubair, Robert Hill, Nabeel Alwan, Yusuf Khan, Nawab Ali, Grégory Guisbiers, Brian Berry, Noureen Siraj.
      Herein, a cost-effective and prompt approach to develop ionic material-based combination nanodrugs for cancer therapy is presented. A chemotherapeutic (phosphonium) cation and photodynamic therapeutic (porphyrin) anion are combined using a single step ion exchange reaction. Afterward, a nanomedicine is prepared from this ionic materials-based combination drug using a simplistic strategy of reprecipitation. Improved photophysical characteristics such as a slower nonradiative rate constant, an enhanced phosphorescence emission, a longer lifetime, and a bathochromic shift in absorbance spectra of porphyrin are observed in the presence of a chemotherapeutic countercation. The photodynamic therapeutic activity of nanomedicines is investigated by measuring the singlet oxygen quantum yield using two probes. As compared to the parent porphyrin compound, the synthesized combination material showed a 2-fold increase in the reactive oxygen species quantum yield, due to inhibition of face-to-face aggregation of porphyrin units in the presence of bulky chemotherapeutic ions. The dark cytotoxicity of combination therapy nanomedicines in the MCF-7 (cancerous breast) cell line is also increased as compared to their corresponding parent compounds in vitro. This is due to the high cellular uptake of the combination nanomedicines as compared to that of the free drug. Further, selective toxicity toward cancer cells was acquired by functionalizing nanomedicine with folic acid followed by incubation with MCF-7 and MCF-10A (noncancerous breast). Light toxicity experiments indicate that the synthesized ionic nanomedicine shows a greater cell death than either parent drug due to the improved photophysical properties and effective combination effect. This facile and economical strategy can easily be utilized in the future to develop many other combination ionic nanomedicines with improved photodynamics.
    Keywords:  cytotoxicity; ionic liquids; ionic materials; photodynamic therapy; porphyrin
    DOI:  https://doi.org/10.1021/acsabm.1c00961
  103. Biomaterials. 2022 Jan 10. pii: S0142-9612(22)00007-2. [Epub ahead of print]281 121368
    Red-light-triggered self-destructive mesoporous silica nanoparticles for cascade-amplifying chemo-photodynamic therapy favoring antitumor immune responses.
    Yanjun Yang, Fangman Chen, Ning Xu, Qichao Yao, Ran Wang, Xiaochun Xie, Fan Zhang, Yan He, Dan Shao, Wen-Fei Dong, Jiangli Fan, Wen Sun, Xiaojun Peng.
      Although chemo-photodynamic therapy demonstrates promising synergetic therapeutic effects in malignant tumors, the light-controlled drug release, synergism and biocompatibility of current nanocarriers are limited. Herein, we report a red light-responsive, self-destructive carrier constructed using polyethylene glycol-modified, diselenide-bridged mesoporous silica nanoparticles. The carrier is co-encapsulated with the chemo-drug doxorubicin and the photosensitizer methylene blue for chemo-photodynamic therapy. Upon low-dose red light irradiation during photodynamic therapy (PDT), the reactive oxygen species (ROS) mediates a diselenide bond cleavage resulting in the degradation of the organosilica matrix and a dual drug release. This, in turn, results in a synergistic chemo-photodynamic performance in vitro and in vivo. More importantly, such cascade chemo-PDT boosts immunogenic cell death and robust anti-tumor immunity responses. Combination with a PD-1 checkpoint blockade further evokes a series of systemic immunity responses that suppress distant tumor growth and the pulmonary metastasis of breast cancer, as well as offer long-term protection against recurrent tumors. The presented work offers a controllable self-destruction nanoplatform for cascade-amplifying chemo-photodynamic therapy in response to external red light radiation.
    Keywords:  Chemo-photodynamic therapy; Degradation; Immunotherapy; Light-responsive; Mesoporous silica nanoparticles
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121368
  104. ACS Appl Bio Mater. 2020 Nov 16. 3(11): 7989-7999
    Biodegradable Hollow Manganese Silicate Nanocomposites to Alleviate Tumor Hypoxia toward Enhanced Photodynamic Therapy.
    Md Nafiujjaman, Seock-Jin Chung, Irina Kalashnikova, Meghan L Hill, Silver Homa, Jeron George, Christopher H Contag, Taeho Kim.
      Photodynamic therapy (PDT) has been extensively explored as a minimally invasive treatment strategy for malignant cancers. It works with the help of a photosensitizer located within cancer cells that is irradiated by near-infrared light to produce potent toxins and singlet oxygen (1O2) and induce cell death. However, reactive oxygen species can be overexpressed in tumor tissue because of the rapid metabolic activity in cancer cells, and the insufficient oxygenation (hypoxia) can lead to low production of singlet oxygen (1O2) during PDT. In this study, we developed nanocomposites composed of a hollow manganese silicate (HMnOSi) nanoparticle and a photosensitizer (Ce6) that can generate significant amounts of O2 to relieve tumor hypoxia and enhance the therapeutic efficacy of PDT. Our nanocomposites were characterized by UV-vis, fluorescence spectroscopy, transmission electron microscopy (TEM), energy-dispersive X-ray, and dynamic light scattering. Our particles' hollow mesoporous structures were shown to retain large amounts of Ce6 on the particle surface with high loading capacity (33%). TEM imaging showed that the nanoparticles could be biodegradable over time in simulated body fluid, which can imply clinical potentials. Significant H2O2 quenching capabilities to alleviate hypoxic conditions in a solid tumor were also presented. For breast cancer cells, the nanocomposite-treated group revealed that 91% of cells were dead under laser activation compared to 51% for the control group (free Ce6). In an animal study, our nanocomposites showed almost fourfold tumor growth inhibition versus the control and more than twofold over free Ce6 in orthotopic tumor xenografts. In addition, the oxygen saturation contrast inside tumors was evaluated by photoacoustic imaging to demonstrate the alleviated hypoxia in vivo. Our works provide a smart nanosystem to ameliorate the hypoxic tumor microenvironment and augment the efficacy of PDT in a targeted cancer treatment.
    Keywords:  biodegradable; hypoxia; in vivo; nanocomposites; photoacoustic imaging; photodynamic therapy
    DOI:  https://doi.org/10.1021/acsabm.0c01079
  105. ACS Appl Bio Mater. 2021 Apr 19. 4(4): 3670-3685
    Reprogramming Cancer Stem-like Cells with Nanoforskolin Enhances the Efficacy of Paclitaxel in Targeting Breast Cancer.
    Deepika Singh, Priya Singh, Arpan Pradhan, Rohit Srivastava, Sanjeeb Kumar Sahoo.
      Cancer stem-like cells (CSCs) have emerged as an important target for breast cancer therapy owing to their self-renewability, proliferation, and elevated chemoresistance properties. Here, we present a strategy of eliminating CSCs by differentiation therapy where "forced differentiation" reprograms CSCs so that they lose their intrinsic properties and become susceptible for conventional chemotherapeutic drugs. In this study, we report that a conventional chemotherapeutic paclitaxel enhances the stemness of CSCs, while a phytochemical forskolin being essentially nontoxic to CSCs possesses the intrinsic ability to reprogram them. To achieve simultaneous targeting of CSCs and bulk tumor cells, we used a co-delivery system where liquid crystal nanoparticles (LCN) were co-encapsulated with both paclitaxel and forskolin. LCN showed higher uptake, retention, and penetration potential in CSCs overcoming their high drug efflux property. Moreover, LCN improved the pharmacokinetic parameters of forskolin, which otherwise had very low retention and bioavailability. Forskolin-loaded LCN forced CSCs to exit from their mesenchymal state, which reduced their stemness and chemosensitized them while inhibiting E-cadherin-mediated survival and tumor-initiating potential as well as reversing paclitaxel-induced stemness. We further showed that upon administration of paclitaxel and forskolin co-loaded LCN to an orthotropic xenograft mouse model, the nanomedicine showed enhanced passive tumor targeting capability with very potent antitumor activity that eradicated small solid tumor in a single dose and showed no sign of tumor relapse or systemic toxicity over a long period. Overall, these findings give a proof of concept that co-delivery of forskolin and paclitaxel in a single nanoformulation can achieve overall tumor targeting where forskolin can efficiently reprogram/differentiate CSCs and paclitaxel can induce cytotoxicity in both differentiated CSCs and bulk tumor cells simultaneously. Hence, this study can provide a nanoformulation that can offer an efficient strategy for cancer therapy.
    Keywords:  breast cancer; cancer stem cells; chemotherapy; forskolin; liquid crystal nanoparticles; nanomedicine; passive targeting
    DOI:  https://doi.org/10.1021/acsabm.1c00141
  106. Nanomaterials (Basel). 2022 Jan 05. pii: 175. [Epub ahead of print]12(1):
    Advances in Polyhydroxyalkanoate Nanocarriers for Effective Drug Delivery: An Overview and Challenges.
    Priyanka Prakash, Wing-Hin Lee, Ching-Yee Loo, Hau Seung Jeremy Wong, Thaigarajan Parumasivam.
      Polyhydroxyalkanoates (PHAs) are natural polymers produced under specific conditions by certain organisms, primarily bacteria, as a source of energy. These up-and-coming bioplastics are an undeniable asset in enhancing the effectiveness of drug delivery systems, which demand characteristics like non-immunogenicity, a sustained and controlled drug release, targeted delivery, as well as a high drug loading capacity. Given their biocompatibility, biodegradability, modifiability, and compatibility with hydrophobic drugs, PHAs often provide a superior alternative to free drug therapy or treatments using other polymeric nanocarriers. The many formulation methods of existing PHA nanocarriers, such as emulsion solvent evaporation, nanoprecipitation, dialysis, and in situ polymerization, are explained in this review. Due to their flexibility that allows for a vessel tailormade to its intended application, PHA nanocarriers have found their place in diverse therapy options like anticancer and anti-infective treatments, which are among the applications of PHA nanocarriers discussed in this article. Despite their many positive attributes, the advancement of PHA nanocarriers to clinical trials of drug delivery applications has been stunted due to the polymers' natural hydrophobicity, controversial production materials, and high production costs, among others. These challenges are explored in this review, alongside their existing solutions and alternatives.
    Keywords:  challenges; drug delivery; nanocarrier; nanotechnology; polyhydroxyalkanoates
    DOI:  https://doi.org/10.3390/nano12010175
  107. Ther Innov Regul Sci. 2022 Jan 13.
    Anti-lung Cancer Marine Compounds: A Review.
    Mohammad Reza Miri, Afshin Zare, Jamileh Saberzadeh, Neda Baghban, Iraj Nabipour, Amin Tamadon.
      Lung cancer is one of the most common and lethal cancers in human beings. Lung cancer has been divided into two major types: small cell lung cancer (SCLC) and non-small cell lung carcinoma (NSCLC). Current drugs suffer from various side effects, and the insufficient efficacy of present treatments creates a desire for better more efficient new drugs. This review compares the diversity of marine-derived bioactive compounds from different marine species. Some of the natural products from marine resources are in different stages of clinical trials. By the way, most of them have been studied in vitro and in vivo. Additionally, in this review, the mechanisms of action of marine-derived anti-lung cancer components on lung cancer cell lines have been reviewed. In addition, considering growing rate and the high costs of cancer research, attention must be paid to some aspects of targeting and developing anti-lung cancer drug. In better words, like the other therapeutic strategies that have their particular challenges and weak points, several challenges about marine-derived anti-lung cancer components which exist for scientists for doing research are explained. Moreover, as the attentions in the field of cancer therapy are focused on designing and developing new anticancer strategies for the treatment of cancer in the future, the application of marine-derived anti-lung cancer components in the field of future cancer therapy and their role in future anticancer strategies are briefly discussed.
    Keywords:  Anticancer compounds; Lung cancer; Natural products
    DOI:  https://doi.org/10.1007/s43441-022-00375-3
  108. Bioorg Chem. 2022 Jan 07. pii: S0045-2068(22)00004-9. [Epub ahead of print]120 105599
    Structural modification and strategies for the enhanced doxorubicin drug delivery.
    Shah Alam Khan, Md Jawaid Akhtar.
      Doxorubicin belongs to the anthracycline chemical class of the drug and is one of the widely used anticancer drugs. The common side effects of doxorubicin include vomiting, hair loss, rashes to serious side-effects such as irreversible cardiotoxicity, and drug-induced leukemia. This led many researchers around the globe to develop methods aimed to achieve higher efficacy and lower toxicity for doxorubicin. The present review article provides a detailed account of the design strategies i.e., chemical modifications and conjugate formation adopted by various research groups to minimize the side effects without compromising with the significant anticancer profile of the drug doxorubicin. Chemical modification of the drug includes alteration at C4' hydroxyl and C3' amine groups present in the sugar part. The pH-sensitive drug delivery system is covered highlighting use of theranostic tantalum oxide to the traditional approach of conjugating with acyl hydrazine and thiourea. Methods adopted to increase the bioavailability of the drugs inside the cancer cells viz., conjugation with humanized monoclonal antibody and other peptides along with their promising results are also discussed. The review further discusses works from recent years comprising of different nanoforms of doxorubicin for the targeted delivery of drugs inside the tumor cells. Few of the articles targeting nucleus or mitochondria as one of the effective cancer treatments are reported. The brain is inaccessible to the drug and it was modified through galactoxyloglucan-modified gold nanocarrier or conjugated with lactoferrin with enhanced permeability through the blood-brain barrier. Prodrug has particularly been used to target tumor tissues without affecting other tissue organs. The present review article offer clear advantages of one method over another adopted to target the cancer cells and may provide an insight for the researchers working in this area.
    Keywords:  Doxorubicin; Nanoparticles; Peptides; Prodrug; Sialylation; Target drug delivery
    DOI:  https://doi.org/10.1016/j.bioorg.2022.105599
  109. Materials (Basel). 2021 Dec 25. pii: 138. [Epub ahead of print]15(1):
    Reactive Oxygen Species-Sensitive Nanophotosensitizers of Methoxy Poly(ethylene glycol)-Chlorin e6/Phenyl Boronic Acid Pinacol Ester Conjugates Having Diselenide Linkages for Photodynamic Therapy of Cervical Cancer Cells.
    Ju-Il Yang, Hye-Lim Lee, Seon-Hee Choi, Jungsoo Kim, Young-Bob Yu, Young-Il Jeong, Dae-Hwan Kang.
      The aim of this study is to fabricate nanophotosensitizers composed of methoxy poly(ethylene glycol) (mPEG), chlorin e6 (Ce6), and phenylboronic acid pinacol ester (PBAP) with diselenide linkages for reactive oxygen species (ROS)-sensitive photodynamic therapy (PDT) of cervical cancer cells. To fabricate nanophotosensitizers, Ce6 was conjugated with mPEG via selenocystamine linkage and then remaining carboxylic acid groups of Ce6 was attached to PBAP (mPEGseseCe6PBAP conjugates). Nanophotosensitizers of mPEGseseCe6PBAP conjugates were prepared by dialysis method. In transmission electron microscope (TEM) observation, nanophotosensitizers of mPEGseseCe6PBAP conjugates have spherical shapes and their diameters were less than 150 nm. The average diameter of mPEGseseCe6PBAP nanophotosensitizers was 92.7 ± 9.6 nm in particle size analysis. When H2O2 was added to the nanophotosensitizer solution, nanophotosensitizers were sensitively disintegrated according to the H2O2 concentration and then changed from monomodal distribution to multimodal distribution in particle size distribution. Furthermore, Ce6 release from nanophotosensitizers also increased according to the H2O2 concentration. When H2O2 was added to cell culture of HeLa human cervical cancer cells, intracellular Ce6 uptake of nanophotosensitizers were gradually increased according to the H2O2 concentration, indicating that nanophotosensitizers showed ROS-sensitive delivery of Ce6 against cancer cells.As well as free Ce6, nanophotosensitizers in the absence of light irradiation have low intrinsic cytotoxicity against RAW264.7 cells and HeLa cells. However, nanophotosensitizers induced cell death dose-dependently under light irradiation. Especially, nanophotosensitizers showed significantly higher ROS generation and phototoxicity against HeLa cells in vitro. When nanophotosensitizers were intravenously administered to animal tumor xenograft model of HeLa cells, tumor tissues revealed stronger fluorescence intensity than other tissues by light irradiation while absence of light irradiation induced relatively lower fluorescence intensity in tumor tissues, indicating that nanophotosensitizers have sensitivity against oxidative stress in tumor tissues. We suggest that nanophotosensitizers of mPEGseseCe6PBAP conjugates are promising vehicle for PDT of cervical cancer cells.
    Keywords:  ROS-sensitive; cervical cancer; chlorin e6; nanophotosensitizer; photodynamic therapy
    DOI:  https://doi.org/10.3390/ma15010138
  110. ACS Appl Bio Mater. 2020 Feb 17. 3(2): 1216-1225
    Fabrication of a pH/Redox-Triggered Mesoporous Silica-Based Nanoparticle with Microfluidics for Anticancer Drugs Doxorubicin and Paclitaxel Codelivery.
    Jiaqi Yan, Xiaoyu Xu, Junnian Zhou, Chang Liu, Lirong Zhang, Dongqing Wang, Fan Yang, Hongbo Zhang.
      A pH/redox-triggered mesoporous silica nanoparticle (MSN)-based nanoplatform has been fabricated for doxorubicin/paclitaxel (DOX/PTX) codelivery. In this drug-delivery system (DDS), PTX is covalently attached to the surface of DOX loaded MSN via a linker with disulfide bond. By directly attaching PTX to MSN, we can significantly enhance the PTX́s loading degree and achieve the optimum drug loading ratio to DOX, therefore, to generate the best synergistical effect. More importantly, PTX and the linker act as a redox-sensitive "gate" to precisely control the release profile of DOX and PTX. Subsequently, polystyrenesulfonate (PSS) is electrostatically coated to DOX loaded MSN-PTX in microfluidics to achieve acidic pH responsive, because the free amino group on MSN surface has a protonation state at acidic pH, and the electrostatic interaction will be destroyed at pH 5. In addition, PSS can also neutralize the surface zeta potential, thus reduce the nonspecific endocytosis of healthy cells. By evaluating cell viability in cancer cell BT549 and healthy breast cell MCF-10A, we observed that the nanoparticles can selectively release DOX and PTX and eliminate cancer cells, while they will have negligible effect on the healthy breast cells, due to the acidic and redox microenvironment in cancer cells. Overall, we have developed a nanoplatform for precise DOX/PTX combination therapy with high selectivity between cancer cells and healthy cells.
    Keywords:  combination therapy; doxorubicin; mesoporous silica nanoparticles; microfluidic technology; pH/redox-triggered release; paclitaxel
    DOI:  https://doi.org/10.1021/acsabm.9b01111
  111. J Cancer Res Clin Oncol. 2022 Jan 15.
    Targeting PGC1α to wrestle cancer: a compelling therapeutic opportunity.
    Xiangyu Sun, Xiaoyan Liu, Keda Yu, Shouping Xu, Pengfei Qiu, Zhidong Lv, Xinwen Zhang, Yingying Xu.
      Metabolic adaptation is an emerging hallmark of cancer, as it provides tumor cells sufficient energy and metabolic intermediates. Although tumor cells are believed to highly rely on Warburg effect to satisfy their energy demand, more studies have pointed out that various types of tumor cells are highly dependent on oxidative phosphorylation to drive the tumorigenesis. Peroxisome proliferator-activated receptor-c coactivator 1α (PGC1α), the crucial member of PGC1 family, is aberrantly expressed in several cancer types, implicating its role in tumor proliferation, migration, invasion, metastasis, and chemoresistance. Numerous studies have reported that PGC1α participates in the regulation of tumor development by altering the transcriptional programs as well as the metabolic phenotypes. Thus, PGC1α-targeted therapy is therapeutically exploitable to target the metabolic vulnerabilities in tumor cells. This review mainly focuses on the current underlying mechanisms for its roles in regulating metabolic adaptation of tumor cells and its upstream regulators; how PGC1α participates in the regulation of the tumor proliferation, migration, invasion, metastasis, therapy resistance; and the feasibility of PGC1α-targeted therapy for cancer treatment.
    Keywords:  Metabolic reprogramming; Metastasis; Oxidative phosphorylation; PGC1α; Proliferation
    DOI:  https://doi.org/10.1007/s00432-021-03912-z
  112. ACS Appl Bio Mater. 2020 Nov 16. 3(11): 7789-7799
    Doxorubicin and Crocin Co-delivery by Polymeric Nanoparticles for Enhanced Anticancer Potential In Vitro and In Vivo.
    Iliyas Khan, Gaurav Joshi, Bibekananda Sarkar, Kartik T Nakhate, Ajazuddin, Anil K Mantha, Raj Kumar, Ankur Kaul, Shubhra Chaturvedi, Anil K Mishra, Umesh Gupta.
      Development of a biodegradable nanoplatform poly(lactic-co-glycolic acid) (PLGA) for co-delivery of two drugs is hugely imperative and beneficial in anticancer therapeutics. In this study, co-delivery of a natural phytoconstituent, crocin (carotenoid), and a commonly prescribed drug, doxorubicin, was attempted using a nanoparticulate platform in the form of PLGA nanoparticles. Doxorubicin was chemically conjugated, while crocin was encapsulated physically in prepared PLGA nanoparticles (PDCR NPs). Prepared NPs were well-characterized for size, ζ, and surface morphology. PDCR NPs were of 174.2 ± 1.57 nm in size. The transmission electron microscopy (TEM) and atomic force microscopy (AFM) images revealed the spherical shape and smooth surface morphology of the nanoparticles, respectively. The entrapment efficiency and drug loading were found to be 58.95 ± 2.58 and 13.89 ± 1.09%, respectively. The drug release pattern of PDCR NPs showed a sustained and controlled release pattern throughout 48 h in PBS buffer pH 7.4 and acetate buffer pH 6.5. PDCR NPs were significantly less hemolytic than doxorubicin (p < 0.0001). Investigational formulation selectively produced cytotoxic effects on breast cancer cells via decreasing reactive oxygen species (ROS) and altering the mitochondrial potential that led to apoptosis with cell-cycle arrest at the G2/M phase. Prepared NPs were able to upregulate the caspase levels as well as efficient uptake by cells in a time-dependent manner. In vivo plasma drug profile studies in healthy rats revealed prolonged persistence of crocin and doxorubicin in systemic circulation. Additionally, the PDCR NPs portrayed reduced tumor volume as compared to control groups in the tumor-induced animal studies, which were favorable. Conclusively, the co-delivery of natural anticancer bioactive crocin along with doxorubicin in PDCR NPs provides a possible controlled-release nanoplatform for efficient drug delivery in vitro and in vivo.
    Keywords:  PLGA; co-delivery; crocin; doxorubicin; drug delivery; nanoparticles
    DOI:  https://doi.org/10.1021/acsabm.0c00974
  113. Curr Top Med Chem. 2022 Jan 11.
    A medicinal chemist's perspective towards structure activity relationship of heterocycle based anti-cancer agents.
    Bhupender Nehra, Bijo Mathew, Pooja A Chawla.
       AIM: To describe structure activity relationship of heterocyclic derivatives with multi-targeted anticancer activity.
    OBJECTIVES: With the following goals in mind, this review tries to describe significant recent advances in the medicinal chemistry of heterocycle-based compounds: (1) To shed light on recent literature focused on heterocyclic derivatives' anticancer potential; (2) To discuss recent advances in the medicinal chemistry of heterocyclic derivatives, as well as their biological implications for cancer eradication; (3) To summarise the comprehensive correlation of structure activity relationship (SAR) with pharmacological outcomes in cancer therapy.
    BACKGROUND: Cancer remains one of the major serious health issues devastating the world today. Cancer is a complex disease in which improperly altered cells proliferate at an uncontrolled, rapid, and severe rate. Variables such as poor dietary habits, high stress, age, and smoking, can all contribute to the development of cancer. Cancer can affect almost any organ or tissue, although the brain, breast, liver, and colon are the most frequently affected organs. From several years, surgical operations and irradiation are in use along with chemotherapy as a primary treatment of cancer but still effective treatment of cancer remains a huge challenge. Chemotherapy is now one of the most effective strategies to eradicate cancer, although it has been shown to have a number of cytotoxic and unfavourable effects on normal cells. Despite all of these cancer treatments, there are several other targets for anticancer drugs. Cancer can be effectively eradicated by focusing on these targets, which include both cell-specific and receptor-specific targets such as tyrosine kinase receptors (TKIs). Heterocyclic scaffolds also have a variety of applications in drug development and are a common moiety in the pharmaceutical, agrochemical, and textile industries.
    METHODS: The association between structural activity relationship data of many powerful compounds and their anticancer potential in vitro and in vivo has been studied. SAR of powerful heterocyclic compounds can also be generated using molecular docking simulations, as reported vastly in literature.
    CONCLUSIONS: Heterocycles have a wide range of applications, from natural compounds to synthesised derivatives with powerful anticancer properties. To avoid cytotoxicity or unfavourable effects on normal mammalian cells due to a lack of selectivity towards the target site, as well as to reduce the occurrence of drug resistance, safer anticancer lead compounds with higher potency and lower cytotoxicity are needed. This review emphasizes on design and development of heterocyclic lead compounds with promising anticancer potential.
    Keywords:  Anticancer; Cytotoxicity; Docking studies; Heterocycles; SAR; mammalian cells
    DOI:  https://doi.org/10.2174/1568026622666220111142617
  114. Front Cell Dev Biol. 2021 ;9 793428
    Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer.
    Miaomiao Huo, Jingyao Zhang, Wei Huang, Yan Wang.
      Epigenetic modifications and metabolism are two fundamental biological processes. During tumorigenesis and cancer development both epigenetic and metabolic alterations occur and are often intertwined together. Epigenetic modifications contribute to metabolic reprogramming by modifying the transcriptional regulation of metabolic enzymes, which is crucial for glucose metabolism, lipid metabolism, and amino acid metabolism. Metabolites provide substrates for epigenetic modifications, including histone modification (methylation, acetylation, and phosphorylation), DNA and RNA methylation and non-coding RNAs. Simultaneously, some metabolites can also serve as substrates for nonhistone post-translational modifications that have an impact on the development of tumors. And metabolic enzymes also regulate epigenetic modifications independent of their metabolites. In addition, metabolites produced by gut microbiota influence host metabolism. Understanding the crosstalk among metabolism, epigenetic modifications, and gene expression in cancer may help researchers explore the mechanisms of carcinogenesis and progression to metastasis, thereby provide strategies for the prevention and therapy of cancer. In this review, we summarize the progress in the understanding of the interactions between cancer metabolism and epigenetics.
    Keywords:  clinical trails; epigenetic modifications; gut microbiota; metabolic enzymes; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fcell.2021.793428
  115. Molecules. 2021 Dec 22. pii: 48. [Epub ahead of print]27(1):
    Hyaluronic Acid-Conjugated Carbon Nanomaterials for Enhanced Tumour Targeting Ability.
    Oisin Kearns, Adalberto Camisasca, Silvia Giordani.
      Hyaluronic acid (HA) has been implemented for chemo and photothermal therapy to target tumour cells overexpressing the CD44+ receptor. HA-targeting hybrid systems allows carbon nanomaterial (CNM) carriers to efficiently deliver anticancer drugs, such as doxorubicin and gemcitabine, to the tumour sites. Carbon nanotubes (CNTs), graphene, graphene oxide (GO), and graphene quantum dots (GQDs) are grouped for a detailed review of the novel nanocomposites for cancer therapy. Some CNMs proved to be more successful than others in terms of stability and effectiveness at removing relative tumour volume. While the literature has been focused primarily on the CNTs and GO, other CNMs such as carbon nano-onions (CNOs) proved quite promising for targeted drug delivery using HA. Near-infrared laser photoablation is also reviewed as a primary method of cancer therapy-it can be used alone or in conjunction with chemotherapy to achieve promising chemo-photothermal therapy protocols. This review aims to give a background into HA and why it is a successful cancer-targeting component of current CNM-based drug delivery systems.
    Keywords:  carbon nanomaterial; carbon nanotube; drug delivery; graphene; graphene oxide; graphene quantum dot; hyaluronic acid
    DOI:  https://doi.org/10.3390/molecules27010048
  116. ACS Appl Bio Mater. 2021 Jun 21. 4(6): 4862-4871
    Folic Acid-Conjugated Gold Nanostars for Computed Tomography Imaging and Photothermal/Radiation Combined Therapy.
    Ping Hu, Xu Hou, Xiaojun Yu, Xuguo Wei, Yang Li, Dawei Yang, Xiaohong Jiang.
      Fabrication of multifunctional nanoprobes, which integrate tumor targeting, imaging, and effective treatment, has been widely explored in nanomedicine. In the present study, we fabricated tumor-targeting polymer folic acid-terminated polyethylene glycol thiol-modified gold nanostars (GNS-FA), which could realize X-ray computed tomography (CT) imaging and PTT/RT synergistic therapy. The synthesized GNS-FA exhibited good biocompatibility. GNS-FA could be used as a CT imaging contrast agent due to the strong X-ray attenuation of Au. GNS-FA exhibited good near-infrared (NIR) light absorption and excellent photothermal conversion performance, making them promising photothermal transduction agents (PTAs). Furthermore, GNS-FA could be used as an RT sensitizer to enhance the radio-mediated cell death due to the high atomic number (high Z) of gold. Hence, GNS-FA were used as the CT imaging agent, PTA, and radiosensitizer in this work. The in vitro antitumor experiments showed that the PTT/RT combined treatment had enhanced anticancer efficacy compared with the monotherapy (PTT or RT). Our results indicated that the bioconjugated GNS could offer an excellent nanoplatform for CT imaging-guided PTT/RT combined cancer therapy in the future.
    Keywords:  CT imaging; folic acid; gold nanostars; photothermal therapy; radiotherapy
    DOI:  https://doi.org/10.1021/acsabm.1c00171
  117. ACS Appl Bio Mater. 2021 Apr 19. 4(4): 3232-3245
    Traceable Nanocluster-Prodrug Conjugate for Chemo-photodynamic Combinatorial Therapy of Non-small Cell Lung Cancer.
    Yuvasri Genji Srinivasulu, Anbu Mozhi, Nirmal Goswami, Qiaofeng Yao, Jianping Xie.
      In cancer treatment, image-guided combinatorial therapy is usually a more promising approach than conventional therapy because it may overcome the drawbacks of conventional cancer treatment, such as tumor recurrence and multidrug resistance. To achieve a high therapeutic effect in image-guided combinatorial therapy, the therapeutic material should be traceable, biocompatible, and yet highly effective in eradicating tumors. For this purpose, we developed a traceable nanocarrier consisting of atomically precise gold nanoclusters (Au NCs, Au22(SG)18, abbreviated as Au22 NCs, where SG stands for glutathione) and a biopolymer (i.e., chitosan). This traceable nanocarrier (Chito-Au22) was then combined with dual prodrugs (i.e., chemotherapeutic platinum (Pt(IV)) prodrug and photodynamic aminolevulinic acid (ALA) prodrug) through a bioconjugation method. It was found that the final nanocomposite (abbreviated as Pt(IV)-ALA-Chito-Au22) has a pH-responsive drug release behavior, and the cumulative drug release can exceed 50% within 12 h at an acidic pH of 5.0. After 15 min of white light irradiation, the nanocomposite showed a synergistic killing effect on the A549 non-small cell lung carcinoma cell line. The Pt(IV)-ALA-Chito-Au22 nanocomposite also showed a high cellular uptake capacity and reactive oxygen species (ROS) generation capability, resulting in a significant killing effect on three-dimensional (3D) multicellular A549 spheroids. In the presence of light, the volume of the multicellular spheroids treated by our nanocomposites was reduced more than two times compared with those treated by a single prodrug/component. The nanocomposite also showed good cell viability on normal lung cell lines. The multifunctional nanocomposites developed in this study have broad prospects in both therapeutic and diagnostic applications.
    Keywords:  2D monolayer cells; 3D multicellular spheroids (MCs); AIE-type Au22 NCs; ALA prodrug; Pt(IV) prodrug; chitosan; combinatorial therapy; traceable nanocarrier
    DOI:  https://doi.org/10.1021/acsabm.0c01611
  118. ACS Appl Bio Mater. 2021 May 17. 4(5): 4413-4421
    Zeolitic Imidazolate Framework Platform for Combinational Starvation Therapy and Oxygen Self-Sufficient Photodynamic Therapy against a Hypoxia Tumor.
    Yingjie Ouyang, Peng Wang, Baoxuan Huang, Guoliang Yang, Jia Tian, Weian Zhang.
      The antitumor efficacy of photodynamic therapy (PDT) is greatly impeded by the nonspecific targeting of photosensitizers and limited oxygen supply in hypoxic tumors. Aiming to overcome the problem, a dual-locked porphyrin/enzyme-loading zeolitic imidazolate framework (ZIF) nanoplatform was constructed for starvation therapy and O2 self-sufficient PDT. The fluorescence recovery and PDT of photosensitizers could be cooperatively triggered by dual pathological parameters, the low pH and overexpressed GSH in tumor tissues, which makes the PDT process conduct precisely in a tumor microenvironment. The cascade catalysis of glucose oxidase and catalase promotes the nanoplatform dissociation, inhibits the energy supply of tumors (starvation therapy), and provides enough O2 to ameliorate the hypoxia and enhance PDT efficacy. In vitro and in vivo studies were performed to confirm the high antitumor efficacy of the porphyrin/enzyme-loading ZIF nanoplatform. Thus, this work offers a path for precise and efficient PDT-based combination therapy against a hypoxia tumor.
    Keywords:  enzymes; hypoxia tumor; photodynamic therapy; porphyrin; stimuli-responsiveness; zeolitic imidazolate framework
    DOI:  https://doi.org/10.1021/acsabm.1c00174
  119. ACS Appl Bio Mater. 2021 Jun 21. 4(6): 5231-5239
    Highly Efficient Near-Infrared Photosensitizers with Aggregation-Induced Emission Characteristics: Rational Molecular Design and Photodynamic Cancer Cell Ablation.
    Dugang Chen, Zi Long, Cheng Zhong, Li Chen, Yecheng Dang, Jing-Jing Hu, Xiaoding Lou, Fan Xia.
      Photosensitizers (PSs) that play a decisive role in effective photodynamic therapy (PDT) have attracted great research interest. PSs with aggregation-induced emission (AIE) characteristics could overcome the deficiencies of traditional PSs that usually suffer from the aggregation-caused fluorescence quenching (ACQ) effect in applications and show enhanced emission and high singlet oxygen (1O2) generation efficiency in aggregates; therefore, they are outstanding candidates for imaging-guided PDT, and the development of AIE PSs with both excellent photophysical properties and 1O2 generation ability is highly desirable. Herein, three AIE fluorogens (AIEgens), BtM, ThM, and NaM, with a donor-π-acceptor (D-π-A) structure were designed and synthesized, and the photosensitizing ability was adjusted by π-linker engineering. All of the three AIEgens showed excellent photostability and high molar absorption coefficients, and their emission edges were extended to the near-infrared (NIR) region, with peaks at 681, 678, and 638 nm, respectively. NaM demonstrated the smallest ΔES1-T1, which was ascribed to its better separation degree of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). The AIEgens were fabricated into nanoparticles (NPs) by amphipathic mPEG3000-DSPE encapsulating, and thus the obtained NaM NPs exhibited the best 1O2 generation efficiency under white light irradiation, which was almost 3 times that of the renowned PS rose bengal (RB). Furthermore, under white light irradiation, the cell killing efficiency of NaM NPs was also much better than those of the other two AIE PSs and RB. Therefore, NaM NPs revealed great potential to treat superficial diseases as a PS for PDT.
    Keywords:  aggregation-induced emission; near-infrared; photodynamic; photosensitizer; singlet oxygen
    DOI:  https://doi.org/10.1021/acsabm.1c00398
  120. Bioconjug Chem. 2022 Jan 11.
    Vitamin-H Channeled Self-Therapeutic P-gp Inhibitor Curcumin-Derived Nanomicelles for Targeting the Tumor Milieu by pH- and Enzyme-Triggered Hierarchical Disassembly.
    Manita Das, Apeksha Joshi, Ranjitsinh Devkar, Sriram Seshadri, Sonal Thakore.
      An effective nanocarrier-mediated drug delivery to cancer cells primarily faces limitations like the presence of successive drug delivery barriers, insufficient circulation time, drug leakage, and decreased tumor penetration capacity. With the aim of addressing this paradox, a self-therapeutic, curcumin-derived copolymer was synthesized by conjugation with PEGylated biotin via enzyme- and acid-labile ester and acetal linkages. This copolymer is a prodrug of curcumin and self-assembles into ∼150-200 nm-sized nanomicelles; it is capable of encapsulating doxorubicin (DOX) and hence can be designated as self-therapeutic. pH- and enzyme-responsive linkages in the polymer skeleton assist in its hierarchical disassembly only in the tumor microenvironment. Further, the conjugation of biotin and poly(ethylene glycol) (PEG) imparts features of tumor specificity and improved circulation times to the nanocarrier. The dynamic light scattering (DLS) analysis supports this claim and demonstrates rapid swelling and disruption of micelles under acidic pH. UV-vis spectroscopy provided evidence of an accelerated acetal degradation at pH 4.0 and 5.0. The in vitro release studies revealed a controlled release of DOX under acidic conditions and curcumin release in response to the enzyme. The value of the combination index calculated on HepG2 cells was found to be <1, and hence, the drug pair curcumin and DOX acts synergistically for tumor regression. To prove the efficiency of acid-labile linkages and the prodrug strategy for effective cancer therapy, curcumin-derived polymers devoid of sensitive linkages were also prepared. The prodrug stimuli-responsive nanomicelles showed enhanced cell cytotoxicity and tumor penetration capability on HepG2 cells as well as drug-resistant MCF-7 cell lines and no effect on normal NIH/3T3 fibroblasts as compared to the nonresponsive micelles. The results were also supported by in vivo evidence on a hepatocellular carcinoma (HCC)-induced nude mice model. An evident decrease in MMP-2, MMP-9, and α-fetoprotein (AFP), the biomarkers specific to tumor progression, was observed along with metastasis upon treatment with the drug-loaded dual-responsive nanomicelles. These observations corroborated with the SGOT and SGPT data as well as the histoarchitecture of the liver tissue in mice.
    DOI:  https://doi.org/10.1021/acs.bioconjchem.1c00614
  121. Int J Nanomedicine. 2022 ;17 105-123
    RNA-Seq Explores the Mechanism of Oxygen-Boosted Sonodynamic Therapy Based on All-in-One Nanobubbles to Enhance Ferroptosis for the Treatment of HCC.
    Yichi Chen, Haitao Shang, Chunyue Wang, Jiaqi Zeng, Shentao Zhang, Bolin Wu, Wen Cheng.
       Background: The combination of sonodynamic therapy and oxygenation strategy is widely used in cancer treatment. However, due to the complexity, heterogeneity and irreversible hypoxic environment produced by hepatocellular carcinoma (HCC) tissues, oxygen-enhancing sonodynamic therapy (SDT) has failed to achieve the desired results. With the emergence of ferroptosis with reactive oxygen species (ROS) cytotoxicity, this novel cell death method has attracted widespread attention.
    Methods: In this study, nanobubbles (NBs) were connected with the sonosensitizer Indocyanine green (ICG) to construct a 2-in-1 nanoplatform loaded with RAS-selective lethal (RSL3, ferroptosis promoter) (RSL3@O2-ICG NBs), combined with oxygen-enhanced SDT and potent ferroptosis. In addition, nanobubbles (NBs) combined with low-frequency ultrasound (LFUS) are called ultrasound-targeted nanobubble destruction (UTND) to ensure specific drug release and improve safety.
    Results: MDA/GSH and other related experimental results show that RSL3@O2-ICG NBs can enhance SDT and ferroptosis. Through RNA sequencing (RNA-seq), the differential expression of LncRNA and mRNA before and after synergistic treatment was identified, and then GO and KEGG pathways were used to enrich and analyze target genes and pathways related ferroptosis sensitivity. We found that they were significantly enriched in the ferroptosis-related pathway MAPK cascade and cell proliferation. Then, we searched for the expression of differentially expressed genes in the TCGA Hepatocellular carcinoma cohort. At the same time, we evaluated the proportion of immune cell infiltration and the identification of co-expression network modules and related prognostic analysis. We found that it was significantly related to the tumor microenvironment of hepatocellular carcinoma. The prognostic risk genes "SLC37A2" and "ITGB7" may represent new hepatocellular carcinoma ferroptosis-inducing markers and have guiding significance for treating hepatocellular carcinoma.
    Conclusion: The therapeutic effect of the in vitro synergistic treatment has been proven to be significant, revealing the prospect of 2-in-1 nanobubbles combined with SDT and ferroptosis in treating HCC.
    Keywords:  HCC; RSL3; ferroptosis; sonodynamic therapy; synergistic therapy
    DOI:  https://doi.org/10.2147/IJN.S343361
  122. Drug Deliv Transl Res. 2022 Jan 15.
    Synergistic antitumor efficacy of PD-1-conjugated PTX- and ZSQ-loaded nanoliposomes against multidrug-resistant liver cancers.
    Mingjia Gu, Fang Yin, Yuening Qin, Yali Tian, Xinjie Xiu, Hanjing Shen, Jiebin Zhu.
      Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor chemotherapeutic efficiency due to multidrug resistance (MDR); it is very important to develop a targeted nanocarrier for the treatment of HCC. In this study, a programmed death ligand 1 (PD-L1)-conjugated nanoliposome was constructed for co-delivery of paclitaxel (PTX) and P-glycoprotein (P-gp) inhibitor zosuquidar (ZSQ) to overcome MDR in human HCC cells and tumors in vivo. Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were used to examine the nanoparticles morphology and size; PD-1-conjugated PTX and ZSQ-loaded nanoliposomes (PD-PZLP) revealed a spherical shape with a size of 139.5 ± 10.7 nm. Then, the physicochemical properties, as well as the drug loading capacity, release profile, cellular uptake, and cytotoxicity of the dual drug-encapsulated nanoliposomes were characterized. PD-PZLP displayed a high drug loading capacity of 20 ~ 30% for both PTX and ZSQ; the drug release of PTX and ZSQ in pH 5.0 was significantly faster than in pH 7.4. Cellular uptake study demonstrated PD-PZLP had higher internalization efficiency than non-targeted PZLP. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and reactive oxygen species (ROS) analysis demonstrated that PD-PZLP triggered an excessive ROS reaction and cell apoptosis compared with that of free PTX or ZSQ, which was also consistent with the cell antiproliferative effects in MTT assay. Furthermore, PD-PZLP could enhance synergistic antitumor effects on 7721/ADM xenograft tumor model, which also significantly alleviated hepatotoxicity as evident from the decreased aspartate transaminase (AST) and alanine transaminase (ALT) levels. Overall, PD-PZLP exhibited high loading capacity, significant synergistic effects, promising antitumor efficacy, and the lowest toxicity, which provide a promising strategy to overcome MDR in HCC.
    Keywords:  Hepatocellular carcinoma; Multidrug resistance; Nanoliposomes; Paclitaxel; Zosuquidar
    DOI:  https://doi.org/10.1007/s13346-021-01106-1
  123. Neural Regen Res. 2022 Aug;17(8): 1640-1644
    Calorie restriction or dietary restriction: how far they can protect the brain against neurodegenerative diseases?
    Tayana Silva de Carvalho.
      Finding the correct nutritional intervention is one of the biggest challenges in treating patients with neurodegenerative diseases. In general, these patients develop strong metabolic alterations, resulting in lower treatment efficacy and higher mortality rates. However, there are still many open questions regarding the effectiveness of dietary interventions in neurodiseases. Some studies have shown that a reduction in calorie intake activates key pathways that might be important for preventing or slowing down the progression of such diseases. However, it is still unclear whether these neuroprotective effects are associated with an overall reduction in calories (hypocaloric diet) or a specific nutrient restriction (diet restriction). Therefore, here we discuss how commonly or differently hypocaloric and restricted diets modulate signaling pathways and how these changes can protect the brain against neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; diet therapy; dietary intervention; epilepsy; fasting; glucose restriction; hypocaloric diet; multiple sclerosis; stroke
    DOI:  https://doi.org/10.4103/1673-5374.332126
  124. ACS Appl Bio Mater. 2021 Dec 28.
    Cancer-Targeted Chitosan-Biotin-Conjugated Mesoporous Silica Nanoparticles as Carriers of Zinc Complexes to Achieve Enhanced Chemotherapy In Vitro and In Vivo.
    Bidyut Kumar Kundu, Pragti, Wilson Alphonse Carlton Ranjith, Uday Shankar, Rajaretinam Rajesh Kannan, Shaikh M Mobin, Anasuya Bandyopadhyay, Suman Mukhopadhyay.
      Despite being the most common component of numerous metalloenzymes in the human body, zinc complexes are still under-rated as chemotherapeutic agents. Herein, the present study opens up a key route toward enhanced chemotherapy with the help of two ZnII complexes (ZnMBC) synthesized alongside Mannich base ligands to upsurge biological potency. Further, well-established mesoporous silica nanoparticles (MSNs) have been chosen as carriers of the titled metallodrugs in order to achieve anticancer drug delivery. A pH-sensitive additive, namely, chitosan (CTS) conjugated with biotin is tagged to MSNs for the targeted release of core agents inside tumors selectively. In general, CTS blocks ZnMBC inside the mesopores of MSNs, and biotin acts as a targeting ligand to improve tumor-specific cellular uptake. CTS-biotin surface decoration significantly enhanced the cellular uptake of ZnMBC through endocytosis. A panel of four human cancer cell lines has revealed that ZnMBC (1/2)@MSNs-CTS-biotin nanoparticles (NPs) exhibits unprecedented enhanced cytotoxicity toward cancer cells with IC50 values ranging from 6.5 to 28.8 μM through induction of apoptosis. NPs also possess great selectivity between normal and cancer cells despite this potency. Two-photon-excited in vitro imaging of normal (HEK) and cancer (HeLa) cells has been performed to confirm the biased drug delivery. Also, NP-induced apoptosis was found to be dependent on targeting DNA and ROS generation. Moreover, a lower range of LD50 values (153.6-335.5 μM) were observed upon treatment zebrafish embryos with NPs in vivo. Because of the anatomical similarity to the human heart, the heart rate of NP-treated zebrafish has been analyzed in assessing the cardiac functions, which is in favor of the early clinical trials of ZnMBC (1/2)@MSNs-CTS-biotin candidates for their further evaluation as a chemotherapeutic and chemopreventive agent toward human cancers, especially adenocarcinoma.
    Keywords:  chemotherapy; in vivo toxicity; metallodrug; nanocarriers; pH-responsive drug delivery; two-photon
    DOI:  https://doi.org/10.1021/acsabm.1c01041
  125. ACS Appl Bio Mater. 2020 Jun 15. 3(6): 3494-3499
    Conjugated Polymer and Triphenylamine Derivative Codoped Nanoparticles for Photothermal and Photodynamic Antimicrobial Therapy.
    Yuchao Liang, Hongjuan Zhang, Huanxiang Yuan, Wen Lu, Zelin Li, Lei Wang, Li-Hua Gao.
      The photothermal conjugated polymer (DPPT-TT) and a triphenylamine derivative (DPATP-CN) codoped nanoparticles (DDNPs) were designed and prepared via self-assembly. The obtained DDNPs exhibit both efficient and stable photothermal properties and excellent ROS production capability to synergistically achieve photothermal therapy (PTT) and photodynamic therapy (PDT). DDNPs showed antimicrobial activity with more than 70%, 90%, and 99% inhibition ratio, respectively, toward Gram-(-) bacteria (E. coli), Gram-(+) bacteria (S. aureus), and fungi (C. albicans) under combined irradiation of near-infrared light and white light. Therefore, DDNPs are broad-spectrum antimicrobial materials and provide a significant perspective to select an appropriate sterilization strategy for different microorganisms.
    Keywords:  broad-spectrum antimicrobial activity; codoped nanoparticles; conjugated polymer; photodynamic therapy; photothermal therapy
    DOI:  https://doi.org/10.1021/acsabm.0c00320
  126. ACS Appl Bio Mater. 2020 Aug 17. 3(8): 4949-4961
    Folic Acid-Conjugated pH and Redox-Sensitive Ellipsoidal Hybrid Magnetic Nanoparticles for Dual-Triggered Drug Release.
    Gokcen Birlik Demirel, Ebru Aygul, Aydan Dag, Sezen Atasoy, Zeynep Cimen, Busra Cetin.
      Stimuli-sensitive and multifunctional nanoparticles are highly desirable biomedical materials for triggered and targeted drug delivery applications. Here, we have designed pH- and redox-triggered magnetic lipid-polymer hybrid nanoparticles (MHNPs) with a core-shell structure. This design is composed of a silica-/mesoporous silica-coated ellipsoidal magnetic nanoparticle with multifunctionality: carrying the anticancer drug (doxorubicin, DOX), the cancer cell targeting ligand (folic acid-conjugated poly(ethylene glycol), FA-PEG) polymer, and being coated with a biocompatible pH-/redox-responsive (poly-l-histidine-poly(ethylene glycol)-lipoic acid; PLH-PEG-LA) polymer. The lipoic acid units of the PLH-PEG-LA shell of the FA-MHNPs were cross-linked using 1,4-dithiothreitol (DTT). When the FA-MHNPs-DOX were exposed to an endolysosomal pH of 5.5 and 10 mM glutathione (GSH), the particles exhibited a very efficient DOX release profile within 24 h. In addition, cytotoxicity, uptake, and apoptosis assays were performed against breast cancer cell lines. These results showed that FA-MHNPs-DOX promote an enhanced uptake and cell morbidity compared to the nontargeted MHNPs-DOX against tested cell lines. Moreover, the FA-MHNPs-DOX exhibited very effective cytotoxicity and also decreased the cell viability through apoptosis against breast cancer cell lines. In conclusion, it can be said that the pH and redox dual-responsive hybrid FA-MHNPs-DOX has a great potential for controlled drug release.
    Keywords:  core−shell; drug delivery; dual-responsive; magnetic nanoparticles; triggered release
    DOI:  https://doi.org/10.1021/acsabm.0c00488
  127. Cancers (Basel). 2022 Jan 04. pii: 245. [Epub ahead of print]14(1):
    Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives.
    Ruggiero Gorgoglione, Valeria Impedovo, Christopher L Riley, Deborah Fratantonio, Stefano Tiziani, Luigi Palmieri, Vincenza Dolce, Giuseppe Fiermonte.
      Aspartate has a central role in cancer cell metabolism. Aspartate cytosolic availability is crucial for protein and nucleotide biosynthesis as well as for redox homeostasis. Since tumor cells display poor aspartate uptake from the external environment, most of the cellular pool of aspartate derives from mitochondrial catabolism of glutamine. At least four transporters are involved in this metabolic pathway: the glutamine (SLC1A5_var), the aspartate/glutamate (AGC), the aspartate/phosphate (uncoupling protein 2, UCP2), and the glutamate (GC) carriers, the last three belonging to the mitochondrial carrier family (MCF). The loss of one of these transporters causes a paucity of cytosolic aspartate and an arrest of cell proliferation in many different cancer types. The aim of this review is to clarify why different cancers have varying dependencies on metabolite transporters to support cytosolic glutamine-derived aspartate availability. Dissecting the precise metabolic routes that glutamine undergoes in specific tumor types is of upmost importance as it promises to unveil the best metabolic target for therapeutic intervention.
    Keywords:  SLC1A5_var; UCP2; aspartate; aspartate/glutamate carrier; cancer; glutamate carrier; glutamine metabolism; mitochondrial carriers
    DOI:  https://doi.org/10.3390/cancers14010245
  128. Recent Pat Nanotechnol. 2022 Jan 11.
    Enhanced Anti-Proliferative Effect of Carboplatin in Ovarian Cancer Cells Exploiting Chitosan - Poly (lactic glycolic acid) Nanoparticles.
    Fatima Redah Alassaif, Eman Redah Alassaif, Amit Kumar Kaushik, Jeevitha Dhanapal.
      Objective The aim of the present article was to enhance the therapeutic efficacy of carboplatin (CP) using the formulation of chitosan - poly (lactic glycolic acid) nanoparticles (CS-PLGA NPs). Methods Nanoparticles were synthesized by an ionic gelation method and were characterized for their morphology, particle size, and surface potential measurements by TEM and zeta sizer. This study was highlighted for the evaluation of drug entrapment, loading and in vitro drug release capabilities of the prepared nanoparticles by spectrophotometric analysis. The stability study was also conducted after 3 months for their particle size, zeta potential, drug loading and encapsulation efficiencies. Further, ovarian cancer cell line PEO1 were used to evaluate the toxicity and efficacy of nano-formulation by MTT assay. Further, the study was evaluated for apoptosis using flow cytometric analysis. Result The CS-PLGA-CP NPs were uniform and spherical in shape. The particle size and zeta potential of CS-PLGA-CP NPs were measured 156 ± 6.8 nm and +52 ± 2.4 mV, respectively. High encapsulation (87.4 ± 4.5 %) and controlled retention capacities confirmed the efficiency of the prepared nanoparticles in a time and dose dependant manner. The cytotoxicity assay results also showed that CS-PLGA-CP NPs has high efficiency on PEO1 cells compared to the free drug. The flow cytometric result showed 64.25 % of the PEO1 cells were apoptotic and 8.42 % were necrotic when treated with CS-PLGA-CP NPs. Conclusion Chitosan-PLGA combinational polymeric nanoparticles were not only steady but also non-toxic. Our experiments revealed that the chitosan- PLGA nanoparticles could be used as a challenging vehicle candidate for drug delivery for the therapeutic treatment of ovarian cancer.
    Keywords:  Carboplatin; Chitosan; Nanoparticles; Ovarian cancer; PEO1; Poly (lactic glycolic acid)
    DOI:  https://doi.org/10.2174/1872210516666220111160341
  129. ACS Appl Bio Mater. 2021 May 17. 4(5): 4244-4253
    Self-Assembled Hybrid Nanogel as a Multifunctional Theranostic Probe for Enzyme-Regulated Ultrasound Imaging and Tumor Therapy.
    Qing Wu, Qi Zhang, Tianyu Yu, Xia Wang, Chunping Jia, Zonghui Zhao, Jianlong Zhao.
      Multifunctional theranostic nanoprobes integrated with stimuli-responsive imaging and therapeutic capabilities have shown great potential to enhance the early cancer diagnostic efficacy and therapeutic efficiency. Elevated levels of lactate and hydrogen peroxide have been considered as the characteristic feature of the tumor microenvironment and can thus be exploited for developing promising theranostic strategies. We demonstrate here that the biocompatible and responsive enzyme-based nanogel probe has been designed as a promising theranostic tool to target high lactate and hydrogen peroxide for ultrasound imaging (US) and cancer treatment. We encapsulate the dual enzyme lactate oxidase (LOD) and catalase (CAT) into the self-assembled nanogels to fabricate responsive nanoprobe LOD/CAT-loaded nanogels (LCNGs). The nanoprobes can respond to the lactate and H2O2 rich tumor microenvironment to generate abundant oxygen, which further accumulates into microbubbles for enhanced US imaging. Besides, LCNGs@DOX has been further created by integrating the nanoprobes with doxorubicin (DOX) for cancer therapy. Both in vitro and in vivo results demonstrate enhanced US imaging and effective cell proliferation inhibition of LCNGs@DOX, allowing the preparation of safe and efficient theranostic nanoprobes capable of responsive US imaging and treating tumors.
    Keywords:  enzymes; nanogels; self-assembly; tumor therapy; ultrasound imaging
    DOI:  https://doi.org/10.1021/acsabm.1c00079
  130. Nutrients. 2021 Dec 30. pii: 175. [Epub ahead of print]14(1):
    The Role of Bioactive Compounds from Dietary Spices in the Management of Metabolic Syndrome: An Overview.
    Dana Hasan Alkhatib, Abdul Jaleel, Maryam Naveed Muhammad Tariq, Jack Feehan, Vasso Apostolopoulos, Leila Cheikh Ismail, Lily Stojanovska, Ayesha S Al Dhaheri.
      Metabolic syndrome (MetS) is a combination of physiologically dysregulated parameters that can include elevated fasting blood glucose, high blood pressure, central obesity, increased triglyceride levels, insulin resistance, diabetes, elevated low density lipoprotein levels, and reduced high density lipoprotein levels in the blood. Effective clinical management of MetS is critical as it is strongly associated with long lasting and fatal complications in patients. Alongside standard care of lifestyle changes and medication, dietary supplements derived from herbal resources could be an alternative therapeutic strategy that is safe, efficient, culturally acceptable, and has few side effects. Of the dietary supplements, spicy foods have always been considered a great source of functional bioactive compounds. Herbal therapy is broadly used in many countries as a treatment or as a preventive measure in the management of MetS risk factors, including blood glucose, blood pressure, and blood lipid levels. Herein, an attempt is made to evaluate the recent studies in the management of MetS with herbal alternatives, and to explore the possibility of their use as therapeutic treatments or supplements.
    Keywords:  bioactive compounds; diet therapy; herbal therapy; metabolic syndrome; natural products
    DOI:  https://doi.org/10.3390/nu14010175
  131. Front Pharmacol. 2021 ;12 787226
    Nanoparticles use for Delivering Ursolic Acid in Cancer Therapy: A Scoping Review.
    Andang Miatmoko, Ester Adelia Mianing, Retno Sari, Esti Hendradi.
      Ursolic acid is a natural pentacyclic triterpenoid that exerts a potent anticancer effect. Furthermore, it is classified as a BCS class IV compound possessing low permeability and water solubility, consequently demonstrating limited bioavailability in addition to low therapeutic effectiveness. Nanoparticles are developed to modify the physical characteristics of drug and can often be produced in the range of 30-200 nm, providing highly effective cancer therapy due to the Enhanced Permeation and Retention (EPR) Effect. This study aims to provide a review of the efficacy and safety of various types of Ursolic Acid-loading nanoparticles within the setting of preclinical and clinical anticancer studies. This literature study used scoping review method, where the extracted data must comply with the journal inclusion criteria of within years of 2010-2020. The identification stage produced 237 suitable articles. Duplicate screening was then conducted followed by the initial selection of 18 articles that had been reviewed and extracted for data analysis. Based on this review, the use of nanoparticles can be seen to increase the anticancer efficacy of Ursolic Acid in terms of several parameters including pharmacokinetic data, survival rates and inhibition rates, as well as the absence of serious toxicity in preclinical and clinical trials in terms of several parameters including body weight, blood clinical chemistry, and organ histipathology. Based on this review, the use of nanoparticles has been able to increase the anticancer efficacy of Ursolic Acid, as well as show the absence of serious toxicity in preclinical and clinical trials. Evenmore, the liposome carrier provides development data that has reached the clinical trial phase I. The use of nanoparticle provides high potential for Ursolic Acid delivery in cancer therapy.
    Keywords:  cancer; efficacy; liposome; nanoparticle; nanosphere; polymeric micelle; toxicity; ursolic acid
    DOI:  https://doi.org/10.3389/fphar.2021.787226
  132. ACS Appl Bio Mater. 2021 Jun 21. 4(6): 4667-4683
    Recent Advances on Stimuli-Responsive Combination Therapy against Multidrug-Resistant Bacteria and Biofilm.
    Antara Sikder, Amrita Chaudhuri, Saugat Mondal, N D Pradeep Singh.
      The widespread occurrence of infections from multidrug-resistant (MDR) bacteria is a global health problem. It has been amplified over the past few years due to the increase in adaptive traits in bacteria and lack of advanced treatment strategies. Because of the low bioavailability and limited penetration at infected sites, the existing antibiotics often fail to resist bacterial growth. Recently, developed stimuli-responsive drug delivery systems and combinatorial therapeutic systems based on nanoparticles, metal-organic frameworks, hydrogels, and organic chromophores offer the ability to improve the therapeutic efficacy of antibiotics by reducing drug resistance and other side effects. These therapeutic systems have been designed with the relevant chemical and physical properties that respond to specific triggers resulting in spatiotemporal controlled release and site-specific transportability. This review highlights the latest development of single and dual/multistimuli-responsive antibiotic delivery systems for combination therapies to treat MDR bacterial infections and biofilm eradication.
    Keywords:  antibiotics; bacterial infection; combination therapy; drug delivery systems; drug resistance; photodynamic therapy; photothermal therapy; stimuli-responsive
    DOI:  https://doi.org/10.1021/acsabm.1c00150
  133. Adv Mater. 2022 Jan 11. e2108263
    Orchestrated Yolk-Shell Nanohybrids Regulate Macrophage Polarization and Dendritic Cell Maturation for Oncotherapy with Augmented Antitumor Immunity.
    Xiaoyi Zhao, Kangli Guo, Kai Zhang, Shun Duan, Meiwan Chen, Nana Zhao, Fu-Jian Xu.
      The protumoral and immunosuppressive tumor microenvironments (TME) greatly limit the antitumor immune responses of nanoparticles for cancer immunotherapy. Here, we explore the intrinsic immunomodulatory effects of orchestrated nanoparticles and their ability to simultaneously trigger tumor antigen release, thereby reversing immunosuppression and achieving potent antitumor immunity and augmented cancer therapy. By optimizing both the composition and morphology, a facile strategy is proposed to construct yolk-shell nanohybrids (Fe3 O4 @C/MnO2 -PGEA, FCMP). The intrinsic immunomodulatory effects of FCMP are utilized to reprogram macrophages to M1 phenotype and induce the maturation of dendritic cells, which regulate the immunosuppressive TME. In addition, the chemical, magnetic, and optical properties of FCMP contribute to amplified immunogenic cell death induced by multi-augmented chemodynamic therapy (CDT) and synergistic tumor treatment. Taking advantage of the unique yolk-shell structure, accurate T1 -T2 dual-mode magnetic resonance imaging can be realized and CDT can be maximized through sufficient exposure of both the Fe3 O4 core and MnO2 shell. Potent antitumor effects are found to substantially inhibit the growth of both primary and distant tumors. Furthermore, the strategy could be extended to the synthesis of other yolk-shell nanohybrids with tailored properties since the cores are tunable. This work establishes a novel strategy for the fabrication of multifunctional nanoplatforms with yolk-shell structure for effective cancer therapy with immunomodulation-enhanced antitumor immunity. This article is protected by copyright. All rights reserved.
    Keywords:  antitumor immunity; chemodynamic therapy; immunomodulatory effect; tumor microenvironment; yolk-shell structure
    DOI:  https://doi.org/10.1002/adma.202108263
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