bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–01–09
100 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Mesoporous polydopamine-based multifunctional nanoparticles for enhanced cancer phototherapy.
  2. Reactive oxygen species: Key players in the anticancer effects of apigenin?
  3. Near-Infrared Upconversion Mesoporous Tin Dioxide Theranostic Nanocapsules for Synergetic Cancer Chemophototherapy.
  4. Ferroptosis-Inducing Nanomedicine for Cancer Therapy.
  5. A Comprehensive Evaluation of ZrC Nanoparticle in Combined Photothermal and Radiation Therapy for Treatment of Triple-Negative Breast Cancer.
  6. Nanomedicine-enabled chemotherapy-based synergetic cancer treatments.
  7. The role of polyphenols in overcoming cancer drug resistance: a comprehensive review.
  8. Recent advances in nanomedicines for photodynamic therapy (PDT)-driven cancer immunotherapy.
  9. Hyaluronic acid targeted and pH-responsive multifunctional nanoparticles for chemo-photothermal synergistic therapy of atherosclerosis.
  10. Natural medicinal ingredients induce tumor ferroptosis and related mechanisms.
  11. A Supramolecular Nanoparticle of Pemetrexed Improves the Anti-Tumor Effect by Inhibiting Mitochondrial Energy Metabolism.
  12. Tanshinone IIA: New Perspective on the Anti-Tumor Mechanism of A Traditional Natural Medicine.
  13. Adapted suspension tumor cells rewire metabolic pathways for anchorage-independent survival through AKT activation.
  14. Enhancing Penetration Ability of Semiconducting Polymer Nanoparticles for Sonodynamic Therapy of Large Solid Tumor.
  15. Enhanced Intracellular Reactive Oxygen Species by Photodynamic Therapy Effectively Promotes Chemoresistant Cell Death.
  16. Targeting regulated cell death in tumor nanomedicines.
  17. Construction of biomimetic-responsive nanocarriers and their applications in tumor targeting.
  18. A biomimetic nanodrug self-assembled from small molecules for enhanced ferroptosis therapy.
  19. Evaluation of the Effects of Nanomicellar Curcumin, Berberine, and Their Combination with 5-Fluorouracil on Breast Cancer Cells.
  20. Decagram-Scale Synthesis of Multicolor Carbon Nanodots: Self-Tracking Nanoheaters with Inherent and Selective Anticancer Properties.
  21. Folic Acid Decorated Zeolitic Imidazolate Framework (ZIF-8) Loaded with Baicalin as a Nano-Drug Delivery System for Breast Cancer Therapy.
  22. Ultrasmall gold nanorod-polydopamine hybrids for enhanced photoacoustic imaging and photothermal therapy in second near-infrared window.
  23. Tetramethylpyrazine: A Review of Its Antitumor Potential and Mechanisms.
  24. Biodegradable Materials with Disulfide-Bridged-Framework Confine Photosensitizers for Enhanced Photo-Immunotherapy.
  25. Triple-combination therapy assisted with ultrasound-active gold nanoparticles and ultrasound therapy against 3D cisplatin-resistant ovarian cancer model.
  26. Role of Ayurvedic Plants as Anticancer Agents.
  27. Regulation of reactive oxygen species by phytochemicals for the management of cancer and diabetes.
  28. ICG-Loaded PEG-Modified Black Phosphorus Nanosheets for Fluorescence Imaging-Guided Breast Cancer Therapy.
  29. Biphasic effect of the dietary phytochemical linalool on angiogenesis and metastasis.
  30. Biomineralization-inspired synthesis of amorphous manganese phosphates for GLUT5-targeted drug-free catalytic therapy of osteosarcoma.
  31. The Multifaceted Actions of Curcumin in Obesity.
  32. Biomedical applications of tannic acid.
  33. Smart delivery of epirubicin to cancer cells using aptamer-modified ferritin nanoparticles.
  34. Synergistic Disruption of Metabolic Homeostasis Through Hyperbranched Poly(ethylene glycol) Conjugates As Nanotherapeutics to Constrain Cancer Growth.
  35. Vitamin K: A Novel Cancer Chemosensitizer.
  36. A recent development of new therapeutic agents and novel drug targets for cancer treatment.
  37. Therapeutic Potential of Pomegranate in Metabolic Disorders.
  38. ROS-Mediated Anti-Angiogenic Activity of Cerium Oxide Nanoparticles in Melanoma Cells.
  39. Evaluation of cytotoxic activity of Fe doped cobalt oxide nanoparticles.
  40. A novel therapeutic strategy of multimodal nanoconjugates for state-of-the-art brain tumor phototherapy.
  41. Phytochemical and pharmacological anti-diabetic properties of bilberries (Vaccinium myrtillus), recommendations for future studies.
  42. Lymph-Directed Self-Immolative Nitric Oxide Prodrug for Inhibition of Intractable Metastatic Cancer.
  43. Cascade targeting codelivery of ingenol-3-angelate and doxorubicin for enhancing cancer chemoimmunotherapy through synergistic effects in prostate cancer.
  44. Myricetin-Based Self-Assembled Nanoparticles for Tumor Synergistic Therapy by Antioxidation Pathway.
  45. Harnessing in situ glutathione for effective ROS generation and tumor suppression via nanohybrid-mediated catabolism dynamic therapy.
  46. In vitro and in vivo Evaluation of a Novel Estrogen-Targeted PEGylated Oxaliplatin Liposome for Gastric Cancer.
  47. Near-Infrared Light-Controllable Multifunction Mesoporous Polydopamine Nanocomposites for Promoting Infected Wound Healing.
  48. Amplification of anticancer efficacy by co-delivery of doxorubicin and lonidamine with extracellular vesicles.
  49. Coating gold nanorods with silica prevents the generation of reactive oxygen species under laser light irradiation for safe biomedical applications.
  50. Review on design strategies and considerations of polysaccharide-based smart drug delivery systems for cancer therapy.
  51. Anti-obesity natural products and gut microbiota.
  52. Inflammatory Markers, Metabolic Profile, and Psychoneurological Symptoms in Women with Breast Cancer: A Literature Review.
  53. Therapeutic Potential of Emodin for Gastrointestinal Cancers.
  54. Smart NIR-II croconaine dye-peptide for enhanced photo-sonotheranostics of hepatocellular carcinoma.
  55. 2-Methoxy-estradiol Loaded Alpha Lipoic Acid Nanoparticles Augment Cytotoxicity in MCF-7 Breast Cancer Cells.
  56. Update and New Insights on Future Cancer Drug Candidates From Plant-Based Alkaloids.
  57. Leveraging disulfiram to treat cancer: Mechanisms of action, delivery strategies, and treatment regimens.
  58. Lactate Upregulates the Expression of DNA Repair Genes, Causing Intrinsic Resistance of Cancer Cells to Cisplatin.
  59. Mefenamic acid as a promising therapeutic medicine against colon cancer in tumor-bearing mice.
  60. Ethnopharmacological Survey of Traditional Chinese Medicine Pharmacy Prescriptions for Dysmenorrhea.
  61. Mn doped Prussian blue nanoparticles for T1/T2 MR imaging, PA imaging and Fenton reaction enhanced mild temperature photothermal therapy of tumor.
  62. A novel TMTP1-modified theranostic nanoplatform for targeted in vivo NIR-II fluorescence imaging-guided chemotherapy for cervical cancer.
  63. A Review on the Phytochemistry, Pharmacology, and Therapeutic Effects of Rheum ribes.
  64. Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin.
  65. The Potential for Natural Products to Overcome Cancer Drug Resistance by Modulation of Epithelial-Mesenchymal Transition.
  66. Bee Products: An Emblematic Example of Underutilized Sources of Bioactive Compounds.
  67. Health Benefits of Turmeric and Curcumin Against Food Contaminants.
  68. Ceria nanoparticles ameliorate renal fibrosis by modulating the balance between oxidative phosphorylation and aerobic glycolysis.
  69. Hybrid Carbon Dot Assembly as a Reactive Oxygen Species Nanogenerator for Ultrasound-Assisted Tumor Ablation.
  70. Extracellular ATP is increased by release of ATP-loaded microparticles triggered by nutrient deprivation.
  71. S-nitrosoglutathione Functionalized Polydopamine Nanoparticles Incorporated into Chitosan/Gelatin Hydrogel Films with NIR-Controlled Photothermal/NO-Releasing Therapy for Enhanced Wound Healing.
  72. Sodium alginate as a pharmaceutical excipient: novel applications of a well-known polymer.
  73. IRF7 inhibits the Warburg effect via transcriptional suppression of PKM2 in osteosarcoma.
  74. Design of Light-activated Nanoplatform Through Boosting "eat me" Signals for Improved CD47-blocking Immunotherapy.
  75. Light-Triggered Efficient Sequential Drug Delivery of Biomimetic Nanosystem for Multimodal Chemo-, Antiangiogenic, and Anti-MDSC Therapy in Melanoma.
  76. Autophagy in cancer: The cornerstone during glutamine deprivation.
  77. GSH-Responsive Drug Delivery System for Active Therapy and Reducing the Side Effects of Bleomycin.
  78. Tumor microenvironment responsive self-cascade catalysis for synergistic chemo/chemodynamic therapy by multifunctional biomimetic nanozymes.
  79. Novel molecules as the emerging trends in cancer treatment: an update.
  80. Atom-precise fluorescent copper cluster for tumor microenvironment targeting and transient chemodynamic cancer therapy.
  81. Galactose conjugated boron dipyrromethene and hydrogen bonding promoted J-aggregates for efficiently targeted NIR-II fluorescence assistant photothermal therapy.
  82. Use of coumarins as complementary medicine with an integrative approach against cervical cancer: background and mechanisms of action.
  83. Recent advances on chitosan as an adjuvant for vaccine delivery.
  84. The Role of Natural Products in Treatment of Depressive Disorder.
  85. Inhibitory effect of roburic acid in combination with docetaxel on human prostate cancer cells.
  86. Repurposing ferumoxytol: Diagnostic and therapeutic applications of an FDA-approved nanoparticle.
  87. Harnessing chlorin e6 loaded by functionalized iron oxide nanoparticles linked with glucose for target photodynamic therapy and improving of the immunogenicity of lung cancer.
  88. Impact of Nano Preparation of Phytoconstituents in Medulloblastoma.
  89. The Potential of Drug Delivery Nanosystems for Sepsis Treatment.
  90. Clinical development of metabolic inhibitors for oncology.
  91. A Photothermal Nanoplatform with Sugar-Triggered Cleaning Ability for High-Efficiency Intracellular Delivery.
  92. Design, synthesis and bioactivity evaluation of novel N-phenyl-substituted evodiamine derivatives as potent anti-tumor agents.
  93. A hydrogen peroxide economizer for on-demand oxygen production-assisted robust sonodynamic immunotherapy.
  94. Effectiveness of 5-Fluorouracil and Gemcitabine Hydrochloride Loaded Iron‑Based Chitosan-Coated MIL-100 Composite as an Advanced, Biocompatible, pH-Sensitive and Smart Drug Delivery System on Breast Cancer Therapy.
  95. Iron oxide nanoparticle targeted chemo-immunotherapy for triple negative breast cancer.
  96. Transdermal Delivery of Curcumin-Loaded Solid Lipid Nanoparticles as Microneedle Patch: an In Vitro and In Vivo Study.
  97. Nanoparticle mediated gene therapy: a trailblazer armament to fight CNS disorders.
  98. Brazilian tucumã-do-Amazonas (Astrocaryum aculeatum) and tucumã-do-Pará (Astrocaryum vulgare) fruits: bioactive composition, health benefits, and technological potential.
  99. Molecular Docking of Phytochemicals Targeting GFRs as Therapeutic Sites for Cancer: an In Silico Study.
  100. Extracellular matrix-degrading STING nanoagonists for mild NIR-II photothermal-augmented chemodynamic-immunotherapy.
  1. J Colloid Interface Sci. 2021 Dec 29. pii: S0021-9797(21)02316-X. [Epub ahead of print]612 246-260
    Mesoporous polydopamine-based multifunctional nanoparticles for enhanced cancer phototherapy.
    Hang Hu, Xin Liu, Jun Hong, Ningbing Ye, Chen Xiao, Jianhao Wang, Zifu Li, Defeng Xu.
      Cancer phototherapy has attracted increasing attention for its effectiveness, relatively low side effect, and noninvasiveness. The combination of photothermal therapy (PTT) and photodynamic therapy (PDT) has been shown to exhibit promising prospects in cancer treatment. However, the tumor hypoxia, high level of intracellular glutathione (GSH), and insufficient photosensitizer uptake significantly limit the PDT efficacy. In this work, we combine oxygen supply, GSH depletion, and tumor targeting in one nanoplatform, folate-decorated mesoporous polydopamine nanoparticles (FA-MPPD) co-loaded with new indocyanine green (IR-820) and perfluorooctane (PFO) (IR-820/PFO@FA-MPPD), to overcome the PDT resistance for enhanced cancer PDT/PTT. IR-820/PFO@FA-MPPD exhibit efficient singlet oxygen generation and photothermal effect under 808 nm laser irradiation, GSH-promoted IR-820 release, and efficient cellular uptake, resulting in high intracellular reactive oxygen species (ROS) level under 808 nm laser irradiation and strong photocytotoxicity in vitro. Following intratumoral injection, IR-820/PFO@FA-MPPD can relieve tumor hypoxia sustainably by PFO-mediated oxygen transport and deplete intracellular GSH by the Michael addition reaction, which boost the PDT effect and lead to the most potent antitumor effect upon 808 nm laser irradiation. The multifunctional IR-820/PFO@FA-MPPD developed in this work offer a relatively simple and effective strategy to potentiate PDT for efficient cancer phototherapy.
    Keywords:  Glutathione depletion; Mesoporous polydopamine; Perfluorooctane; Photothermal and photodynamic therapy; Relieve tumor hypoxia
    DOI:  https://doi.org/10.1016/j.jcis.2021.12.172
  2. J Food Biochem. 2022 Jan 07. e14060
    Reactive oxygen species: Key players in the anticancer effects of apigenin?
    Omolola R Oyenihi, Ayodeji B Oyenihi, Toyin D Alabi, Oluwatosin G Tade, Anne A Adeyanju, Oluwafemi O Oguntibeju.
      Reactive oxygen species (ROS) exhibit a double-edged sword in cancer-hence their modulation has been an attractive strategy in cancer prevention and therapy. The abundance of scientific information on the pro-oxidant effects of apigenin in cancer cells suggests the crucial role of ROS in its mechanisms of action. Although apigenin is known to enhance the cellular ROS levels to cytotoxic degrees in cancer cells in vitro, it remains to be determined if these pro-oxidant effects prevail or are relevant in experimental tumor models and clinical trials. Here, we critically examine the pro-oxidant and antioxidant effects of apigenin in cancer to provide insightful perspectives on the association between its ROS-modulating action and anticancer potential. We also discussed these effects in a cell/tissue type-specific context to highlight the factors influencing the switch between antioxidant and pro-oxidant effects. Finally, we raised some questions that need addressing for the potential translation of these studies into clinical applications. Further research into this duality in oxidant actions of apigenin, especially in vivo, may enable better exploitation of its anticancer potential. PRACTICAL APPLICATION: Apigenin is a naturally occurring compound found in chamomile flowers, parsley, celery, peppermint, and citrus fruits. Many human trials of dietary interventions with apigenin-containing herbs and flavonoid mixture on oxidative stress markers, for instance, point to their antioxidant effects and health benefits in many diseases. Preclinical studies suggest that apigenin alone or its combination with chemotherapeutics has a strong anti-neoplastic effect and can induce ROS-mediated cytotoxicity at concentrations in the micromolar (μM) range, which may not be feasible with dietary interventions. Enhancing the in vivo pharmacokinetic properties of apigenin may be indispensable for its potential cancer-specific pro-oxidant therapy and may provide relevant information for clinical studies of apigenin either as a single agent or an adjuvant to chemotherapeutics.
    Keywords:  antioxidant; apigenin; cancer; clinical translation; free radicals; pro-oxidant
    DOI:  https://doi.org/10.1111/jfbc.14060
  3. ACS Appl Mater Interfaces. 2022 Jan 07.
    Near-Infrared Upconversion Mesoporous Tin Dioxide Theranostic Nanocapsules for Synergetic Cancer Chemophototherapy.
    Lu Yang, Ruipeng Shi, Ruoxi Zhao, Yanlin Zhu, Bin Liu, Shili Gai, Lili Feng.
      Smart nanotheranostic systems (SNSs) have attracted extensive attention in antitumor therapy. Nevertheless, constructing SNSs with disease diagnosis ability, improved drug delivery efficiency, inherent imaging performance, and high treatment efficiency remains a scientific challenge. Herein, ultrasmall tin dioxide (SnO2) was assembled with upconversion nanoparticles (UCNPs) to form mesoporous nanocapsules by an in situ hydrothermal deposition method, followed by loading with doxorubicin (DOX) and modification with bovine serum albumin (BSA). pH/near-infrared dual-responsive nanotheranostics was constructed for computed tomography (CT) and magnetic resonance (MR) imaging-induced collaborative cancer treatment. The mesoporous channel of SnO2 was utilized as a reservoir to encapsulate DOX, an antineoplastic drug, for chemotherapy and as a semiconductor photosensitizer for photodynamic therapy (PDT). Furthermore, the DOX-loaded UCNPs@SnO2-BSA nanocapsules combined PDT, Nd3+-doped UCNP-triggered hyperthermia effect, and DOX-triggered chemotherapy simultaneously and demonstrated prominently enhanced treatment efficiency compared to the monotherapy model. Moreover, tin, as one of the trace elements in the human body, has a similar X-ray attenuation coefficient to iodine and therefore can act as a contrast agent for CT imaging to monitor the treatment process. Such an orchestrated synergistic anticancer treatment exhibited apparent inhibition of tumor growth in tumor-bearing mice with negligible side effects. Our study demonstrates nanocapsules with excellent biocompatibility and great potential for cancer treatment.
    Keywords:  chemotherapy; mesoporous tin dioxide; nanocapsules; phototherapy; upconversion nanoparticles
    DOI:  https://doi.org/10.1021/acsami.1c23174
  4. Front Pharmacol. 2021 ;12 735965
    Ferroptosis-Inducing Nanomedicine for Cancer Therapy.
    Yang Wang, Tianfu Liu, Xiang Li, Hui Sheng, Xiaowen Ma, Liang Hao.
      Ferroptosis, a new iron- and reactive oxygen species-dependent form of regulated cell death, has attracted much attention in the therapy of various types of tumors. With the development of nanomaterials, more and more evidence shows the potential of ferroptosis combined with nanomaterials for cancer therapy. Recently, there has been much effort to develop ferroptosis-inducing nanomedicine, specially combined with the conventional or emerging therapy. Therefore, it is necessary to outline the previous work on ferroptosis-inducing nanomedicine and clarify directions for improvement and application to cancer therapy in the future. In this review, we will comprehensively focus on the strategies of cancer therapy based on ferroptosis-inducing nanomedicine currently, elaborate on the design ideas of synthesis, analyze the advantages and limitations, and finally look forward to the future perspective on the emerging field.
    Keywords:  ROS; cancer therapy; combination strategies; ferroptosis; nanomedicine
    DOI:  https://doi.org/10.3389/fphar.2021.735965
  5. Front Oncol. 2021 ;11 801352
    A Comprehensive Evaluation of ZrC Nanoparticle in Combined Photothermal and Radiation Therapy for Treatment of Triple-Negative Breast Cancer.
    Shan Jiang, Zhao Liu, Yuhang Tian, Ming Zhuang, Shiqi Piao, Yan Gao, Andrew Tam, Hongtao Hu, Wen Cheng.
      Because of the difficulty in treating triple-negative breast cancer (TNBC), the search for treatments has never stopped. Treatment opinions remain limited for triple-negative breast cancer (TNBC). The current treatment approach of using photothermal therapy (PTT) is often imprecise and has limited penetration below the surface of the skin. On the other hand, radiation therapy (RT) has its unavoidable disadvantages, such as side effects or ineffectiveness against hypoxic tumor microenvironment (TME). In this study, we proposed the use of ZrC nanoparticles in conjunction with RT/PTT to enhance antitumor and antimetastatic effect. We modified the ZrC nanoparticle with bovine serum albumin (BSA) and folic acid (FA), sizing desirable about 100nm. The photothermal conversion efficiency was calculated to be 40.51% and sensitizer enhancement ration (SER) was 1.8. With addition of ZrC NPs, more DNA were damaged in γ-H2AX and more ROS were detected with immunofluorescence. In vitro and vivo, the combined therapy with ZrC NPS showed the best effect of tumor cell inhibition and safety. Our results provide evidence that the combination of ZrC NPs, PT, and RT is effective in of TNBC, making it a great potential application for cancer therapy in clinic.
    Keywords:  PTT; RT; breast cancer; nanoparticle; sensitizer
    DOI:  https://doi.org/10.3389/fonc.2021.801352
  6. J Nanobiotechnology. 2022 Jan 04. 20(1): 4
    Nanomedicine-enabled chemotherapy-based synergetic cancer treatments.
    Wencheng Wu, Yinying Pu, Jianlin Shi.
      Chemotherapy remains one of the most prevailing regimens hitherto in the fight against cancer, but its development has been being suffering from various fatal side effects associated with the non-specific toxicity of common chemical drugs. Advances in biomedical application of nanomedicine have been providing alternative but promising approaches for cancer therapy, by leveraging its excellent intrinsic physicochemical properties to address these critical concerns. In particular, nanomedicine-enabled chemotherapy has been established as a safer and promising therapeutic modality, especially the recently proposed nanocatalytic medicine featuring the capabilities to generate toxic substances by initiating diverse catalytic reactions within the tumor without directly relying on highly toxic but non-selective chemotherapeutic agents. Of special note, under exogenous/endogenous stimulations, nanomedicine can serve as a versatile platform that allows additional therapeutic modalities (photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), etc.) to be seamlessly integrated with chemotherapy for efficacious synergistic treatments of tumors. Here, we comprehensively review and summarize the representative studies of multimodal synergistic cancer treatments derived from nanomedicine and nanocatalytic medicine-enabled chemotherapy in recent years, and their underlying mechanisms are also presented in detail. A number of existing challenges and further perspectives for nanomedicine-synergized chemotherapy for malignant solid tumor treatments are also highlighted for understanding this booming research area as comprehensively as possible.
    Keywords:  Chemotherapy; Nanomedicine; Synergisitic cancer treatments
    DOI:  https://doi.org/10.1186/s12951-021-01181-z
  7. Cell Mol Biol Lett. 2022 Jan 03. 27(1): 1
    The role of polyphenols in overcoming cancer drug resistance: a comprehensive review.
    Parisa Maleki Dana, Fatemeh Sadoughi, Zatollah Asemi, Bahman Yousefi.
      Chemotherapeutic drugs are used to treat advanced stages of cancer or following surgery. However, cancers often develop resistance against drugs, leading to failure of treatment and recurrence of the disease. Polyphenols are a family of organic compounds with more than 10,000 members which have a three-membered flavan ring system in common. These natural compounds are known for their beneficial properties, such as free radical scavenging, decreasing oxidative stress, and modulating inflammation. Herein, we discuss the role of polyphenols (mainly curcumin, resveratrol, and epigallocatechin gallate [EGCG]) in different aspects of cancer drug resistance. Increasing drug uptake by tumor cells, decreasing drug metabolism by enzymes (e.g. cytochromes and glutathione-S-transferases), and reducing drug efflux are some of the mechanisms by which polyphenols increase the sensitivity of cancer cells to chemotherapeutic agents. Polyphenols also affect other targets for overcoming chemoresistance in cancer cells, including cell death (i.e. autophagy and apoptosis), EMT, ROS, DNA repair processes, cancer stem cells, and epigenetics (e.g. miRNAs).
    Keywords:  Chemoresistance; Curcumin; Epigallocatechin gallate; Polyphenols; Resveratrol
    DOI:  https://doi.org/10.1186/s11658-021-00301-9
  8. Theranostics. 2022 ;12(1): 434-458
    Recent advances in nanomedicines for photodynamic therapy (PDT)-driven cancer immunotherapy.
    Bin Ji, Minjie Wei, Bin Yang.
      Cancer immunotherapy has made tremendous clinical progress in advanced-stage malignancies. However, patients with various tumors exhibit a low response rate to immunotherapy because of a powerful immunosuppressive tumor microenvironment (TME) and insufficient immunogenicity of tumors. Photodynamic therapy (PDT) can not only directly kill tumor cells, but also elicit immunogenic cell death (ICD), providing antitumor immunity. Unfortunately, limitations from the inherent nature and complex TME significantly reduce the efficiency of PDT. Recently, smart nanomedicine-based strategies could subtly modulate the pharmacokinetics of therapeutic compounds and the TME to optimize both PDT and immunotherapy, resulting in an improved antitumor effect. Here, the emerging nanomedicines for PDT-driven cancer immunotherapy are reviewed, including hypoxia-reversed nanomedicines, nanosized metal-organic frameworks, and subcellular targeted nanoparticles (NPs). Moreover, we highlight the synergistic nanotherapeutics used to amplify immune responses combined with immunotherapy against tumors. Lastly, the challenges and future expectations in the field of PDT-driven cancer immunotherapy are discussed.
    Keywords:  cancer immunotherapy; emerging nanomedicines; immune response; photodynamic therapy; synergistic nanotherapeutics
    DOI:  https://doi.org/10.7150/thno.67300
  9. J Mater Chem B. 2022 Jan 04.
    Hyaluronic acid targeted and pH-responsive multifunctional nanoparticles for chemo-photothermal synergistic therapy of atherosclerosis.
    Shun Liu, Yun Zhao, Meili Shen, Yujiao Hao, Xiaodong Wu, Yixuan Yao, Yapeng Li, Qingbiao Yang.
      Atherosclerosis is a global disease with an extremely high morbidity and fatality rate, so it is necessary to develop effective treatments to reduce its impact. In this work, we successfully prepared a multifunctional drug-loaded nano-delivery system with pH-responsive, CD44-targeted, and chemical-photothermal synergistic treatment. Dendritic mesoporous silica nanoparticles capped with copper sulfide (CuS) were synthesized via an oil-water biphase stratification reaction system; these served as the carrier material and encapsulated the anticoagulant drug heparin (Hep). The pH-sensitive Schiff base bond was used as a gatekeeper and targeting agent to modify hyaluronic acid (HA) on the surface of the nanocarrier. HA coating endowed the nanocomposite with the ability to respond to pH and target CD44-positive inflammatory macrophages. Based on this multifunctional nanocomposite, we achieved precise drug delivery, controlled drug release, and chemical-photothermal synergistic treatment of atherosclerosis. The in vitro drug release results showed that the nanocarriers exhibited excellent drug-controlled release properties, and could release drugs in the weakly acidic microenvironment of atherosclerotic inflammation. Cytotoxicity and cell uptake experiments indicated that nanocarriers had low cytotoxicity against RAW 264.7 cells. Modification of HA to nanocarriers can be effectively internalized by RAW 264.7 cells stimulated by lipopolysaccharide (LPS). Combining CuS photothermal treatment with anti-atherosclerosis chemotherapy showed better effects than single treatment in vitro and in vivo. In summary, our research proved that H-CuS@DMSN-NC-HA has broad application prospects in anti-atherosclerosis.
    DOI:  https://doi.org/10.1039/d1tb02000e
  10. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2021 Oct 25. 50(5): 601-606
    Natural medicinal ingredients induce tumor ferroptosis and related mechanisms.
    Zixue Xuan, Yiwen Zhang, Zongfu Pan, Xiaowei Zheng, Ping Huang.
      Ferroptosis is an iron-dependent programmed cell death characterized by reactive oxygen species-induced lipid peroxide accumulation, which is different from cell apoptosis, pyroptosis, necrosis or autophagy. Ferroptosis plays an important role in the regulation of tumorigenesis and tumor development. Recent studies have shown that natural medicinal ingredients can induce ferroptosis in tumor cells through glutathione (GSH)/glutathione peroxidase 4 (GPx4) pathway, iron metabolism, lipid metabolism or other mechanisms. It has been reported that more than 30 natural medicinal ingredients can induce ferroptosis in tumor cells with multiple pathways and multiple targets. This article reviews the current research progress on the antitumor effects of natural medicinal ingredients through inducing cell ferroptosis.
    Keywords:  Ferroptosis; Natural medicine; Regulatory mechanism; Review; Traditional Chinese medicine; Tumor
    DOI:  https://doi.org/10.3724/zdxbyxb-2021-0198
  11. Front Bioeng Biotechnol. 2021 ;9 804747
    A Supramolecular Nanoparticle of Pemetrexed Improves the Anti-Tumor Effect by Inhibiting Mitochondrial Energy Metabolism.
    Hui Liu, Chunlei Guo, Yuhong Shang, Lin Zeng, Haixue Jia, Zhongyan Wang.
      In recent years, supramolecular nanoparticles consisting of peptides and drugs have been regarded as useful drug delivery systems for tumor therapy. Pemetrexed (PEM) is a multitarget drug that is effective for many cancers, such as non-small cell lung cancer. Here, RGD-conjugated molecular nanoparticles mainly composed of an anticancer drug of PEM (PEM-FFRGD) were prepared to deliver PEM to tumors. The peptide could self-assemble into a nanoparticle structure with diameter of about 20 nm. Moreover, the nanoparticle showed favorable solubility and biocompatibility compared with those of PEM, and the MTT test on A549 and LLC cells showed that the PEM-FFRGD nanoparticles had stronger cytotoxic activity than PEM alone. Most importantly, the nanoparticle could promote tumor apoptosis and decrease mitochondrial energy metabolism in tumors. In vivo studies indicated that PEM-FFRGD nanoparticles had enhanced antitumor efficacy in LLC tumor-bearing mice compared to that of PEM. Our observations suggested that PEM-FFRGD nanoparticles have great practical potential for application in lung cancer therapy.
    Keywords:  metabolism; mitochondrial; pemetrexed; supramolecular nanoparticle; tumor therapy
    DOI:  https://doi.org/10.3389/fbioe.2021.804747
  12. Am J Chin Med. 2022 Jan 04. 1-31
    Tanshinone IIA: New Perspective on the Anti-Tumor Mechanism of A Traditional Natural Medicine.
    Wenfeng Zhang, Cun Liu, Jie Li, Yiping Lu, Huayao Li, Jing Zhuang, Xin Ren, Mengmeng Wang, Changgang Sun.
      The search for natural and efficacious antineoplastic drugs, with minimal toxicity and side effects, is an important part of antitumor drug research and development. Tanshinone IIA is the most evaluated lipophilic active component of Salvia miltiorrhiza. Tanshinone IIA is a path-breaking traditional drug applied in cardiovascular treatment. It has also been found that tanshinone IIA plays an important role in the digestive, respiratory and circulatory systems, as well as in other tumor diseases. Tanshinone IIA significantly inhibits the proliferation of several types of tumors, blocks the cell cycle, induces apoptosis and autophagic death, in addition to inhibiting cell migration and invasion. Among these, the regulation of tumor-cell apoptosis signaling pathways is the key breakthrough point in several modes of antitumor therapy. The PI3K/AKT/MTOR signaling pathway and the JNK pathway are the key pathways for tanshinone IIA to induce tumor cell apoptosis. In addition to glycolysis, reactive oxygen species and signal transduction all play an active role with the participation of tanshinone IIA. Endogenous apoptosis is considered the main mechanism of tumor apoptosis induced by tanshinone IIA. Multiple pathways and targets play a role in the process of endogenous apoptosis. Tanshinone IIA can protect chemotherapy drugs, which is mainly reflected in the protection of the side effects of chemotherapy drugs, such as neurotoxicity and inhibition of the hematopoietic system. Tanshinone IIA also has a certain regulatory effect on tumor angiogenesis, which is mainly manifested in the control of hypoxia. Our findings indicated that tanshinone IIA is an effective treatment agent in the cardiovascular field and plays a significant role in antitumor therapeutics. This paper reviews the pharmacological potential and inhibitory effect of tanshinone IIA on cancer. It is greatly anticipated that tanshinone IIA will be employed as an adjuvant in the treatment of various cancers.
    Keywords:  Apoptosis; Autophagic; Proliferation; Review; Tanshinone IIA; Traditional Chinese Medicine
    DOI:  https://doi.org/10.1142/S0192415X22500070
  13. Exp Cell Res. 2021 Dec 31. pii: S0014-4827(21)00561-9. [Epub ahead of print] 113005
    Adapted suspension tumor cells rewire metabolic pathways for anchorage-independent survival through AKT activation.
    Hyun Jeong Joo, Ga Eun Chung, Sora Han, Hye In Ka, Su Jung Soh, Young Yang.
      Metastatic spread of cancer cells is the main cause of cancer-related death. As cancer cells adapt themselves in a suspended state in the blood stream before penetration and regrowth at distal tissues, understanding their survival strategy in an anchorage-independent condition is important to develop appropriate therapeutics. We have previously generated adapted suspension cells (ASCs) from parental adherent cancer cells to study the characteristics of circulating tumor cells. In this study, we explored metabolic rewiring in MDA-MB-468 ASCs to adapt to suspension growth conditions through extracellular flux analyses and various metabolic assays. We also determined the relationship between AKT activation and metabolic rewiring in ASCs using the AKT inhibitor, MK2206. ASCs reprogramed metabolism to enhance glycolysis and basal oxygen consumption rate. RNA-sequencing analysis revealed the upregulation in the genes related to glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. The changes in the metabolic program led to a remarkable dependency of ASCs on carbohydrates as an energy source for proliferation as compared to parental adherent cells (ADs). AKT activation was observed in ASCs and those generated from pancreatic and other breast cancer cells, and AKT activation inhibition in ASCs decreased glycolysis and oxygen consumption. AKT activation is an important strategy for obtaining energy through the enhancement of glycolysis in ASCs. The regulation of AKT activity and/or glycolysis may provide a strong therapeutic strategy to prevent the metastatic spread of cancer cells.
    Keywords:  AKT; Adapted suspension cell; Anchorage-independent growth; Circulating tumor cell; Glycolysis; Metabolism
    DOI:  https://doi.org/10.1016/j.yexcr.2021.113005
  14. Adv Sci (Weinh). 2022 Jan 06. e2104125
    Enhancing Penetration Ability of Semiconducting Polymer Nanoparticles for Sonodynamic Therapy of Large Solid Tumor.
    Xin Wang, Min Wu, Haoze Li, Jianli Jiang, Sensen Zhou, Weizhi Chen, Chen Xie, Xu Zhen, Xiqun Jiang.
      Sonodynamic therapy (SDT) holds growing promise in deep-seated or large solid tumor treatment owing to its high tissue penetration depth ability; however, its therapeutic efficacy is often compromised due to the hypopermeable and hypoxic characteristics in the tumor milieu. Herein, a semiconducting polymer nanoparticle (SPNC) that synergistically enhances tumor penetration and alleviates tumor hypoxia is reported for sonodynamic therapy of large solid tumors. SPNC comprises a semiconducting polymer nanoparticle core as a sonodynamic converter coated with a poly (ethylene glycol) corona. An oxygen-modulating enzyme, catalase, is efficiently conjugated to the surface of nanoparticles via the coupling reaction. Superior to its counterpart SPNCs (SPNC2 (84 nm) and SPNC3 (134 nm)), SPNC with the smallest size (SPNC1 (35 nm)) can efficiently penetrate throughout the tumor interstitium to alleviate whole tumor hypoxia in a large solid tumor model. Upon ultrasound (US) irradiation, SPNC1 can remotely generate sufficient singlet oxygen to eradicate tumor cells at a deep-tissue depth. Such a single treatment of SPNC1-medicated sonodynamic therapy effectively inhibits tumor growth in a large solid tumor mouse model. Therefore, this study provides a generalized strategy to synergistically overcome both poor penetration and hypoxia of large tumors for enhanced cancer treatment.
    Keywords:  large solid tumor therapy; polymer nanoparticles; sonodynamic therapy; tumor hypoxia; tumor penetration
    DOI:  https://doi.org/10.1002/advs.202104125
  15. Int J Biol Sci. 2022 ;18(1): 374-385
    Enhanced Intracellular Reactive Oxygen Species by Photodynamic Therapy Effectively Promotes Chemoresistant Cell Death.
    Xiaolin Xu, Chenglong Wang, Peipei Zhang, Xuzhu Gao, Wencai Guan, Fanchen Wang, Xin Li, Jia Yuan, Hongjing Dou, Guoxiong Xu.
      Anti-cancer chemo-drugs can cause a rapid elevation of intracellular reactive oxygen species (ROS) levels. An imbalance in ROS production and elimination systems leads to cancer cell resistance to chemotherapy. This study aimed to evaluate the mechanism and effect of ROS on multidrug resistance in various human chemoresistant cancer cells by detecting the changes in the amount of ROS, the expression of ROS-related and glycolysis-related genes, and cell death. We found that ROS was decreased while oxidative phosphorylation was increased in chemoresistant cells. We verified that the chemoresistance of cancer cells was achieved in two ways. First, chemoresistant cells preferred oxidative phosphorylation instead of anaerobic glycolysis for energy generation, which increased ATPase activity and produced much more ATP to provide energy. Second, ROS-scavenging systems were enhanced in chemoresistant cancer cells, which in turn decreased ROS amount and thus inhibited chemo-induced cell death. Our in vitro and in vivo photodynamic therapy further demonstrated that elevated ROS production efficiently inhibited chemo-drug resistance and promoted chemoresistant cell death. Taken together, targeting ROS systems has a great potential to treat cancer patients with chemoresistance.
    Keywords:  Chemoresistance; ROS; glycolysis; malignant tumor; oxidative phosphorylation; photodynamic therapy
    DOI:  https://doi.org/10.7150/ijbs.66602
  16. Theranostics. 2022 ;12(2): 817-841
    Targeting regulated cell death in tumor nanomedicines.
    Qinghu Zeng, Xiangyi Ma, Yangmeihui Song, Qiqing Chen, Qiuling Jiao, Liqiang Zhou.
      Nanomedicines hold great potential in anticancer therapy by modulating the biodistribution of nanomaterials and initiating targeted oxidative stress damage, but they are also limited by the inherent self-protection mechanism and the evolutionary treatment resistance of cancer cells. New emerging explorations of regulated cell death (RCD), including processes related to autophagy, ferroptosis, pyroptosis, and necroptosis, substantially contribute to the augmented therapeutic efficiency of tumors by increasing the sensitivity of cancer cells to apoptosis. Herein, paradigmatic studies of RCD-mediated synergistic tumor nanotherapeutics are introduced, such as regulating autophagy-enhanced photodynamic therapy (PDT), targeting ferroptosis-sensitized sonodynamic therapy (SDT), inducing necroptosis-augmented photothermal therapy (PTT), and initiating pyroptosis-collaborative chemodynamic therapy (CDT), and the coordination mechanisms are discussed in detail. Multiangle analyses addressing the present challenges and upcoming prospects of RCD-based nanomedicines have also been highlighted and prospected for their further strengthening and the broadening of their application scope. It is believed that up-and-coming coadjutant therapeutic methodologies based on RCDs will considerably impact precision nanomedicine for cancer.
    Keywords:  Nanomaterials; Nanomedicine; Regulated cell death; Sensitized apoptosis; Tumor therapy
    DOI:  https://doi.org/10.7150/thno.67932
  17. Anticancer Agents Med Chem. 2022 Jan 06.
    Construction of biomimetic-responsive nanocarriers and their applications in tumor targeting.
    Xuexia Tian, Anhua Shi, Junzi Wu.
      Backgroud：At present, the tumor is still the leading cause of death. Biomimetic nanocarriers for precision cancer therapy are attracting increasing attention. Nanocarriers with a good biocompatible surface could reduce the recognition and elimination of nanoparticles as foreign substances by the immune system, offer specific targeting, and improve the efficacy of precision medicine for tumors, thereby providing outstanding prospects for application in cancer therapy. In particular, cell membrane biomimetic camouflaged nanocarriers have become a research hotspot because of their excellent biocompatibility, prolonged circulation in the blood, and tumor targeting. Objective：To summarize the biological targeting mechanisms of different cell membrane-encapsulated nanocarriers in cancer therapy. In this article, the characteristics, application, and stage of progress of bionic encapsulated nanocarriers for different cell membranes are discussed, as are the field's developmental prospects. Methods：The findings on the characteristics of bionic encapsulated nanocarriers for different cell membranes and tumor treatment have been analyzed and summarized. Results：Biomimetic nanosystems based on various natural cell and hybrid cell membranes have been shown to efficiently control targeted drug delivery systems. They can reduce immune system clearance, prolong blood circulation time, and improve drug loading and targeting, thereby enhancing the diagnosis and treatment of tumors and reducing the spread of CTCs. Conclusion：With advances in the development of biomimetic nanocarrier DDSs, novel ideas for tumor treatment and drug delivery have been developed. However, there are still some problems in biomimetic nanosystems. Therefore, it needs to be optimized through further research, from the laboratory to the clinic for the benefit of a wide range of patients.
    Keywords:  biocompatible surface; biomimetic nanocarriers; cancer; cancer therapy; cell membrane; tumor-targeted therapy
    DOI:  https://doi.org/10.2174/1871520622666220106105315
  18. Biomater Sci. 2022 Jan 06.
    A biomimetic nanodrug self-assembled from small molecules for enhanced ferroptosis therapy.
    Xueming Xu, Yuan Chen, Jinyong Gui, Peilian Liu, Yong Huang, Baihao Shao, Yuan Ping, Bowen Li.
      Ferroptosis drugs often induce oxidative damage or block antioxidant defense due to the key mechanism of ferroptosis involved in cancer treatment, regulating the intracellular redox balance. However, these ferroptosis drugs are unstable during systemic circulation, and they lack tumor-targeting capability. Herein, we developed a stimuli-responsive and cell membrane-coated nanodrug for the simultaneous delivery of two ferroptosis drugs, an iron-chelating drug as a ROS inducer and sorafenib as an antioxidase inhibitor. The coating of the cancer cell membrane over the nanodrug can enhance the tumor-targeting capability and improve the stability in the blood circulation. In addition, the nanodrug exhibits sensitive drug release profiles in response to glutathione (GSH) and reactive oxygen species (ROS) in tumor microenvironments due to the dynamic diselenide bonds. The released iron-chelating drug and sorafenib not only produce hydroxyl radicals (˙OH) to induce ferroptosis, but also inhibit the expression of GPX4 to mitigate the ferroptosis resistance. Excitingly, the systemic administration of this biomimetic nanodrug displays superior antitumor and anti-metastatic effects in tumor-bearing mice. Our findings provide a promising therapeutic strategy for the co-delivery of ferroptosis inducers and antioxidase inhibitors to strengthen the therapeutic efficacy of ferroptosis.
    DOI:  https://doi.org/10.1039/d1bm01746b
  19. Adv Exp Med Biol. 2021 ;1328 21-35
    Evaluation of the Effects of Nanomicellar Curcumin, Berberine, and Their Combination with 5-Fluorouracil on Breast Cancer Cells.
    Parisa Ziasarabi, Amirhossein Sahebkar, Faezeh Ghasemi.
       INTRODUCTION: Breast cancer is one of the main challenging areas in cancer treatment. Natural compounds such as curcumin and berberine have been approved with anticancer effects and are more favorable to people. Here, we investigated the potential synergistic anticancer effects of these two compounds in combination with the standard cancer drug 5-FU on the growth of MCF-7 breast cancer cells.
    MATERIALS AND METHODS: This study tested the effects of six different treatments on cancer cell growth: A) control; B) curcumin; C) berberine; D) 5-FU; E) curcumin + berberine; and F) curcumin + berberine + 5-FU. The IC50 concentration of each treatment on cancer cell growth was determined using the MTT assay. Invasiveness of cells grown in 3D culture was analyzed using the transwell chamber technique. Expression levels of genes involved in cancer cell growth and survival (WNT1, APC, AXIN1, CTNNB1, TCF, MTOR, AKT1, MAPK1, PTEN, BIRC5, CCNG1) were evaluated by real-time PCR.
    RESULTS: There was a reduction in cancer cell growth and invasion, and an increase in cellular decomposition across all treatment groups compared to the control with the strongest effects seen in the combined curcumin/berberine/5-FU group. The expression levels of all tested genes were altered in all treatment groups compared to the control, with that of WNT1, CTNNB1, TCF, MTOR, AKT1, BIRC5, and CCND1 showing the most robust changes in the combined curcumin/berberine/5-FU treatment.
    CONCLUSIONS: All treatment groups had anti-growth, anti-invasion, and pro-apoptotic effects on MCF-7 breast cancer cells in culture. In addition, all treatment groups showed changes in the expression of the genes involved in cancer cell growth and survival with the strongest effects found for the curcumin/berberine/5-FU combination. Therefore, curcumin and berberine may improve the anticancer effects of chemotherapy and these natural compounds should undergo further testing as potential adjuvants.
    Keywords:  5-FU; Berberine; Breast cancer; Curcumin; MCF-7 cells; Nano-curcumin
    DOI:  https://doi.org/10.1007/978-3-030-73234-9_3
  20. ACS Appl Mater Interfaces. 2022 Jan 05.
    Decagram-Scale Synthesis of Multicolor Carbon Nanodots: Self-Tracking Nanoheaters with Inherent and Selective Anticancer Properties.
    Nicolò Mauro, Mara Andrea Utzeri, Alice Sciortino, Fabrizio Messina, Marco Cannas, Radian Popescu, Dagmar Gerthsen, Gianpiero Buscarino, Gennara Cavallaro, Gaetano Giammona.
      Carbon nanodots (CDs) are a new class of carbon-based nanoparticles endowed with photoluminescence, high specific surface area, and good photothermal conversion, which have spearheaded many breakthroughs in medicine, especially in drug delivery and cancer theranostics. However, the tight control of their structural, optical, and biological properties and the synthesis scale-up have been very difficult so far. Here, we report for the first time an efficient protocol for the one-step synthesis of decagram-scale quantities of N,S-doped CDs with a narrow size distribution, along with a single nanostructure multicolor emission, high near-infrared (NIR) photothermal conversion efficiency, and selective reactive oxygen species (ROS) production in cancer cells. This allows achieving targeted and multimodal cytotoxic effects (i.e., photothermal and oxidative stresses) in cancer cells by applying biocompatible NIR laser sources that can be remotely controlled under the guidance of fluorescence imaging. Hence, our findings open up a range of possibilities for real-world biomedical applications, among which is cancer theranostics. In this work, indocyanine green is used as a bidentate SOx donor which has the ability to tune surface groups and emission bands of CDs obtained by solvothermal decomposition of citric acid and urea in N,N-dimethylformamide. The co-doping implies various surface states providing transitions in the visible region, thus eliciting a tunable multicolor emission from blue to red and excellent photothermal efficiency in the NIR region useful in bioimaging applications and image-guided anticancer phototherapy. The fluorescence self-tracking capability of SOx-CDs reveals that they can enter cancer cells more quickly than healthy cell lines and undergo a different intracellular fate after cell internalization. This could explain why sulfur doping entails pro-oxidative activities by triggering more ROS generation in cancer cells when compared to healthy cell lines. We also find that oxidative stress can be locally enhanced under the effects of a NIR laser at moderate power density (2.5 W cm-2). Overall, these findings suggest that SOx-CDs are endowed with inherent drug-independent cytotoxic effects toward cancer cells, which would be selectively enhanced by external NIR light irradiation and helpful in precision anticancer approaches. Also, this work opens a debate on the role of CD surface engineering in determining nanotoxicity as a function of cell metabolism, thus allowing a rational design of next-generation nanomaterials with targeted anticancer properties.
    Keywords:  carbon nanodots; high yield synthesis; multicolor emission; targeted cancer therapy; theranostics
    DOI:  https://doi.org/10.1021/acsami.1c19599
  21. Int J Nanomedicine. 2021 ;16 8337-8352
    Folic Acid Decorated Zeolitic Imidazolate Framework (ZIF-8) Loaded with Baicalin as a Nano-Drug Delivery System for Breast Cancer Therapy.
    Xiao Mi, Meigeng Hu, Mingran Dong, Zhihong Yang, Xia Zhan, Xinyue Chang, Juan Lu, Xi Chen.
       Background: Baicalin (BAN) has attracted widespread attention due to its low-toxicity and efficient antitumor activity, but its poor water solubility and low bioavailability severely limit its clinical application. Development of a targeted drug delivery system is a good strategy to improve the antitumor activity of baicalin.
    Methods: We prepared a BAN nano-drug delivery system PEG-FA@ZIF-8@BAN with a zeolite imidazole framework-8 (ZIF-8) as a carrier, which can achieve the response of folate receptor (FR). We characterized this system in terms of morphology, particle size, zeta-potential, infrared (IR), ultraviolet (UV), x-ray diffraction (XRD), and Brunel-Emmett-Teller (BET), and examined the in vitro cytotoxicity and cellular uptake properties of PEG-FA@ZIF-8@BAN using MCF-7 cells. Lastly, we established a 4T1 tumor-bearing mouse model and evaluated its in vivo anti-mammary cancer activity.
    Results: The PEG-FA@ZIF-8@BAN nano-delivery system had good dispersion with a BAN loading efficiency of 41.45 ± 1.43%, hydrated particle size of 176 ± 8.1 nm, Zeta-potential of -23.83 ± 1.1 mV, and slow and massive drug release in an acidic environment (pH 5.0), whereas release was 11.03% in a neutral environment (pH 7.4). In vitro studies showed that PEG-FA@ZIF-8@BAN could significantly enhance the killing effect of BAN on MCF-7 cells, and the folic acid-mediated targeting could lead to better uptake of nanoparticles by tumor cells and thus better killing of cancer cells. In vivo studies also showed that PEG-FA@ZIF-8@BAN significantly increased the inhibition of the proliferation of solid breast cancer tumors (p < 0.01 or p < 0.001).
    Conclusion: The PEG-FA@ZIF-8@BAN nano-drug delivery system significantly enhanced the anti-breast cancer effect of baicalin both in vivo and in vitro, providing a more promising drug delivery system for the clinical applications and tumor management.
    Keywords:  baicalin; breast cancer therapy; folic acid response; metal-organic framework
    DOI:  https://doi.org/10.2147/IJN.S340764
  22. Nanotheranostics. 2022 ;6(1): 79-90
    Ultrasmall gold nanorod-polydopamine hybrids for enhanced photoacoustic imaging and photothermal therapy in second near-infrared window.
    Wonjun Yim, Raina M Borum, Jiajing Zhou, Yash Mantri, Zhuohong Wu, Jingcheng Zhou, Zhicheng Jin, Matthew Creyer, Jesse V Jokerst.
      Gold nanorods (GNRs) have attracted great interest for photo-mediated biomedicines due to their tunable and high optical absorption, high photothermal conversion efficiency and facile surface modifiability. GNRs that have efficient absorption in second near-infrared (NIR-II) window hold further promise in bio-applications due to low background signal from tissue and deep tissue penetration. However, bare GNRs readily undergo shape deformation (termed as 'melting effect') during the laser illumination losing their unique localized surface plasmon resonance (LSPR) properties, which subsequently leads to PA signal attenuation and decreased photothermal efficiency. Polydopamine (PDA) is a robust synthetic melanin that has broad absorption and high photothermal conversion. Herein, we coated GNRs with PDA to prepare photothermally robust GNR@PDA hybrids for enhanced photo-mediated theranostic agents. Ultrasmall GNRs (SGNRs) and conventional large GNRs (LGNRs) that possess similar LSPR characteristics as well as GNR@PDA hybrids were compared side-by-side in terms of the size-dependent photoacoustic (PA) imaging, photothermal therapy (PTT), and structural stability. In vitro experiments further demonstrated that SGNR@PDA showed 95% ablation of SKOV3 ovarian cancer cells, which is significantly higher than that of LGNRs (66%) and SGNRs (74%). Collectively, our PDA coating strategy represents a rational design for enhanced PA imaging and efficient PTT via a nanoparticle, i.e., nanotheranostics.
    Keywords:  core-shell structure; miniature gold nanorod; second near-infrared; synthetic melanin
    DOI:  https://doi.org/10.7150/ntno.63634
  23. Front Pharmacol. 2021 ;12 764331
    Tetramethylpyrazine: A Review of Its Antitumor Potential and Mechanisms.
    Shaojie Yang, Shuodong Wu, Wanlin Dai, Liwei Pang, Yaofeng Xie, Tengqi Ren, Xiaolin Zhang, Shiyuan Bi, Yuting Zheng, Jingnan Wang, Yang Sun, Zhuyuan Zheng, Jing Kong.
      Cancer remains a major public health threat. The mitigation of the associated morbidity and mortality remains a major research focus. From a molecular biological perspective, cancer is defined as uncontrolled cell division and abnormal cell growth caused by various gene mutations. Therefore, there remains an urgent need to develop safe and effective antitumor drugs. The antitumor effect of plant extracts, which are characterized by relatively low toxicity and adverse effect, has attracted significant attention. For example, increasing attention has been paid to the antitumor effects of tetramethylpyrazine (TMP), the active component of the Chinese medicine Chuanqiong, which can affect tumor cell proliferation, apoptosis, invasion, metastasis, and angiogenesis, as well as reverse chemotherapeutic resistance in neoplasms, thereby triggering antitumor effects. Moreover, TMP can be used in combination with chemotherapeutic agents to enhance their effects and reduce the side effect associated with chemotherapy. Herein, we review the antitumor effects of TMP to provide a theoretical basis and foundation for the further exploration of its underlying antitumor mechanisms and promoting its clinical application.
    Keywords:  angiogenesis; antitumor; apoptosis; chemotherapy; ligustrazine; metastasis; multidrug resistant; tetramethylpyrazine
    DOI:  https://doi.org/10.3389/fphar.2021.764331
  24. Int J Nanomedicine. 2021 ;16 8323-8334
    Biodegradable Materials with Disulfide-Bridged-Framework Confine Photosensitizers for Enhanced Photo-Immunotherapy.
    Dongbei Li, Fangman Chen, Cheng Cheng, Haijun Li, Xudong Wei.
       Purpose: Photodynamic therapy (PDT) with spatiotemporal controlled and noninvasive advantages has obtained growing attention in cancer treatment. Nevertheless, PDT still suffers from self-aggregation-induced photosensitizer quenching and reactive oxygen species (ROS) scavenging in cancer cells with abundant glutathione (GSH) pools, leading to insufficient performance.
    Methods: In this study, we develop a versatile nanocarrier (SSNs) with a disulfide-bond-bridged silica framework for enhanced photo-immunotherapy. Such SSNs spatially confine photosensitizers Ce6 in the matrix to prevent self-aggregation. Under the high GSH level of cancer cells, the disulfide-bond-bridged framework was degradable and triggered the exposure of photosensitizers to oxygen, accelerating the ROS generation during PDT. In addition, GSH depletion via the break of the disulfide-bond increased the ROS level, together resulting in efficient tumor killing outcomes with a considerable immunogenic cell death effect in vitro. Importantly, the SSNs@Ce6 accumulated in the tumor site and exhibited enhanced PDT efficacy with low systemic toxicity in vivo.
    Results: The GEN-loaded nanoplatform (Ag-MONs@GEN) showed glutathione-responsive matrix degradation, resulting in the simultaneous controlled release of GEN and silver ions. Ag-MONs@GEN exhibited excellent anti-bacterial activities than Ag-MONs and GEN alone, especially enhancing synergetic effects against four antibiotic-resistant bacteria including Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis. Moreover, Ag-MONs@GEN showed good biocompatibility on L929 and HUVECS.
    Conclusion: Notably, SSNs@Ce6-mediated PDT completely eradicated 4T1 tumors when combined with the PD-1 checkpoint blockade. Overall, the confinement of photosensitizers in a biodegradable disulfide-bridged-framework provides a promising strategy to unleash the potential of photosensitizers in PDT, especially in combined cancer photo-immunotherapy.
    Keywords:  cancer immunotherapy; degradation; glutathione depletion; photodynamic therapy; photosensitizer confinement
    DOI:  https://doi.org/10.2147/IJN.S344679
  25. Ultrason Sonochem. 2021 Dec 29. pii: S1350-4177(21)00445-4. [Epub ahead of print]82 105903
    Triple-combination therapy assisted with ultrasound-active gold nanoparticles and ultrasound therapy against 3D cisplatin-resistant ovarian cancer model.
    Bilgi Kip, Cansu Umran Tunc, Omer Aydin.
      Cancer chemotherapy suffers from drug resistance and side effects of the drugs. Combination therapies have been attracted attention to overcome these limitations of traditional cancer treatments. Recently, increasing in intracellular chemotherapeutic concentration in the presence of ultrasonic waves (US) has been shown in the preclinical stage. In addition, some recent studies have shown that nanoparticles increase the effectiveness of ultrasound therapy. In this study, the US-active property of gold nanocones (AuNCs) was utilized for combinational US and cisplatin (Cis) to overcome drug resistance. The effect of the triple combination therapy US + AuNCs + Cis with low-dose Cis on 2/3D models of cisplatin-resistant ovarian cancer cell line (A2780cis) were investigated. In the 2D cell culture, 60% of the A2780cis cell population was suppressed with triple combination therapy; and the long-term therapeutic efficacy of the US + AuNCs + Cis with the low-dose drug was demonstrated by suppressing 83% of colony formation. According to the results in the 3D cell model, 60% of the spheroid formation was suppressed by the triple combination therapy with low-dose Cis. These results not only demonstrate the success of the US + AuNCs + Cis triple combination therapy for its long-term therapeutic effect on resistant cancer cells but also verified that it might enable effective cancer therapy in vivo and clinical stages based on the 3D tumor models. In addition, enhanced anti-cancer activity was demonstrated at the low-dose Cis on drug-resistant cancer cells indicating the triple-combination therapy successfully overcame drug resistance and this is a promising strategy to reduce the side effects of chemotherapy. This work exhibits a novel US and AuNCs-mediated combination cancer therapy, which demonstrates the role of ultrasound-active AuNCs to combat drug resistance with low-dose chemotherapy.
    Keywords:  Cisplatin; Drug resistance; Gold Nanocones; Ovarian cancer; Triple combination therapy; Ultrasound therapy; Ultrasound-active gold nanoparticles
    DOI:  https://doi.org/10.1016/j.ultsonch.2021.105903
  26. Methods Mol Biol. 2022 ;2423 141-150
    Role of Ayurvedic Plants as Anticancer Agents.
    Nikhil Pandey, Y B Tripathi.
      The use of natural products has been increasing at a rapid pace, worldwide, with the aim to maintain a healthy lifestyle and to modify one's dietary habits. Ayurveda is a domain that has numerous wealth of information concerning medicinal plants and its part in controlling numerous ailments, such as neoplastic, cardiovascular, neurological plus immunological ailments. The use of such medicinal plants is important for preventing such diseases, especially "cancer" which is the succeeding foremost cause of mortality collectively. Even though abundant developments have been made in the management and control of cancer progression, substantial deficits and scope for advancement still continue to be unchanged. Several lethal adjacent consequences occur throughout the course of chemotherapy. Natural treatments, such as the use of plant-derived products in the treatment of cancer, might reduce the hostile side effects. Presently, a few plant-based products and its phytoconstituents are being utilized for the management of cancer. Here we have focused on numerous plant-derived phytochemicals and promising compounds from these plants to act as anticancer agents, along with their mechanisms of action.
    Keywords:  Anticancer; Ayurveda; Cannabidiol (CBD); Curcumin; Genistein; Natural compounds; Phytoconstituents; Tetrahydrocannabinol (THC)
    DOI:  https://doi.org/10.1007/978-1-0716-1952-0_14
  27. Crit Rev Food Sci Nutr. 2022 Jan 07. 1-26
    Regulation of reactive oxygen species by phytochemicals for the management of cancer and diabetes.
    Heui Min Lim, See-Hyoung Park.
      Cancer and diabetes mellitus are served as typical life-threatening diseases with common risk factors. Developing therapeutic measures in cancers and diabetes have aroused attention for a long time. However, the problems with conventional treatments are in challenge, including side effects, economic burdens, and patient compliance. It is essential to secure safe and efficient therapeutic methods to overcome these issues. As an alternative method, antioxidant and pro-oxidant properties of phytochemicals from edible plants have come to the fore. Phytochemicals are naturally occurring compounds, considered promising agent applicable in treatment of various diseases with beneficial effects. Either antioxidative or pro-oxidative activity of various phytochemicals were found to contribute to regulation of cell proliferation, differentiation, cell cycle arrest, and apoptosis, which can exert preventive and therapeutic effects against cancer and diabetes. In this article, the antioxidant or pro-oxidant effects and underlying mechanisms of flavonoids, alkaloids, and saponins in cancer or diabetic models demonstrated by the recent studies are summarized.
    Keywords:  Cancers; antioxidant; diabetes; phytochemicals; pro-oxidant; reactive oxygen species
    DOI:  https://doi.org/10.1080/10408398.2022.2025574
  28. ACS Omega. 2021 Dec 28. 6(51): 35505-35513
    ICG-Loaded PEG-Modified Black Phosphorus Nanosheets for Fluorescence Imaging-Guided Breast Cancer Therapy.
    Wanwan Pan, Weijian Chen, Yuanzeng Min, Jing Wang, Zhenye Yang, Tian Xu, Fazhi Yu, Guodong Shen, Yuan Hu, Xiaopeng Ma.
      Indocyanine green (ICG) has been used in various surgical navigation systems and plays an important role in intraoperative imaging diagnosis. However, the poor photostability and unsatisfactory tumor-targeting ability have limited its broad application prospects. In the decades, the construction of a nanodrug delivery system for tumor-targeting diagnosis and therapy has become a research hotspot. Black phosphorus nanosheets (BPNS), as a new kind of biodegradable nanomaterials, have the advantages of high loading capacity, good biocompatibility, tumor targeting, and photothermal effect over other two-dimensional (2D) reported nanomaterials. Herein, ICG-loaded poly(ethylene glycol) (PEG)-modified BPNS (ICG@BPNS-PEG) nanocomposites are constructed to improve the tumor-targeting capacity and guide photothermal therapy through real-time fluorescence imaging. In this study, ICG@BPNS-PEG nanocomposites with a suitable size (240 ± 28 nm) have been successfully constructed. The photostability of ICG@BPNS-PEG nanocomposites surpassed that of free ICG after four on-off cycles of near laser irradiation (NIR). Moreover, ICG@BPNS-PEG nanocomposites have enhanced photothermal conversion ability. The cellular uptake result through flow cytometry showed that ICG@BPNS-PEG nanocomposites could be swallowed easily owing to the suitable size and passive cellular uptake. In addition, the cytotoxicity evaluation of MCF-7, 4T1 breast cancer cells, and healthy RPE cells through the MTT assay demonstrated that ICG@BPNS-PEG nanocomposites have lower cytotoxicity and good cellular compatibility without irradiation. However, the cytotoxicity and live/dead staining proved that ICG@BPNS-PEG nanocomposites have satisfactory photothermal therapeutic effects when irradiated. In the 4T1-bearing mice model, the fluorescence imaging after intravenous injection of nanocomposites showed that ICG@BPNS-PEG nanocomposites have superior passive tumor targeting accumulation through the enhanced permeability and retention (EPR) effect compared with that of free ICG. Also, changes in tumor volume showed a remarkable tumor growth inhibition effect compared with other groups. Moreover, the results of hematoxylin-eosin (H&E) staining of major organs in 4T1-bearing mice also demonstrated that the nanocomposites have good biocompatibility. Therefore, the constructed ICG@BPNS-PEG nanocomposites have substantial potential in breast cancer therapy.
    DOI:  https://doi.org/10.1021/acsomega.1c04909
  29. Mol Cell Biochem. 2022 Jan 07.
    Biphasic effect of the dietary phytochemical linalool on angiogenesis and metastasis.
    Priyanka Pal, Samarjit Jana, Ipsita Biswas, Deba Prasad Mandal, Shamee Bhattacharjee.
      Cytotoxic chemotherapy dominates the field of cancer treatment. Consequently, anticancer phytochemicals are largely screened on the basis of their cytotoxicity towards cancer cells which are achieved at higher doses, leading to various toxic side effects. Some phytochemicals also showed pro-carcinogenic effects at certain doses. The concept of hormesis has taught us to look into biphasic responses of phytochemicals in a more systematic way. Interestingly, the monoterpenoid alcohol, linalool, also has been reported to display both anti-oxidant and pro-oxidant properties, which prompted us to explore a probable biphasic effect on cancer cells. Cytotoxicity of various concentrations of linalool (0.1-4 mM) was tested on B16F10 murine melanoma cell line, and two sub-lethal concentrations (0.4 and 0.8 mM) were selected for further experiments. 0.4 mM linalool inhibited angiogenesis and metastasis, while 0.8 mM increased them. Similarly, B16F10 cell migration, invasion, and epithelial-mesenchymal transition markers also showed inhibition and induction with lower and higher linalool concentrations, respectively. Chorioallantoic membrane assay, scratch wound assay, and Boyden's chamber were used to analyze angiogenesis and metastasis. Expression of molecular markers such as vascular endothelial growth factor (VEGF) and its receptor phosphorylated VEGF receptor II (p-VEGFRII or p-Flk-1), Hypoxia-inducible factor-1 α (HIF-1α), E-cadherin, and vimentin were detected using Western blot, ELISA, PCR, qPCR, and immunofluorescence. Finally, ChIP assay was performed to evaluate HIF-1α association with VEGF promoter. Interestingly, measurement of intracellular reactive oxygen species at the selected concentrations of linalool using DCFDA in a flow cytometer showed that the phytochemical induced significant amount of ROS at 0.8 mM. This work sheds light on bimodal dose-response relationship exhibited by dietary phytochemicals like linalool, and it should be taken into consideration to elicit a desirable therapeutic effect.
    Keywords:  Angiogenesis; B16F10; Biphasic effect; Linalool; Metastasis; Oxidative stress
    DOI:  https://doi.org/10.1007/s11010-021-04341-9
  30. Nanoscale. 2022 Jan 05.
    Biomineralization-inspired synthesis of amorphous manganese phosphates for GLUT5-targeted drug-free catalytic therapy of osteosarcoma.
    Chunlin Zhang, Jianping Hu, Yingying Jiang, Shuo Tan, Kunpeng Zhu, Chao Xue, Yunlu Dai, Feng Chen.
      Osteosarcoma, occurring most frequently in children, teens, and young adults, is a lethal bone cancer with a high incidence of distant metastases and drug resistance. Developing a therapeutic platform that integrates targeting, curing and imaging is highly desirable for enhanced osteosarcoma therapy, yet quite challenging. In this work, we demonstrate a novel biomineralization-inspired strategy for the synthesis of a fructose incorporated manganese phosphate (Fru-MnP) nanoplatform for tumour targeting, drug-free therapy, and MRI imaging. Benefitting from the glucose transporter 5 (GLUT5)-mediated endocytosis, our Fru-MnP nanoplatform produces a high level of reactive oxygen species (ROS) via the Mn2+-driven Fenton reaction within osteosarcoma cells, leading to efficient cancer cell killing due to caspase-mediated apoptosis. By virtue of the T1 signal enhancement of Mn2+, our Fru-MnP nanoplatform also acts as an effective tumour-specific MRI contrast agent, realizing the MRI-monitored chemodynamic therapy. The proposed synergistic therapeutic platform opens new possibilities for high efficacy therapy for osteosarcoma.
    DOI:  https://doi.org/10.1039/d1nr06220d
  31. Adv Exp Med Biol. 2021 ;1328 81-97
    The Multifaceted Actions of Curcumin in Obesity.
    Vanessa Bianconi, Matteo Pirro, Seyed Mohammad Hassan Moallem, Muhammed Majeed, Paola Bronzo, Marco D'Abbondanza, Tannaz Jamialahmadi, Amirhossein Sahebkar.
      Obesity remains a pervasive health concern worldwide with concomitant comorbidities such as cardiovascular diseases, diabetes, inflammation, and other metabolic disorders. A wealth of data validates dietary and lifestyle modifications such as restricting caloric intake and increasing physical activity to slow the obesity development. Recently, the advent of phytochemicals such as curcumin, the active ingredient in turmeric, has attracted considerable research interest in tracking down their possible effects in protection against obesity and obesity-related comorbidities. According to the existing literature, curcumin may regulate lipid metabolism and suppress chronic inflammation interacting with white adipose tissue, which plays a central role in the complications associated with obesity. Curcumin also inhibits the differentiation of adipocyte and improves antioxidant properties. In the present review, we sought to deliberate the possible effects of curcumin in downregulating obesity and curtailing the adverse health effects of obesity.
    Keywords:  Adiposity; Curcumin; Inflammation; Metabolism
    DOI:  https://doi.org/10.1007/978-3-030-73234-9_6
  32. J Biomater Appl. 2022 Jan 07. 8853282211058099
    Biomedical applications of tannic acid.
    Andrew Baldwin, Brian W Booth.
      Tannic Acid (TA) is a naturally occurring antioxidant polyphenol that has gained popularity over the past decade in the field of biomedical research for its unique biochemical properties. Tannic acid, typically extracted from oak tree galls, has been used in many important historical applications. TA is a key component in vegetable tanning of leather, iron gall ink, red wines, and as a traditional medicine to treat a variety of maladies. The basis of TA utility is derived from its many hydroxyl groups and its affinity for forming hydrogen bonds with proteins and other biomolecules. Today, the study of TA has led to the development of many new pharmaceutical and biomedical applications. TA has been shown to reduce inflammation as an antioxidant, act as an antibiotic in common pathogenic bacterium, and induce apoptosis in several cancer types. TA has also displayed antiviral and antifungal activity. At certain concentrations, TA can be used to treat gastrointestinal disorders such as hemorrhoids and diarrhea, severe burns, and protect against neurodegenerative diseases. TA has also been utilized in biomaterials research as a natural crosslinking agent to improve mechanical properties of natural and synthetic hydrogels and polymers, while also imparting anti-inflammatory, antibacterial, and anticancer activity to the materials. TA has also been used to develop thin film coatings and nanoparticles for drug delivery. In all, TA is fascinating molecule with a wide variety of potential uses in pharmaceuticals, biomaterials applications, and drug delivery strategies.
    Keywords:  Tannic acid; antibiotic; antioxidant; biomaterials; cancer; chemotherapy; inflammation; nanoparticles; toxicity
    DOI:  https://doi.org/10.1177/08853282211058099
  33. J Drug Target. 2022 Jan 07. 1-12
    Smart delivery of epirubicin to cancer cells using aptamer-modified ferritin nanoparticles.
    Rezvan Yazdian-Robati, Payam Bayat, Sina Dehestani, Maryam Hashemi, Seyed Mohammad Taghdisi, Khalil Abnous.
      Epirubicin is a chemotherapy agent which is commonly used in treatment of cancers. However, despite being efficient, the tendency to use this drug is declining mostly due to its myocardiopathy and drug-resistance of tumor cells. Such side effects could be prevented using targeted nanocarriers. This study aims to evaluate targeted delivery of epirubicin (Epi) to colon cancer cells using ferritin nanoparticles (Ft NPs) and MUC1 aptamer (Apt) and formation of Apt-Epi Ft NPs. In the current study, Apt-Epi Ft NPs were prepared. Then, physicochemical properties of nanoparticles, including size and zeta potential, morphology, drug loading, drug release from nanoparticles, drug uptake of cancer cells, cytotoxicity and in vivo results were collected. The results showed that the nanoparticles were synthesized with a mean size of 37.9 nm and encapsulation efficiency of 67%. The drug release from these nanoparticles was about 90% within 4 h in acidic medium. Also, targeted delivery of Epi enhanced its anticancer effects in both in vitro and in vivo. In this study, targeted delivery of Epi using aptamer-modified ferritin nanoparticles improved in vitro and in vivo results which indicates that it could be useful as a successful drug delivery system against cancer cells.
    Keywords:  Epirubicin; Ferritin; MUC-1 Aptamer; Smart drug delivery system; pH sensitive
    DOI:  https://doi.org/10.1080/1061186X.2022.2025600
  34. Adv Mater. 2022 Jan 06. e2109036
    Synergistic Disruption of Metabolic Homeostasis Through Hyperbranched Poly(ethylene glycol) Conjugates As Nanotherapeutics to Constrain Cancer Growth.
    Dayi Pan, Xiuli Zheng, Lu Zhang, Xin Li, Guonian Zhu, Meng Gong, Michal Kopytynski, Luonan Zhou, Yong Yi, Hongyan Zhu, Xiaohe Tian, Rongjun Chen, Hu Zhang, Zhongwei Gu, Qiyong Gong, Kui Luo.
      Combination therapy is a promising approach for effective treatment of tumors through synergistically regulating pathways. However, the synergistic effect is limited, likely by uncontrolled co-delivery of different therapeutic payloads in a single nanoparticle. Herein, we developed a combination nanotherapeutic by using two amphiphilic conjugates hyperbranched poly(ethylene glycol)-pyropheophorbide-a (Ppa) (HP-P) and hyperbranched poly(ethylene glycol)-doxorubicin (DOX) (HP-D) to construct co-assembly nanoparticles (HP-PD NPs) for controllably co-loading and co-delivering Ppa and DOX. In vitro and in vivo anti-tumor studies confirmed the synergistic effect of photodynamic therapy and chemotherapy from HP-PD NPs. Metabolic variations revealed that tumor suppression was associated with disruption of metabolic homeostasis, leading to reduced protein translation. Our study uncovers the manipulation of metabolic changes in tumor cells through disruption of cellular homeostasis using HP-PD NPs and provides a new insight into rational design of synergistic nanotherapeutics for combination therapy. This article is protected by copyright. All rights reserved.
    Keywords:  combination therapy; computational simulation; hyperbranched polymer; multi-omics; self-assembly; tumor metabolism
    DOI:  https://doi.org/10.1002/adma.202109036
  35. Biotechnol Appl Biochem. 2022 Jan 07.
    Vitamin K: A Novel Cancer Chemosensitizer.
    Sameena Gul, Muhammad Faisal Maqbool, Amara Maryam, Muhammad Khan, Hafiz Abdullah Shakir, Muhammad Irfan, Chaman Ara, Yongming Li, Tonghui Ma.
      Cancer incidences are growing rapidly and causing millions of deaths globally. Cancer treatment is one of the most exigent challenges. Drug resistance is a natural phenomenon and is considered as one of the major obstacles in successful treatment of cancer by chemotherapy. Combination therapy by amalgamation of various anticancer drugs has suggested modulating tumor response by targeting various signaling pathways in synergistic or additive manner. Vitamin K is an essential nutrient and have recently been investigated as a potential anticancer agent. Combination of Vitamin K analogues such as Vitamin K1, Vitamin K2, Vitamin K3 and Vitamin K5 with other chemotherapeutic drugs have demonstrated a safe, cost effective and most efficient way to overcome drug resistance and improve the outcomes of prevailing chemotherapy. Published research reports have shown that Vitamin K in combination therapy improved the efficacy of clinical drugs by promoting apoptosis and cell cycle arrest and overcome drug resistance by inhibiting P-glycoprotein. In this review article, we discuss the mechanism, cellular targets and possible way to develop Vitamin K subtypes into effective cancer chemosensitizers. Finally, this review article will provide scientific basis for exploiting Vitamin K as a potential agent to improve the efficacy of chemotherapeutic drugs. This article is protected by copyright. All rights reserved.
    Keywords:  apoptosis. cancer chemosensitizers; cell cycle arrest; combination therapy; multiple signaling pathways; vitamin K
    DOI:  https://doi.org/10.1002/bab.2312
  36. SAGE Open Med. 2021 ;9 20503121211067083
    A recent development of new therapeutic agents and novel drug targets for cancer treatment.
    Zemene Demelash Kifle, Meklit Tadele, Eyerusalem Alemu, Tadele Gedamu, Akeberegn Gorems Ayele.
      Despite recent advances in cancer diagnosis, prevention, detection, as well as management, the disease is expected to be the top cause of death globally. The chemotherapy approach for cancer has become more advanced in its design, yet no medication can cure enough against all types of cancer and its stage. Thus, this review aimed to summarize a recent development of new therapeutic agents and novel drug targets for the treatment of cancer. Several obstacles stand in the way of effective cancer treatment and drug development, including inaccessibility of tumor site by appropriate drug concentration, debilitating untoward effects caused by non-selective tissue distribution of chemotherapeutic agents, and occurrence of drug resistance, which leads to cross-resistance to a variety of drugs. Resistance to treatment with anticancer drugs results from multiple factors and the most common reason for acquiring drug resistance is marking and expelling drugs that prevent cancer cells to be targeted by chemotherapeutic agents. Moreover, insensitivity to drug-induced apoptosis, alteration, and mutation of drug target and interference/change of DNA replication are other main causes of treatment failure.
    Keywords:  Cancer; development; drug targets; therapeutic agent
    DOI:  https://doi.org/10.1177/20503121211067083
  37. Adv Exp Med Biol. 2021 ;1328 421-440
    Therapeutic Potential of Pomegranate in Metabolic Disorders.
    Maryam Akaberi, Zahra Boghrati, Amirhossein Sahebkar, Seyed Ahmad Emami.
      Metabolic syndrome and associated disorders have become one of the major challenging health problems over the last decades. Considerable attention has been paid to natural products and herbal medicines for the management of metabolic disorders in recent years. Many studies have investigated the therapeutic effects of different parts (arils, peels, seeds, and flowers) of pomegranate (Punica granatum L.) for the prevention and treatment of this syndrome. This study aims to provide an updated review on the in vitro and in vivo studies as well as clinical trials investigating the effects of pomegranate and its active compounds on different components of metabolic problems such as hyperglycemia, hyperlipidemia, hypertension, as well as obesity over the last two decades. Besides, the key mechanisms by which pomegranate affects these pathogenic conditions are also discussed. The studies show that although pomegranate has promising beneficial effects on diabetes, hypertension, hyperlipidemia, and obesity in various cellular, animal, and clinical models of studies, there are some conflicting results, particularly for hyperglycemic conditions. The main mechanisms include influencing oxidative stress and anti-inflammatory responses. Overall, pomegranate seems to have positive effects on the pathogenic conditions of metabolic syndrome according to the reviewed studies. Although pomegranate is not suggested as the first line of therapy or monotherapy, it could be only used as an adjunctive therapy. Nevertheless, further large and long-term clinical studies are still required.
    Keywords:  Ellagic acid; Lythraceae; Metabolic syndrome; Pomegranate; Punica granatum; Punicalagin; Punicic acid
    DOI:  https://doi.org/10.1007/978-3-030-73234-9_28
  38. ACS Biomater Sci Eng. 2022 Jan 06.
    ROS-Mediated Anti-Angiogenic Activity of Cerium Oxide Nanoparticles in Melanoma Cells.
    Joel M Yong, Lu Fu, Fengying Tang, Peimin Yu, Rhiannon P Kuchel, John M Whitelock, Megan S Lord.
      Angiogenesis plays a key role in cancer progression, including transition to the metastatic phase via reactive oxygen species (ROS)-dependent pathways, among others. Antivascular endothelial growth factor (VEGF) antibodies have been trialed as an anti-angiogenic therapy for cancer but are associated with high cost, limited efficacy, and side effects. Cerium oxide nanoparticles (nanoceria) are promising nanomaterials for biomedical applications due to their ability to modulate intracellular ROS. Nanoceria can be produced by a range of synthesis methods, with chemical precipitation as the most widely explored. It has been reported that chemical precipitation can fine-tune primary particle size where a limited number of synthesis parameters were varied. Here, we explore the effect of temperature, precipitating agent concentration and rate of addition, stirring rate, and surfactant concentration on nanoceria primary particle size using a fractional factorial experimental design approach. We establish a robust synthesis method for faceted nanoceria with primary particle diameters of 5-6 nm. The nanoceria are not cytotoxic to a human melanoma cell line (Mel1007) at doses up to 400 μg/mL and are dose-dependently internalized by the cells. The intracellular ROS level for some cells that internalized the nanoceria is reduced, which correlates with a dose-dependent reduction in angiogenic gene expression including VEGF. These findings contribute to our knowledge of the anti-angiogenic effects of nanoceria and help to develop our understanding of potentially new anti-angiogenic agents for combination cancer therapies.
    Keywords:  angiogenesis; cerium oxide; melanoma; nanoparticle; redox
    DOI:  https://doi.org/10.1021/acsbiomaterials.1c01268
  39. J Trace Elem Med Biol. 2021 Dec 22. pii: S0946-672X(21)00206-6. [Epub ahead of print]70 126916
    Evaluation of cytotoxic activity of Fe doped cobalt oxide nanoparticles.
    C S Jincy, P Meena.
       BACKGROUND: This contribution of work describes a new strategy for manufacturing cobalt oxide nanoparticles and the results assured that, its efficiency was increased by adding Fe ions. The anticancer drugs usually have a limited medical value owing to their nonspecific cytotoxicity. It has been proven that by using the nanosystems to deliver tablets to tumour cells reduces the toxic quality. Because of these qualities, nanoparticles can be used as a stronger rival for potent cancer treatment.
    METHOD: This study investigated the cytotoxicity of iron doped cobalt oxide nanoparticles through trypan blue exclusion method.
    RESULT: The newly generated Fe doped Co3O4 nanoparticles had proved its biocompatibility from the report of reduced toxicity below 200 μg/mL on malignant cell lines.
    CONCLUSION: The observed findings may encourage the development of anticancer drugs based on the inorganic particles, especially Fe doped Co3O4 nanoparticles, that could be serve as an excellent framework for the drug delivery and provide a new perspective for interpreting and targeting various therapeutic methodologies to tumours.
    Keywords:  Cell viability; Cobalt oxide; Doping; Drug delivery; Nanotechnology
    DOI:  https://doi.org/10.1016/j.jtemb.2021.126916
  40. J Nanobiotechnology. 2022 Jan 04. 20(1): 14
    A novel therapeutic strategy of multimodal nanoconjugates for state-of-the-art brain tumor phototherapy.
    Hyung Shik Kim, Minwook Seo, Tae-Eun Park, Dong Yun Lee.
       BACKGROUND: The outcome of phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT) for glioblastoma multiforme (GBM), is disappointing due to insufficient photoconversion efficiency and low targeting rate. The development of phototherapeutic agents that target GBM and generate high heat and potent ROS is important to overcome the weak anti-tumor effect.
    RESULTS: In this study, nanoconjugates composed of gold nanoparticles (AuNPs) and photosensitizers (PSs) were prepared by disulfide conjugation between Chlorin e6 (Ce6) and glutathione coated-AuNP. The maximum heat dissipation of the nanoconjugate was 64.5 ± 4.5 °C. Moreover, the proximate conjugation of Ce6 on the AuNP surface resulted in plasmonic crossover between Ce6 and AuNP. This improves the intrinsic ROS generating capability of Ce6 by 1.6-fold compared to that of unmodified-Ce6. This process is called generation of metal-enhanced reactive oxygen species (MERos). PEGylated-lactoferrin (Lf-PEG) was incorporated onto the AuNP surface for both oral absorption and GBM targeting of the nanoconjugate (denoted as Ce6-AuNP-Lf). In this study, we explored the mechanism by which Ce6-AuNP-Lf interacts with LfR at the intestinal and blood brain barrier (BBB) and penetrates these barriers with high efficiency. In the orthotopic GBM mice model, the oral bioavailability and GBM targeting amount of Ce6-AuNP-Lf significantly improved to 7.3 ± 1.2% and 11.8 ± 2.1 μg/kg, respectively. The order of laser irradiation, such as applying PDT first and then PTT, was significant for the treatment outcome due to the plasmonic advantages provided by AuNPs to enhance ROS generation capability. As a result, GBM-phototherapy after oral administration of Ce6-AuNP-Lf exhibited an outstanding anti-tumor effect due to GBM targeting and enhanced photoconversion efficiency.
    CONCLUSIONS: The designed nanoconjugates greatly improved ROS generation by plasmonic crossover between AuNPs and Ce6, enabling sufficient PDT for GBM as well as PTT. In addition, efficient GBM targeting through oral administration was possible by conjugating Lf to the nanoconjugate. These results suggest that Ce6-AuNP-Lf is a potent GBM phototherapeutic nanoconjugate that can be orally administered.
    Keywords:  Generation of metal-enhanced reactive oxygen species (MERos); Glioblastoma multiforme (GBM); Gold nanoparticles (AuNPs); Oral absorbable GBM targeting; Photodynamic photothermal combination therapy (PDT + PTT)
    DOI:  https://doi.org/10.1186/s12951-021-01220-9
  41. Prim Care Diabetes. 2022 Jan 04. pii: S1751-9918(21)00233-3. [Epub ahead of print]
    Phytochemical and pharmacological anti-diabetic properties of bilberries (Vaccinium myrtillus), recommendations for future studies.
    Anita Chehri, Reza Yarani, Zahra Yousefi, Seyed Kazem Shakouri, Alireza Ostadrahimi, Majid Mobasseri, Mostafa Araj-Khodaei.
      Nowadays, extensive attention has focused on dietary constituents that may be valuable for treating, eating, and preventing diabetes. Numerous studies have shown that anthocyanin's are one of the most important nutritional factors associated with diabetes. Anthocyanin's are the leading group of water-soluble pigments in the plant kingdom, and they are generally available in some human diet in fruits, vegetables, cereals, beans. Amongst, bilberries (Vaccinium myrtillus), is one of the essential sources for dietary anthocyanin consumption containing vast amounts of anthocyanin's, making them the main plant in the treatment and prevention of diabetes. Although the bilberries have other valuable properties such as anti-cancer, anti-inflammatory, and antioxidant, the main focus of the present study is to present the effects of bilberries (V. myrtillus) on the prevention and treatment of diabetes.
    Keywords:  Anthocyanins; Bilberries; Diabetes mellitus; Vaccinium myrtillus
    DOI:  https://doi.org/10.1016/j.pcd.2021.12.017
  42. Adv Sci (Weinh). 2022 Jan 05. e2101935
    Lymph-Directed Self-Immolative Nitric Oxide Prodrug for Inhibition of Intractable Metastatic Cancer.
    Taejeong Kim, Jeeyeon Suh, Jihoon Kim, Won Jong Kim.
      There has been a significant clinical demand for lymph-directed anti-metastatic therapy as tumor-draining lymph nodes play pivotal roles in cancer metastasis which accounts for more than 90% of tumor-related deaths. Despite the high potential of nitric oxide (NO) in anti-cancer therapy owing to its biocompatibility and tumor cell-specific cytotoxicity, the poor stability and lack of target specificity of present NO donors and delivery systems have limited its clinical applications. Herein, a redox-triggered self-immolative NO prodrug that can be readily conjugated to various materials containing free thiol groups such as albumin, is reported. The prodrug and its conjugates demonstrate smart release of NO donor via intramolecular cyclization under reductive conditions, followed by spontaneously generating NO in physiological conditions. The albumin-prodrug conjugate inhibits tumor metastasis by inducing cytotoxicity preferentially on tumor cells after efficiently draining into lymph nodes. This novel prodrug can contribute to the development of on-demand NO delivery systems for anti-metastatic therapy and other treatments.
    Keywords:  lymph-directed drug delivery; metastatic cancer therapy; nitric oxide; prodrug; redox chemistry
    DOI:  https://doi.org/10.1002/advs.202101935
  43. Mater Today Bio. 2022 Jan;13 100189
    Cascade targeting codelivery of ingenol-3-angelate and doxorubicin for enhancing cancer chemoimmunotherapy through synergistic effects in prostate cancer.
    Zhicheng Wang, Chao Sun, Haijun Wu, Jizhen Xie, Tong Zhang, Yumin Li, Xuelian Xu, Peilin Wang, Cheng Wang.
      Immunotherapy has led to an expansion of the treatment of malignancies, but its effect in prostate cancer (PCa) patients is modest. Chemoimmunotherapy is a promising approach that has attracted substantial attention. Although the widely used clinical chemotherapeutic drug doxorubicin (DOX) elicits immunogenic cell death (ICD), its weak ICD effect and the abnormal vasculature of tumors severely limit its efficacy in chemoimmunotherapy. Ingenol-3-angelate (I3A), an emerging antitumor drug with dual chemotherapeutic and immune response-eliciting effects, is expected to exert synergistic effects when administered in combination with DOX. I3A induces the ICD of PCa cells by triggering mitophagy and apoptosis and promotes the normalization of tumor vessels, resulting in sufficient infiltration of immune cells into tumors. A synergistic effect of I3A and DOX was observed in vitro at a molar ratio of 1:4. To codeliver this ratio of I3A and DOX to tumor and ensure their uptake, we designed a dual-targeting delivery system, polylactide-poly(ethylene) glycol-2-(3-((S)-5-amino-1-carboxypentyl)-ureido) pentanedioate/triphenylphosphonium (PLA-PEG-ACUPA/TPP), which targets prostate-specific membrane antigen (PSMA) and mitochondria. Delivery of these nanomedicines led to inhibited tumor growth and a strong antitumor immune response. This study sheds light on the mitophagic and antiangiogenic mechanisms underlying I3A treatment of PCa and provides a strategy for combining vascular normalization and chemoimmunotherapy for PCa treatment.
    Keywords:  Anti-angiogenesis; Chemoimmunotherapy; Immunogenic cell death; Ingenol-3-angelate; Mitophagy; Nanoparticles
    DOI:  https://doi.org/10.1016/j.mtbio.2021.100189
  44. J Biomed Nanotechnol. 2021 Dec 01. 17(12): 2399-2412
    Myricetin-Based Self-Assembled Nanoparticles for Tumor Synergistic Therapy by Antioxidation Pathway.
    Yumei Qian, Fang Zhao, Jing Wang, Hongxia Li, Lisheng Xu, Weiwei Wang, Weixiong Yu, Lingling Shan.
      Nanoplatforms are nano-scale systems that can transport different small molecular anticancer drugs or chemosensitization motif to accumulate in tumor cells without obvious side-effect in normal cells and achieve a synergistic therapy. In this paper the new self-assembled nanoparticles (NPs) merging doxorubicin (DOX) and myricetin (MYR) with ferric ions (Fe3+) and polyphenol was employed for forming the DOX@MYR-Fe3+ NP (FDMP NP). The FDMP NPs could reduce the DOX-induced toxicity in blood; and they could not cause damage to the heart and kidney tissues by the reasons that the MYR could enhance the anti-oxidation capability in normal cells, which resulted in preventing ROS-induced damage. Additionally, the FDMP NPs were characteristic of small size (37.70 ± 6.30 nm), high DOX loading efficiency (46.67 ± 1.58%), pH-controlled release and excellent stable pharmacokinetics, that inducing drug release and enhancing drug accumulation in the tumor. Moreover, the FDMP NPs could inhibit the expression of the hypoxia-inducible factor-1 α(HIF-1α) and the key angiogenesis mediator vascular endothelial growth factor (VEGF) both in vitro and in vivo, which succeed in preventing the generation of new blood vessel networks; that is the mechanism of the synergistic effect against tumors induced by FDMP NPs.
    DOI:  https://doi.org/10.1166/jbn.2021.3197
  45. Biomaterials. 2021 Dec 30. pii: S0142-9612(21)00714-6. [Epub ahead of print]281 121358
    Harnessing in situ glutathione for effective ROS generation and tumor suppression via nanohybrid-mediated catabolism dynamic therapy.
    Si-Yuan Peng, Xin-Hua Liu, Qi-Wen Chen, Yun-Jian Yu, Miao-Deng Liu, Xian-Zheng Zhang.
      The overexpression of glutathione (GSH) in cancer cells has long been regarded as the primary obstacle for reactive oxygen species (ROS)-involved anti-tumor therapies. To solve this issue, a ferric ion and selenite-codoped calcium phosphate (Fe/Se-CaP) nanohybrid here is fabricated to catabolize endogenous GSH, instead of directly deleting it, to trigger a ROS storm for tumor suppression. The selenite component in Fe/Se-CaP can catabolize GSH to superoxide anion (O2•-) and hydroxyl radicals (•OH) via cascade catalytic reactions, elevating oxidative stress while destroying antioxidant system. The doped Fe can further catalyze the soaring hydrogen peroxide (H2O2) originated from O2•- to •OH via Fenton reactions. Collectively, Fe/Se-CaP mediated self-augmented catabolism dynamic therapy finally induces apoptosis of cancer cells owing to the significant rise of ROS and, combined with CaP adjuvant, evokes adaptive immune responses to suppress tumor progression, providing an innovative train of thought for ROS-involved anti-tumor therapies.
    Keywords:  Biocascade conversion; Glutathione catabolism; Immune response; Reactive oxygen species; Tumor therapy
    DOI:  https://doi.org/10.1016/j.biomaterials.2021.121358
  46. Int J Nanomedicine. 2021 ;16 8279-8303
    In vitro and in vivo Evaluation of a Novel Estrogen-Targeted PEGylated Oxaliplatin Liposome for Gastric Cancer.
    Yuxin Sun, Yizhuo Xie, Huan Tang, Zhihui Ren, Xue Luan, Yan Zhang, Ming Zhu, Zhe Lv, Han Bao, Yan Li, Rui Liu, Yujia Shen, Yucui Zheng, Jin Pei.
       Background: Chemotherapy is still the main first-line treatment for advanced metastatic gastric cancer, but it has the limitations of serious side effects and drug resistance. Conventional liposome has been substantially used as drug carriers, but they lack targeting character with lower drug bioavailability in tumor tissues. Based on the above problems, a novel estrogen-targeted PEGylated liposome loaded with oxaliplatin (ES-SSL-OXA) was prepared to further improve the metabolic behavior, the safety profile, and the anti-tumor efficacy of oxaliplatin.
    Methods: Four kinds of oxaliplatin (OXA) liposomes were prepared by film hydration method. The obtained formulations were characterized in terms of entrapment efficiency (EE), particle size, and so on by HPLC and DLS (dynamic light scanning). The morphology of ES-SSL-OXA was detected by transmission electron microscope (TEM). The in vitro and in vivo targeting effect of ES-SSL-OXA was verified by fluorescence microscopy and in vivo imaging system in gastric cancer cells (SGC-7901) and tumor-bearing athymic mice. The in vitro and in vivo antitumor efficacies of ES-SSL-OXA were investigated on SGC-7901 cells and athymic tumor-bearing mice. Pharmacokinetic, biodistribution, and acute toxicity tests of ES-SSL-OXA were performed on ICR mice.
    Results: The ES-SSL-OXA exhibited an average particle size of about 153.37 nm with an encapsulation efficiency of 46.20% and low leakage rates at 4°C and 25°C. In vivo and in vitro targeting study confirmed that ES-SSL-OXA could effectively target the tumor site. The antitumor activity demonstrated the strongest inhibition in tumor growth of ES-SSL-OXA. Pharmacokinetics and acute toxicity study showed that ES-SSL-OXA could significantly improve the metabolic behavior and toxicity profile of oxaliplatin.
    Conclusion: In this study, a novel estrogen-targeted long-acting liposomal formulation of OXA was successfully prepared. ES fragment effectively targeted the delivery system to tumor tissues which highly express estrogen receptor, providing a promising therapeutic method for gastric cancer in clinic.
    Keywords:  antitumor activity; chemotherapy; estrogen receptors; long-acting liposomes; pharmacokinetics; targeted drug delivery
    DOI:  https://doi.org/10.2147/IJN.S340180
  47. ACS Appl Mater Interfaces. 2022 Jan 05.
    Near-Infrared Light-Controllable Multifunction Mesoporous Polydopamine Nanocomposites for Promoting Infected Wound Healing.
    Wei-Nan Zeng, Duan Wang, Qiu-Ping Yu, Ze-Ping Yu, Hao-Yang Wang, Cheng-Yu Wu, Si-Wei Du, Xing-Yu Chen, Jia-Fei Li, Zong-Ke Zhou, Yu Zeng, Yun Zhang.
      The successful treatment of infected wounds requires strategies with effective antimicrobial, anti-inflammatory, and healing-promoting properties. Accordingly, the use of Cu2+ and tetracycline (TC), which can promote angiogenesis, re-epithelialization, and collagen deposition, also antibacterial activity, at the wound site, has shown application prospects in promoting infected wound repair. However, realizing controllable release to prolong action time and avoid potential toxicities is critical. Moreover, near-infrared light (NIR)-activated mesoporous polydopamine nanoparticles (MPDA NPs) reportedly exert anti-inflammatory effects by eliminating the reactive oxygen species generated during inflammatory responses. In this study, we assess whether Cu2+ and TC loaded in MPDA NPs can accelerate infected wound healing in mice. In particular, Cu2+ is chelated and immobilized on the surface of MPDA NPs, while a thermosensitive phase-change material (PCM; melting point: 39-40 °C), combined with antibiotics, was loaded into the MPDA NPs as a gatekeeper (PPMD@Cu/TC). Results show that PPMD@Cu/TC exhibits significant great photothermal properties with NIR irradiation, which induces the release of Cu2+, while inducing PCM melting and, subsequent, TC release. In combination with anti-inflammatory therapy, NIR-triggered Cu2+ and TC release enables the nanocomposite to eradicate bacterial wound infections and accelerate healing. Importantly, negligible damage to primary organs and satisfactory biocompatibility were observed in the murine model. Collectively, these findings highlight the therapeutic potential of this MPDA-based platform for controlling bacterial infection and accelerating wound healing.
    Keywords:  angiogenesis; antibacterial; infected wound healing; mesoporous polydopamine; multifunction nanocomposites
    DOI:  https://doi.org/10.1021/acsami.1c19209
  48. Drug Deliv. 2022 Dec;29(1): 192-202
    Amplification of anticancer efficacy by co-delivery of doxorubicin and lonidamine with extracellular vesicles.
    Huizhen Li, Wan Xu, Fang Li, Ru Zeng, Xiuming Zhang, Xianwu Wang, Shaojun Zhao, Jian Weng, Zhu Li, Liping Sun.
      Chemotherapy is commonly used for the treatment of lung cancer, but strong side effects and low treatment efficacy limit its clinical application. Here, extracellular vesicles (EVs) as natural drug delivery carriers were used to load conventional anticancer drug doxorubicin (DOX) and a chemosensitizer lonidamine (LND). Two types of EVs with different sizes (16k EVs and 120k EVs) were prepared using different centrifugation forces. We found that co-delivery of DOX and LND with both EVs enhanced the cytotoxicity and reduced the dose of the anticancer drug significantly in vitro. Effective delivery of anti-cancer drugs to cancer cells was achieved by direct fusion of EVs with the plasma membrane of cancer cells. On the other hand, DOX and LND inhibited cancer cell proliferation by increasing DNA damage, suppressing ATP production, and accelerating ROS generation synergistically. DOX and LND loaded EVs were also applied to the mouse lung cancer model and exhibited significant anticancer activity. In vivo study showed that smaller EVs exhibited higher anticancer efficiency. In conclusion, the co-delivery of the anticancer drug and the chemosensitizer with EVs may have potential clinical applications for cancer therapy.
    Keywords:  Extracellular vesicles; cancer therapy; doxorubicin; lonidamine; lung cancer
    DOI:  https://doi.org/10.1080/10717544.2021.2023697
  49. J Mater Chem B. 2022 Jan 05.
    Coating gold nanorods with silica prevents the generation of reactive oxygen species under laser light irradiation for safe biomedical applications.
    Sarra Mitiche, Syrine Gueffrache, Sylvie Marguet, Jean-Frédéric Audibert, Robert Bernard Pansu, Bruno Palpant.
      Gold nanoparticles can produce reactive oxygen species (ROS) under the action of ultrashort pulsed light. While beneficial for photodynamic therapy, this phenomenon is prohibitive for other biomedical applications such as imaging, photo-thermal drug release, or targeted gene delivery. Here, ROS are produced in water by irradiating gold nanorods and silica-coated gold nanorods with near-infrared femtosecond laser pulses and are detected using two fluorescent probes. Our results demonstrate that a dense silica shell around gold nanorods inhibits the formation of singlet oxygen (1O2) and hydroxyl radical (˙OH) efficiently. The silica coating prevents the Dexter energy transfer between the nanoparticles and 3O2, stopping thus the generation of 1O2. In addition, numerical simulations accounting for the use of ultrashort laser pulses show that the plasmonic field enhancement at the nanoparticle vicinity is lessened once adding the silica layer. With the multiphotonic ejection of electrons being also blocked, all the possible pathways for ROS production are hindered by adding the silica shell around gold nanorods, making them safer for a range of biomedical developments.
    DOI:  https://doi.org/10.1039/d1tb02207e
  50. Carbohydr Polym. 2022 Mar 01. pii: S0144-8617(21)01400-4. [Epub ahead of print]279 119013
    Review on design strategies and considerations of polysaccharide-based smart drug delivery systems for cancer therapy.
    Qingye Meng, Shuangling Zhong, Lifeng Xu, Jingfei Wang, Zhenqian Zhang, Yan Gao, Xuejun Cui.
      The unique natural advantages of polysaccharide materials have attracted attention in biomedical applications. The abundant modifiable functional groups on the polysaccharide materials surface can facilitate the synthesis of various multifunctional drug delivery carriers. Especially in tumor therapy, the designs of polysaccharide-based drug delivery carriers are diverse. Therefore, this review summarized several latest types of polysaccharide-based drug carriers designs, and focused on the latest design strategies and considerations of drug carriers with polysaccharides as the main structure. It is expected to provide some design ideas and inspiration for subsequent polysaccharide-based drug delivery systems.
    Keywords:  Cancer therapy; Drug delivery system; Polysaccharide
    DOI:  https://doi.org/10.1016/j.carbpol.2021.119013
  51. Food Res Int. 2022 Jan;pii: S0963-9969(21)00719-5. [Epub ahead of print]151 110819
    Anti-obesity natural products and gut microbiota.
    Shang-Zhen Li, Su-Ling Zeng, E-Hu Liu.
      The link between gut microbiota and obesity or other metabolic syndromes is growing increasingly clear. Natural products are appreciated for their beneficial health effects in humans. Increasing investigations demonstrated that the anti-obesity bioactivities of many natural products are gut microbiota dependent. In this review, we summarized the current knowledge on anti-obesity natural products acting through gut microbiota according to their chemical structures and signaling metabolites. Manipulation of the gut microbiota by natural products may serve as a potential therapeutic strategy to prevent obesity.
    Keywords:  Bacterial messengers; Gut microbiota; Natural products; Obesity
    DOI:  https://doi.org/10.1016/j.foodres.2021.110819
  52. Cureus. 2021 Nov;13(11): e19953
    Inflammatory Markers, Metabolic Profile, and Psychoneurological Symptoms in Women with Breast Cancer: A Literature Review.
    Ahmad M Al-Bashaireh, Omar Khraisat, Eman K Alnazly, Mohannad Aldiqs.
      Breast cancer is one of the most prevalent cancers in women. The improvement in breast cancer treatment has significantly increased the proportion of survival rate for women with breast cancer. Despite the advancement in breast cancer treatment, a great proportion of survivors suffer from co-occurring psychoneurological symptoms which impact their quality of life. The most frequently reported psychoneurological symptoms among women with breast cancer are depressive symptoms, anxiety, fatigue, sleep disturbances, and pain. These symptoms usually appear as a cluster. Inflammatory activation and serum metabolic alterations have been associated with the etiology of cancer and with various chronic neurocognitive disorders. However, to date, no studies considered the combined effects of inflammatory markers and metabolites in the development of psychoneurological symptoms in women with breast cancer especially those who were treated with chemotherapy. Further clarification of the relationships between the inflammatory markers, serum metabolic alterations, and psychoneurological symptoms in women with breast cancer should be pursued.
    Keywords:  breast cancer; inflammatory markers; metabolic profile; metabolites; psychoneurological symptoms
    DOI:  https://doi.org/10.7759/cureus.19953
  53. Integr Cancer Ther. 2022 Jan-Dec;21:21 15347354211067469
    Therapeutic Potential of Emodin for Gastrointestinal Cancers.
    Sierra J McDonald, Brandon N VanderVeen, Kandy T Velazquez, Reilly T Enos, Ciaran M Fairman, Thomas D Cardaci, Daping Fan, E Angela Murphy.
      Gastrointestinal (GI) cancers cause one-third of all cancer-related deaths worldwide. Natural compounds are emerging as alternative or adjuvant cancer therapies given their distinct advantage of manipulating multiple pathways to both suppress tumor growth and alleviate cancer comorbidities; however, concerns regarding efficacy, bioavailability, and safety are barriers to their development for clinical use. Emodin (1,3,8-trihydroxy-6-methylanthraquinone), a Chinese herb-derived anthraquinone, has been shown to exert anti-tumor effects in colon, liver, and pancreatic cancers. While the mechanisms underlying emodin's tumoricidal effects continue to be unearthed, recent evidence highlights a role for mitochondrial mediated apoptosis, modulated stress and inflammatory signaling pathways, and blunted angiogenesis. The goals of this review are to (1) highlight emodin's anti-cancer properties within GI cancers, (2) discuss the known anti-cancer mechanisms of action of emodin, (3) address emodin's potential as a treatment complementary to standard chemotherapeutics, (4) assess the efficacy and bioavailability of emodin derivatives as they relate to cancer, and (5) evaluate the safety of emodin.
    Keywords:  cancer treatments; complementary and alternative medicine; emodin; gastrointestinal cancers; natural compounds
    DOI:  https://doi.org/10.1177/15347354211067469
  54. Theranostics. 2022 ;12(1): 76-86
    Smart NIR-II croconaine dye-peptide for enhanced photo-sonotheranostics of hepatocellular carcinoma.
    Shuang Li, Yang Zhang, Xue Liu, Ye Tian, Yi Cheng, Longguang Tang, Huirong Lin.
      Background: Hepatocellular carcinoma (HCC) is associated with high morbidity and mortality rates. The development of novel nanomaterials represents an important direction for precise HCC theranostics. The combination of photothermal and sonodynamic therapy has provided great benefits for HCC therapy. Theranostic agents in the second near-infrared window (NIR-II, 1000-1700 nm) show great prospects because of their extraordinarily high detection sensitivity, resolution, and deep penetration. Methods: A sharp pH-sensitive self-assembling Glypican-3 (GPC3)-binding peptide (GBP) dye, CR-PEG-GBP, was developed as an intelligent nanoprobe for NIR-II imaging and photoacoustic (PA) imaging-guided photothermal therapy (PTT) and sonodynamic therapy (SDT) of HCC. Results: This small molecule assembled nanoprobe exhibited advantageous properties, such as responding to a decrease in pH (from normal tissue (pH 7.4) to the tumor microenvironment (pH ~6.5)) and aggregating - from small nanoprobes (<20 nm at pH 7.4) - into large nanoparticles (>160 nm at pH 6.5 and >510 nm at pH 5.5) that enables enhanced imaging and therapeutic effects. Because CR-PEG-GBP can self-aggregate in situ in an acidic tumor microenvironment, it shows high tumor accumulation and long tumor retention time, while being excretable from normal tissues and safe. Conclusions: This intelligent self-assembling small molecule strategy provides a simple yet efficient solution for HCC theranostics and may open up new avenues for designing clinically translatable probes for HCC treatment.
    Keywords:  HCC; NIR-II; in situ self-assembly; microenvironment; theranostics
    DOI:  https://doi.org/10.7150/thno.64759
  55. Dose Response. 2021 Oct-Dec;19(4):19(4): 15593258211055023
    2-Methoxy-estradiol Loaded Alpha Lipoic Acid Nanoparticles Augment Cytotoxicity in MCF-7 Breast Cancer Cells.
    Nabil A Alhakamy, Mohammed W Al-Rabia, Hani Z Asfour, Samah Alshehri, Waleed S Alharbi, Abdulrahman Halawani, Abdulmohsin J Alamoudi, Ahmad O Noor, Douha F Bannan, Usama A Fahmy, Sabna Kotta.
      The therapeutic effectiveness of anticancer drugs with a selective target for the nucleus of cancer cells may be improved by experimental approaches. In this regard, the formulation of anticancer drugs is considered one of the best ways to improve their effectiveness in targeting cancerous tissues. To enhance the anticancer activity of 2-methoxy-estradiol (2 ME) for breast cancer, 2-methoxyestradiol loaded alpha lipoic acid nanoparticles have been formulated. The prepared formula was observed to be spherical with a nanometer-scale and low PDI size (.234). The entrapment efficiency of the 2ME-ALA NPs was 87.32 ± 2.21% with > 85% release of 2 ME within 24 h. There was a 1.2-fold increase in apoptosis and a 3.46-fold increase in necrosis of the MCF-7 cells when incubated with 2ME-ALA NPs when compared to control cells. This increased apoptosis was also associated with increased ROS and increased p53 expression in 2ME-ALA NPs treated cells compared to the raw-2 ME group. Evaluation of cell-cycle data showed a substantial arrest of the G2-M phase of the MCF-7 cells when incubated with 2ME-ALA NPs. At the same time, a dramatically increased number of pre-G1 cells showed the increased apoptotic potential of the 2 ME when administered via the proposed formulation. In the end, the differential upregulation of caspase-3, p53, and ROS in MCF-7 cells established the superiority of the 2ME-ALA-Ms approach in targeting breast cancer. In summary, these results demonstrate that 2ME-ALA NPs are an efficient delivery tool for controlling the growth of breast cancer cells.
    Keywords:  2-methoxy-estradiol; P53 expression; alpha lipoic acid; cell-cycle assay; molecular markers; nanoparticles
    DOI:  https://doi.org/10.1177/15593258211055023
  56. Front Pharmacol. 2021 ;12 719694
    Update and New Insights on Future Cancer Drug Candidates From Plant-Based Alkaloids.
    Mounir Tilaoui, Hassan Ait Mouse, Abdelmajid Zyad.
      Cancer is a complex multifactorial disease that results from alterations in many physiological and biochemical functions. Over the last few decades, it has become clear that cancer cells can acquire multidrug resistance to conventional anticancer drugs, resulting in tumor relapse. Thus, there is a continuous need to discover new and effective anticancer drugs. Natural products from plants have served as a primary source of cancer drugs and continue to provide new plant-derived anticancer drugs. The present review describes plant-based alkaloids, which have been reported as active or potentially active in cancer treatment within the past 4 years (2017-2020), both in preclinical research and/or in clinical trials. In addition, recent insights into the possible molecular mechanism of action of alkaloid prodrugs naturally present in plants are also highlighted.
    Keywords:  cancer; clinical trials; molecular mechanism; plant-based alkaloids; preclinical research
    DOI:  https://doi.org/10.3389/fphar.2021.719694
  57. Biomaterials. 2021 Dec 28. pii: S0142-9612(21)00691-8. [Epub ahead of print]281 121335
    Leveraging disulfiram to treat cancer: Mechanisms of action, delivery strategies, and treatment regimens.
    Yao Lu, Qingqing Pan, Wenxia Gao, Yuji Pu, Kui Luo, Bin He, Zhongwei Gu.
      Disulfiram (DSF) has been used as an alcoholism drug for 70 years. Recently, it has attracted increasing attention owing to the distinguished anticancer activity, which can be further potentiated by the supplementation of Cu2+. Although encouraging anticancer results are obtained in lab, the clinical outcomes of oral DSF are not satisfactory, which urges an in-depth understanding of the underlying mechanisms, bottlenecks, and proposal of potential methods to address the dilemma. In this review, a critical summarization of various molecular biological anticancer mechanisms of DSF/Cu2+ is provided and the predicament of orally delivering DSF in clinical oncotherapy is explained by the metabolic barriers. We highlight the recent advances in the DSF/Cu2+ delivery strategies and the emerging treatment regimens for cancer treatment. Last but not the least, we summarize the clinical trials regarding DSF and make a prospect of DSF/Cu-based cancer therapy.
    Keywords:  Anticancer mechanism; Anticancer therapy; Copper; Disulfiram; Drug delivery
    DOI:  https://doi.org/10.1016/j.biomaterials.2021.121335
  58. Pathol Oncol Res. 2021 ;27 1609951
    Lactate Upregulates the Expression of DNA Repair Genes, Causing Intrinsic Resistance of Cancer Cells to Cisplatin.
    Marzia Govoni, Valentina Rossi, Giuseppina Di Stefano, Marcella Manerba.
      Intrinsic or acquired drug resistance is one of the major problems compromising the success of antineoplastic treatments. Several evidences correlated some therapeutic failures with changes in cell metabolic asset and in line with these findings, hindering the glycolytic metabolism of cancer cells via lactate dehydrogenase (LDH) inhibition was found to overcome the resistance to chemotherapeutic agents. Lactate, the product of LDH reaction, was shown to be involved in epigenetic regulation of gene expression. The experiments described in this paper were aimed at highlighting a possible direct effect of lactate in modifying the response of cancer cells to a chemotherapeutic treatment. To discriminate between the effects potentially caused by glycolytic metabolism from those directly referable to lactate, we selected cancer cell lines able to grow in glucose deprived conditions and evaluated the impact of lactate on the cellular response to cisplatin-induced DNA damage. In lactate-exposed cells we observed a reduced efficacy of cisplatin, which was associated with reduced signatures of DNA damage, enhanced DNA recombination competence and increased expression of a panel of genes involved in DNA repair. The identified genes take part in mismatch and nucleotide excision repair pathways, which were found to contribute in restoring the cisplatin-induced DNA damage. The obtained results suggest that this metabolite could play a role in reducing the efficacy of antineoplastic treatments.
    Keywords:  DNA damage; DNA repair; cisplatin; glycolysis; lactate
    DOI:  https://doi.org/10.3389/pore.2021.1609951
  59. Med Oncol. 2022 Jan 04. 39(2): 18
    Mefenamic acid as a promising therapeutic medicine against colon cancer in tumor-bearing mice.
    Reza Seyyedi, Fereshteh Talebpour Amiri, Soghra Farzipour, Ehsan Mihandoust, Seyed Jalal Hosseinimehr.
      Although radiotherapy is an effective strategy for cancer treatment, tumor resistance to ionizing radiation (IR) and its toxic effects on normal tissues are limiting its use. The aim of this study is to evaluate the anti-cancer effects of mefenamic acid (MEF), as an approved medicine, and its combination with IR against colon tumor cells in mice. Tumor-bearing mice were received MEF at a dose of 25 mg/kg for 6 successive days. The tumor size was measured. In the second experiment, after MEF treatment, tumor-bearing mice locally received an X-ray at dose 6 Gy. Tumor growth and biochemical, histological, and immunohistological assay (caspase-3) were performed. MEF significantly decreased tumor size in mice in comparison to the control group. IR and/or MEF treatment significantly reduced the tumor volume and inhibited tumor growth by 49%, 55%, and 67% by MEF, IR, and MEF + IR groups as compared with the control group. Administration of MEF in combination with radiation had a synergistic effect on enhanced histopathological changes in tumor tissues. MEF treatment in IR exposure mice showed a significant increase in the immunoreactivity of caspase-3 in the colon tumor tissue. MEF has an anti-tumor effect in colon tumor-bearing mice. MEF in combination with IR increased pathological changes and apoptosis in tumor tissues, suggesting that MEF might be clinically useful in the treatment of colon cancer.
    Keywords:  Anti-cancer; Apoptosis; Colon cancer cells; Mefenamic acid; Radiosensitizer; Radiotherapy
    DOI:  https://doi.org/10.1007/s12032-021-01618-3
  60. Front Pharmacol. 2021 ;12 746777
    Ethnopharmacological Survey of Traditional Chinese Medicine Pharmacy Prescriptions for Dysmenorrhea.
    Kuo-Han Su, Shan-Yu Su, Chien-Yu Ko, Yung-Chi Cheng, Shyh-Shyun Huang, Jung Chao.
      Chinese herbal medicines have long been used for the treatment of dysmenorrhea. The treatment experiences of traditional Chinese medicine (TCM) pharmacies passed down through generations have contributed to a wealth of prescriptions for dysmenorrhea that have achieved significant therapeutic effects in countless Taiwanese women. Therefore, surveying and analyzing these prescriptions may enable us to elucidate the core medication combinations used in TCM prescriptions for dysmenorrhea. In the present study, a field investigation was conducted on various TCM pharmacies in Taiwan. A total of 96 TCM pharmacies were sampled, and 99 prescriptions for dysmenorrhea containing 77 different medicinal materials were collected. Compositae (8%) was the most common botanical source of the medicinal materials, and the predominant TCM property and flavor of the materials were warm (45%) and sweet (73%), respectively. The blood-activating and stasis-dispelling effect (23%) and the qi-tonifying effect (23%) were the most prevalent traditional effects, and the modern pharmacological effects most commonly found in the materials were anti-inflammatory (73%), antitumor (59%), and analgesic (12%) effects. Network analysis of the 77 medicinal materials used in the prescriptions, which was performed using the Traditional Chinese Medicine Inheritance Support System, yielded seven core medicinal materials and the corresponding network diagram. The seven core medicinal materials ranked in order of relative frequency of citation (RFC) were Angelica sinensis (Oliv.) Diels (Dang Gui), Ligusticum chuanxiong Hort (Chuan Qiong), Rehmannia glutinosa Libosch (Di Huang), Paeonia lactiflora Pall (Bai Shao), Hedysarum polybotrys Hand.-Mazz (Hong Qi), Lycium chinense Mill (Gou Qi Zi), and Cinnamomum cassia (L.). J. Presl (Gui Zhi). A total of 58 combinations, each consisting of two to five of the seven medicinal materials and 107 association rules among the materials, were identified. This study provides a record of valuable knowledge on TCM pharmacy prescriptions for dysmenorrhea. The rich medicinal knowledge of TCM pharmacies in Taiwan is worthy of further exploration, and the results of this study can serve as a basis for future pharmacological research and the development of naturally derived medications for dysmenorrhea.
    Keywords:  Chinese herbal medicines; Taiwan; dysmenorrhea; ethnopharmacology; traditional Chinese medicine pharmacy
    DOI:  https://doi.org/10.3389/fphar.2021.746777
  61. J Nanobiotechnology. 2022 Jan 04. 20(1): 18
    Mn doped Prussian blue nanoparticles for T1/T2 MR imaging, PA imaging and Fenton reaction enhanced mild temperature photothermal therapy of tumor.
    Quan Tao, Genghan He, Sheng Ye, Di Zhang, Zhide Zhang, Li Qi, Ruiyuan Liu.
       BACKGROUND: Combining the multimodal imaging and synergistic treatment in one platform can enhance the therapeutic efficacy and diagnosis accuracy.
    RESULTS: In this contribution, innovative Mn-doped Prussian blue nanoparticles (MnPB NPs) were prepared via microemulsion method. MnPB NPs demonstrated excellent T1 and T2 weighted magnetic resonance imaging (MRI) enhancement in vitro and in vivo. The robust absorbance in the near infrared range of MnPB NPs provides high antitumor efficacy for photothermal therapy (PTT) and photoacoustics imaging property. Moreover, with the doping of Mn, MnPB NPs exhibited excellent Fenton reaction activity for chemodynamic therapy (CDT). The favorable trimodal imaging and Fenton reaction enhanced mild temperature photothermal therapy in vitro and in vivo were further confirmed that MnPB NPs have significant positive effectiveness for integration of diagnosis and treatment tumor.
    CONCLUSIONS: Overall, this Mn doped Prussian blue nanoplatform with multimodal imaging and chemodynamic/mild temperature photothermal co-therapy provides a reliable tool for tumor treatment.
    Keywords:  Chemodynamic therapy; Fenton reaction; MR imaging; Mild temperature photothermal therapy; Photoacoustic imaging
    DOI:  https://doi.org/10.1186/s12951-021-01235-2
  62. J Mater Chem B. 2022 Jan 06.
    A novel TMTP1-modified theranostic nanoplatform for targeted in vivo NIR-II fluorescence imaging-guided chemotherapy for cervical cancer.
    Nuernisha Alifu, Rong Ma, Lijun Zhu, Zhong Du, Shuang Chen, Ting Yan, Gulinigaer Alimu, Linxue Zhang, Xueliang Zhang.
      Near-infrared II (NIR-II, 900-1700 nm) fluorescence bioimaging with advantages of good biosafety, excellent spatial resolution, high sensitivity, and contrast has attracted great attention in biomedical research fields. However, most of the nanoprobes used for NIR-II fluorescence imaging have poor tumor-targeting ability and therapeutic efficiency. To overcome these limitations, a novel NIR-II-emissive theranostic nanoplatform for fluorescence imaging and treatment of cervical cancer was designed and prepared. The NIR-II-emissive dye IR-783 and chemotherapy drug doxorubicin (DOX) were encapsulated into liposomes, and the tumor-targeting peptide TMTP1 (a polypeptide with a sequence of cyclic ASN Val Val Arg Gln Cys) was conjugated to the surface of the liposomes to form IR-783-DOX-TMTP1 nanoparticles (NPs) via self-assembly methods. The IR-783-DOX-TMTP1 NPs showed strong NIR-II emission, excellent biocompatibility and a long lifetime in vivo. Furthermore, high-definition NIR-II fluorescence microscopy images of ear blood vessels and intratumoral blood vessels were obtained from IR-783-DOX-TMTP1 NP-stained mice with high spatial resolution under 808 nm laser excitation. Moreover, IR-783-DOX-TMTP1 NPs showed strong tumor-targeting ability and highly efficient chemotherapeutic characteristics towards cervical tumors. The novel targeting and NIR-II-emissive IR-783-DOX-TMTP1 NPs have great potential in diagnosis and therapy for cervical cancer.
    DOI:  https://doi.org/10.1039/d1tb02481g
  63. Adv Exp Med Biol. 2021 ;1328 447-461
    A Review on the Phytochemistry, Pharmacology, and Therapeutic Effects of Rheum ribes.
    Zakieh Keshavarzi, Farzaneh Shakeri, Fatemeh Maghool, Tannaz Jamialahmadi, Thomas P Johnston, Amirhossein Sahebkar.
      Herbal medications are typically used for the treatment of diverse diseases without significant adverse effects. The Rheum ribes (R. ribes), commonly called rhubarb, is a hardy perennial herb and is consumed all over the world. There is growing evidence of the therapeutic benefits of R. ribes. Extensive in vitro and in vivo investigations have shown that R. ribes reveals beneficial properties via different mechanisms. In the current article, various pharmacological and therapeutic effects of R. ribes have been reviewed. For this purpose, different online databases using keywords such as R. ribes, therapeutic effects, and pharmacological effects were searched until the end of December 2020. R. ribes has been suggested to be effective in the treatment of a wide range of disorders including stomachache, nausea and vomiting, hemorrhoids, and measles. Additionally, different studies have demonstrated that R. ribes possesses numerous pharmacological properties including anti-inflammatory, anticancer, antibacterial, and antiviral, and may also function as an expectorant. The present narrative review provides a detailed survey of scientific investigations regarding the pharmacological properties and therapeutic effects of R. ribes.
    Keywords:  Anti-inflammatory; Antibacterial; Anticancer; Antidiabetic; Antioxidant; Neuroprotective; Pharmacological properties; Rheum ribes
    DOI:  https://doi.org/10.1007/978-3-030-73234-9_30
  64. Front Oncol. 2021 ;11 781800
    Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin.
    Seyed Mehdi Havaei, Marc G Aucoin, Ali Jahanian-Najafabadi.
      Cancer is one of the prominent causes of death worldwide. Despite the existence of various modalities for cancer treatment, many types of cancer remain uncured or develop resistance to therapeutic strategies. Furthermore, almost all chemotherapeutics cause a range of side effects because they affect normal cells in addition to malignant cells. Therefore, the development of novel therapeutic agents that are targeted specifically toward cancer cells is indispensable. Immunotoxins (ITs) are a class of tumor cell-targeted fusion proteins consisting of both a targeting moiety and a toxic moiety. The targeting moiety is usually an antibody/antibody fragment or a ligand of the immune system that can bind an antigen or receptor that is only expressed or overexpressed by cancer cells but not normal cells. The toxic moiety is usually a protein toxin (or derivative) of animal, plant, insect, or bacterial origin. To date, three ITs have gained Food and Drug Administration (FDA) approval for human use, including denileukin diftitox (FDA approval: 1999), tagraxofusp (FDA approval: 2018), and moxetumomab pasudotox (FDA approval: 2018). All of these ITs take advantage of bacterial protein toxins. The toxic moiety of the first two ITs is a truncated form of diphtheria toxin, and the third is a derivative of Pseudomonas exotoxin (PE). There is a growing list of ITs using PE, or its derivatives, being evaluated preclinically or clinically. Here, we will review these ITs to highlight the advances in PE-based anticancer strategies, as well as review the targeting moieties that are used to reduce the non-specific destruction of non-cancerous cells. Although we tried to be as comprehensive as possible, we have limited our review to those ITs that have proceeded to clinical trials and are still under active clinical evaluation.
    Keywords:  Pseudomonas exotoxin A; bacterial toxin; cancer; immunotoxin; targeted therapy
    DOI:  https://doi.org/10.3389/fonc.2021.781800
  65. Nutr Cancer. 2022 Jan 07. 1-27
    The Potential for Natural Products to Overcome Cancer Drug Resistance by Modulation of Epithelial-Mesenchymal Transition.
    Asefeh Dahmardeh Ghalehno, Arad Boustan, Hakimeh Abdi, Zahra Aganj, Fatemeh Mosaffa, Khadijeh Jamialahmadi.
      The acquisition of resistance and ultimately disease relapse after initial response to chemotherapy put obstacles in the way of cancer therapy. Epithelial-mesenchymal transition (EMT) is a biologic process that epithelial cells alter to mesenchymal cells and acquire fibroblast-like properties. EMT plays a significant role in cancer metastasis, motility, and survival. Recently, emerging evidence suggested that EMT pathways are very important in making drug-resistant involved in cancer. Natural products are gradually emerging as a valuable source of safe and effective anticancer compounds. Natural products could interfere with the different processes implicated in cancer drug resistance by reversing the EMT process. In this review, we illustrate the molecular mechanisms of EMT in the emergence of cancer metastasis. We then present the role of natural compounds in the suppression of EMT pathways in different cancers to overcome cancer cell drug resistance and improve tumor chemotherapy. HighlightsDrug-resistance is one of the obstacles to cancer treatment.EMT signaling pathways have been correlated to tumor invasion, metastasis, and drug-resistance.Various studies on the relationship between EMT and resistance to chemotherapy agents were reviewed.Different anticancer natural products with EMT inhibitory properties and drug resistance reversal effects were compared.
    DOI:  https://doi.org/10.1080/01635581.2021.2022169
  66. J Agric Food Chem. 2022 Jan 02.
    Bee Products: An Emblematic Example of Underutilized Sources of Bioactive Compounds.
    Francesca Giampieri, Jose Luis Quiles, Danila Cianciosi, Tamara Yuliett Forbes-Hernández, Francisco Josè Orantes-Bermejo, José Miguel Alvarez-Suarez, Maurizio Battino.
      Beside honey, honeybees (Apis mellifera L.) are able to produce many byproducts, including bee pollen, propolis, bee bread, royal jelly, and beeswax. Even if the medicinal properties of these byproducts have been recognized for thousands of years by the ancient civilizations, in the modern era, they have a limited use, essentially as nutritional supplements or health products. However, these natural products are excellent sources of bioactive compounds, macro- and micronutrients, that, in a synergistic way, confer multiple biological activities to these byproducts, such as, for example, antimicrobial, antioxidant, and anti-inflammatory properties. This work aims to update the chemical and phytochemical composition of bee pollen, propolis, bee bread, royal jelly, and beeswax and to summarize the main effects exerted by these byproducts on human health, from the anticancer and immune-modulatory activities to the antidiabetic, hypolipidemic, hypotensive, and anti-allergic properties.
    Keywords:  bee bread; bee pollen; beeswax; honeybee byproducts; propolis; royal jelly
    DOI:  https://doi.org/10.1021/acs.jafc.1c05822
  67. Adv Exp Med Biol. 2021 ;1328 171-197
    Health Benefits of Turmeric and Curcumin Against Food Contaminants.
    Bahareh Sadat Yousefsani, Majid Dadmehr, Kobra Shirani, Amirhossein Jamshidi, Thozhukat Sathyapalan, Amirhossein Sahebkar.
      Food contaminants are one of the most important and concerning issues worldwide. Protecting the public from the harm of contaminated foods has become a daunting task. On the other hand, the elimination of these contaminants from food seems impossible. Therefore, one of the best solutions is to recommend inexpensive and publicly available food additives like many spices used in food as flavoring and coloring. Curcuma longa or turmeric is one of the well-known spice, which confers many medicinal properties. Curcumin is the main active ingredient in turmeric, which has many health benefits. Recent research has revealed that turmeric/curcumin has protective effects against toxicants, mostly natural and chemical toxins. In this review article, we reviewed studies related to the protective effects of turmeric and its active ingredient against food contaminants.
    Keywords:  Curcumin; Food contaminant; Toxicity
    DOI:  https://doi.org/10.1007/978-3-030-73234-9_12
  68. J Nanobiotechnology. 2022 Jan 04. 20(1): 3
    Ceria nanoparticles ameliorate renal fibrosis by modulating the balance between oxidative phosphorylation and aerobic glycolysis.
    Mengling Wang, Feng Zeng, Fengling Ning, Yinhang Wang, Shilin Zhou, Jiaqi He, Cong Li, Cong Wang, Xiaolin Sun, Dongliang Zhang, Jisheng Xiao, Ping Hu, Svetlana Reilly, Hong Xin, Xudong Xu, Xuemei Zhang.
       BACKGROUND AND AIMS: Renal fibrosis is the common outcome in all progressive forms of chronic kidney disease. Unfortunately, the pathogenesis of renal fibrosis remains largely unexplored, among which metabolic reprogramming plays an extremely crucial role in the evolution of renal fibrosis. Ceria nanoparticles (CeNP-PEG) with strong ROS scavenging and anti-inflammatory activities have been applied for mitochondrial oxidative stress and inflammatory diseases. The present study aims to determine whether CeNP-PEG has therapeutic value for renal fibrosis.
    METHODS: The unilateral ureteral obstructive fibrosis model was used to assess the therapeutic effects in vivo. Transforming growth factor beta1-induced epithelial-to-mesenchymal transition in HK-2 cells was used as the in vitro cell model. The seahorse bioscience X96 extracellular flux analyzer was used to measure the oxygen consumption rate and extracellular acidification rate.
    RESULTS: In the present study, CeNP-PEG treatment significantly ameliorated renal fibrosis by increased E-cadherin protein expression, and decreased α-SMA, Vimentin and Fibronectin expression both in vitro and in vivo. Additionally, CeNP-PEG significantly reduced the ROS formation and improved the levels of mitochondrial ATP. The seahorse analyzer assay demonstrated that the extracellular acidification rate markedly decreased, whereas the oxygen consumption rate markedly increased, in the presence of CeNP-PEG. Furthermore, the mitochondrial membrane potential markedly enhanced, hexokinase 1 and hexokinase 2 expression significantly decreased after treatment with CeNP-PEG.
    CONCLUSIONS: CeNP-PEG can block the dysregulated metabolic status and exert protective function on renal fibrosis. This may provide another therapeutic option for renal fibrosis.
    Keywords:  Aerobic glycolysis; Ceria nanoparticles; Metabolic reprogramming; Oxidative phosphorylation; Renal fibrosis
    DOI:  https://doi.org/10.1186/s12951-021-01122-w
  69. JACS Au. 2021 Dec 27. 1(12): 2328-2338
    Hybrid Carbon Dot Assembly as a Reactive Oxygen Species Nanogenerator for Ultrasound-Assisted Tumor Ablation.
    Deblin Jana, Dongdong Wang, Praveenbalaji Rajendran, Anivind Kaur Bindra, Yi Guo, Jiawei Liu, Manojit Pramanik, Yanli Zhao.
      The efficacy of reactive oxygen species (ROS)-based therapy is substantially constrained by the limited ROS generation, stern activation conditions, and lack of a straightforward reaction paradigm. Carbon dots (CDs) have been highly sought after for therapeutic applications for their biocompatibility and intrinsic fluorescence imaging capabilities, making them suitable for ROS generation. Herein, we synthesized a CD-based ultrasmall hybrid nanostructure possessing active sites of Mo, Cu, and IR-780 dye. After cooperative self-assembly with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol), the obtained assembly (CMIR-CDa) exhibits near-infrared fluorescence imaging and photoacoustic tomography. Interestingly, CMIR-CDa can generate singlet oxygen (1O2), hydroxyl radical (·OH), and superoxide radical anion (O2 • -) upon ultrasound stimulus owing to its sonosensitizing and enzyme-mimicking properties, showing an enhanced efficacy for tumor ablation in vivo. The collective in vitro and in vivo results indicate that CMIR-CDa has a high potency as an ROS nanogenerator under US irradiation, even at a low concentration. The present study offers an approach for engineering hybrid CDs in a bioinspired way for intratumoral ROS augmentation in response to deep tissue penetrable external stimuli.
    DOI:  https://doi.org/10.1021/jacsau.1c00422
  70. Theranostics. 2022 ;12(2): 859-874
    Extracellular ATP is increased by release of ATP-loaded microparticles triggered by nutrient deprivation.
    Valentina Vultaggio-Poma, Simonetta Falzoni, Paola Chiozzi, Alba Clara Sarti, Elena Adinolfi, Anna Lisa Giuliani, Alejandro Sánchez-Melgar, Paola Boldrini, Michele Zanoni, Anna Tesei, Paolo Pinton, Francesco Di Virgilio.
      Rationale: Caloric restriction improves the efficacy of anti-cancer therapy. This effect is largely dependent on the increase of the extracellular ATP concentration in the tumor microenvironment (TME). Pathways for ATP release triggered by nutrient deprivation are largely unknown. Methods: The extracellular ATP (eATP) concentration was in vivo measured in the tumor microenvironment of B16F10-inoculated C57Bl/6 mice with the pmeLuc probe. Alternatively, the pmeLuc-TG-mouse was used. Caloric restriction was in vivo induced with hydroxycitrate (HC). B16F10 melanoma cells or CT26 colon carcinoma cells were in vitro exposed to serum starvation to mimic nutrient deprivation. Energy metabolism was monitored by Seahorse. Microparticle release was measured by ultracentrifugation and by Nanosight. Results: Nutrient deprivation increases eATP release despite the dramatic inhibition of intracellular energy synthesis. Under these conditions oxidative phosphorylation was dramatically impaired, mitochondria fragmented and glycolysis and lactic acid release were enhanced. Nutrient deprivation stimulated a P2X7-dependent release of ATP-loaded, mitochondria-containing, microparticles as well as of naked mitochondria. Conclusions: Nutrient deprivation promotes a striking accumulation of eATP paralleled by a large release of ATP-laden microparticles and of naked mitochondria. This is likely to be a main mechanism driving the accumulation of eATP into the TME.
    Keywords:  P2X7.; extracellular ATP; microparticles; nutrient deprivation; tumor microenvironment
    DOI:  https://doi.org/10.7150/thno.66274
  71. Int J Biol Macromol. 2021 Dec 30. pii: S0141-8130(21)02755-0. [Epub ahead of print]
    S-nitrosoglutathione Functionalized Polydopamine Nanoparticles Incorporated into Chitosan/Gelatin Hydrogel Films with NIR-Controlled Photothermal/NO-Releasing Therapy for Enhanced Wound Healing.
    Wenyu Wang, Huan Sheng, Daihong Cao, Fenglian Zhang, Weifen Zhang, Fang Yan, Dejun Ding, Ni Cheng.
      Nitric oxide (NO) has aroused wide interest in the treating infected wounds due to its characteristic functionalities. However, its utilization is limited due to its volatile properties, high reactivity, direct potential toxicity, and byproducts of NO donors limited its application. Herein, endogenously NO donor S-nitrosoglutathione (GSNO) was connected covalently to polydopamine nanoparticles (PDA-GSNO NPs) to minimize the loss of NO in aqueous medium. Meanwhile, near-infrared (NIR)-controlled NO release and photothermal therapy (PTT) was obtained through the photothermal conversion by PDA. Then chitosan (CS)/gelatin (GE) biocomposite hydrogel films with preferable biocompatibility, surface hydrophilicity, hydroabsorptivity, and mechanical adhesive properties were constructed. By embedding PDA-GSNO NPs into the films, a multifunctional wound dressing was fabricated. Under NIR light irradiation, the combination of PTT, NO-releasing, and CS antibacterial agents can strengthen the in vitro antimicrobial efficacy and in vivo wound healing activities. Meanwhile, the obtained wound dressing presented good biocompatibility. This work outlines an approach for combating bacterial infections and demonstrating the possibility for synergistic NO-releasing wound healing.
    Keywords:  NIR-Controlled; Nitric Oxide; Photothermal Therapy; S-nitrosoglutathione; Wound Healing
    DOI:  https://doi.org/10.1016/j.ijbiomac.2021.12.125
  72. J Pharm Sci. 2022 Jan 02. pii: S0022-3549(21)00720-6. [Epub ahead of print]
    Sodium alginate as a pharmaceutical excipient: novel applications of a well-known polymer.
    Barbara Jadach, Weronika Świetlik, Anna Froelich.
      Alginates are naturally occurring polymers revealing low toxicity, good biocompatibility and biodegradability, excellent gelling and thickening properties, as well as low production cost and good availability. One of the most important features typical for alginates is the ability to undergo ionotropic gelation which is gel formation process occurring upon the contact with cations. Because of their advantageous properties, alginates have been extensively utilized in food and pharmaceutical industries. In this review the current knowledge regarding the most recent studies involving both popularly applied dosage forms, like tablets or hydrogels, and novel advanced drug delivery systems applied in targeted therapies are summarized and discussed. The presented studies indicate that although sodium alginate is a well-established polymer, the compound is still widely applied as pharmaceutical excipient and the presented research studies indicate that there are still research areas that can be explored and provide innovation in drug delivery systems.
    Keywords:  biodegradable polymer; carrier; controlled release; drug delivery system; sodium alginate
    DOI:  https://doi.org/10.1016/j.xphs.2021.12.024
  73. Int J Biol Sci. 2022 ;18(1): 30-42
    IRF7 inhibits the Warburg effect via transcriptional suppression of PKM2 in osteosarcoma.
    Zhikun Li, Mei Geng, Xiaojian Ye, Yunhan Ji, Yifan Li, Xiangyang Zhang, Wei Xu.
      Osteosarcoma (OS) is a malignant bone tumor among adolescents and young adults. IRF7 belongs to the transcription factor family of interferon regulatory factors (IRFs) and has previously been described to function as a tumor suppressor in multiple cancer types. However, the biological functions and cellular mechanism of IRF7 in OS remain elusive. In this study, by quantitative real-time PCR (qRT-PCR) and western blotting, we found that IRF7 was downregulated in OS, and the higher expression of IRF7 was correlated with a better survival prognosis. Moreover, loss-of-function and gain-of-function studies have proved the critical functions of IRF7 in suppressing aerobic glycolysis of osteosarcoma cells as evidenced by glucose uptake, lactate production, extracellular acidification rate, and oxygen consumption rate. Mechanistically, IRF7 inhibited the expression of key glycolytic gene PKM2 via direct transcriptional regulation. Moreover, the in vitro and in vivo tumor-suppressive roles of IRF7 were uncovered in OS and these effects were largely glycolysis-dependent. Therefore, our study unveils a previous unprecedented role of IRF7 in glucose metabolism reprogram and suggests that IRF7 might serve as a potential therapeutic target for patients with OS.
    Keywords:  Aerobic glycolysis; IRF7; Osteosarcoma; PKM2; Warburg effect
    DOI:  https://doi.org/10.7150/ijbs.65255
  74. Adv Healthc Mater. 2022 Jan 03. e2102712
    Design of Light-activated Nanoplatform Through Boosting "eat me" Signals for Improved CD47-blocking Immunotherapy.
    Yan Lu, Yonghua Gong, Xianghui Zhu, Xia Dong, Dunwan Zhu, Guilei Ma.
      Here, we propose a light-activated reactive oxygen species (ROS)-responsive nanoplatform that can boost immunogenic cell death (ICD) to release "eat me" signals, and improve CD47-blocking immunotherapy by tumor-targeted co-delivery of photosensitizer IR820 and anti-CD47 antibody (αCD47). Human serum albumin and αCD47 were first constructed into a single nanoparticle using ROS-responsive linkers, which were further conjugated with photosensitizer IR820 via a matrix metalloproteinase-sensitive peptide as linker and then modified with poly(ethylene glycol) on the surface of the obtained nanoparticles. When exposed to the first wave of near infrared (NIR) laser irradiation, the obtained nanoplatform (M-IR820/αCD47@NP) could generate ROS, which triggered nanoparticles dissociation and thus, facilitated the release of αCD47 and IR820. The second wave of NIR laser irradiation was subsequently used to perform phototherapy and induce ICD of tumor cells. An in vitro cellular study showed that M-IR820/αCD47@NP could stimulate dendritic cells activation while simultaneously enhancing the phagocytic activity of macrophage against tumor cells. In 4T1 tumor-bearing mice, M-IR820/αCD47@NP-mediated combination of phototherapy and CD47 blockade could effectively induce the synergistical antitumor immune responses to inhibit the growth of tumors and prevent local tumor recurrence. This work offers a promising strategy to improve the CD47-blocking immunotherapy efficacy using αCD47 nanomedicine. This article is protected by copyright. All rights reserved.
    Keywords:  CD47-blocking immunotherapy; combination therapy; immunogenic cell death; stimulus response; αCD47 nanomedicine
    DOI:  https://doi.org/10.1002/adhm.202102712
  75. Adv Mater. 2022 Jan 05. e2106682
    Light-Triggered Efficient Sequential Drug Delivery of Biomimetic Nanosystem for Multimodal Chemo-, Antiangiogenic, and Anti-MDSC Therapy in Melanoma.
    Xing Lai, Xue-Liang Liu, Hong Pan, Mao-Hua Zhu, Mei Long, Yihang Yuan, Zhong Zhang, Xiao Dong, Qin Lu, Peng Sun, Jonathan F Lovell, Hong-Zhuan Chen, Chao Fang.
      In view of the multiple pathological hallmarks of tumors, nanosystems for the sequential delivery of various drugs whose targets are separately located inside and outside tumor cells are desired for improved cancer therapy. However, current sequential delivery is mainly achieved through enzyme- or acid-dependent degradation of the nanocarrier, which would be influenced by the heterogeneous tumor microenvironment, and unloading efficiency of the drug acting on the target outside tumor cells is usually unsatisfactory. Here, we developed a light-triggered sequential delivery strategy based on a liposomal formulation of doxorubicin (DOX)-loaded small-sized polymeric nanoparticles (DOX-NP) and free sunitinib in the aqueous cavity. The liposomal membrane was doped with photosensitizer porphyrin-phospholipid (PoP) and hybridized with red blood cell membrane to confer biomimetic features. Near-infrared light-induced membrane permeabilization triggered the "ultrafast" and "thorough" release of sunitinib (100% release in 5 min) for antiangiogenic therapy and also MDSC inhibition to reverse the immunosuppressive tumor environment. Subsequently, the small-sized DOX-NP liberated from the liposomes was more easily uptaken by tumor cells for improved immunogenic chemotherapy. RNA sequencing and immune-related assay indicated therapeutic immune enhancement. This light-triggered sequential delivery strategy demonstrates the potency in cancer multimodal therapy against multiple targets in different spatial positions in tumor microenvironment. This article is protected by copyright. All rights reserved.
    Keywords:  Biomimetic; MDSC; Near-infrared light; multimodal therapy; sequential drug delivery
    DOI:  https://doi.org/10.1002/adma.202106682
  76. Eur J Pharmacol. 2021 Dec 30. pii: S0014-2999(21)00879-7. [Epub ahead of print] 174723
    Autophagy in cancer: The cornerstone during glutamine deprivation.
    Hamza M Fares, Xiaodan Lyu, Xiaoting Xu, Renchao Dong, Muyao Ding, Shichao Mi, Yifan Wang, Xue Li, Shengtao Yuan, Li Sun.
      Over the past two decades, researchers have revealed the crucial functions of glutamine in supporting the hyperproliferation state of cancer cells. Glutamine acts on maintaining high energy production, supporting redox status and amino acid homeostasis. Therefore, cancer cells exhibit excessive uptake of the extracellular glutamine, synthesize it in some cases, and recycle intracellular and extracellular proteins to provide an additional source of glutamine to satisfy the increasing glutamine demand. On the other hand, autophagy's role is still debated regarding tumor initiation and progression. However, most cancer cells urgently need autophagy to overcome the existential threats during glutamine restriction stress. Downstream to various stress pathways induced during such a condition, autophagy is considered an indispensable cytoprotective tool to maintain cell integrity and survival. However, the overactivation of the autophagy process is related to lethal consequences. This review summarized glutamine pathways to control autophagy and highlighted autophagy's primary activation pathways, and discussed the roles during glutamine deprivation.
    Keywords:  Autophagy; Cancer cell metabolism; Glutamine deprivation
    DOI:  https://doi.org/10.1016/j.ejphar.2021.174723
  77. ACS Appl Mater Interfaces. 2022 Jan 03.
    GSH-Responsive Drug Delivery System for Active Therapy and Reducing the Side Effects of Bleomycin.
    Man Zhang, Chao Jia, Ji Zhuang, Yuan-Yuan Hou, Xi-Wen He, Wen-You Li, Gang Bai, Yu-Kui Zhang.
      The application of drug delivery system (DDS) has achieved breakthroughs in many aspects, especially in the field of tumor treatment. In this work, polyethylene glycol (PEG)-modified hollow mesoporous manganese dioxide (HMnO2@PEG) nanoparticles were used to load the anti-tumor drug bleomycin (BLM). When the DDS reached the tumor site, HMnO2@PEG was degraded and reduced to Mn2+ by the overexpression of glutathione in the tumor microenvironment, and the drug was released simultaneously. BLM coordinated with Mn2+ in situ, thereby greatly improving the therapeutic activity of BLM. The results of in vivo and in vitro treatment experiments showed that the DDS had excellent responsive therapeutic activation ability. In addition, Mn2+ exhibited strong paramagnetism and was used for T1-weighted magnetic resonance imaging in vivo. Furthermore, this therapeutic mode of responsively releasing drugs and activating in situ effectively attenuated pulmonary fibrosis initiated by BLM. In short, this DDS could help in avoiding the side effects of drugs.
    Keywords:  MRI; active therapy; avoiding side effects; coordination; drug delivery system
    DOI:  https://doi.org/10.1021/acsami.1c21828
  78. J Mater Chem B. 2022 Jan 06.
    Tumor microenvironment responsive self-cascade catalysis for synergistic chemo/chemodynamic therapy by multifunctional biomimetic nanozymes.
    Nannan Zheng, Yang Fu, Xijian Liu, Ziwen Zhang, Jinxia Wang, Qixiang Mei, Xingyan Wang, Guoying Deng, Jie Lu, Junqing Hu.
      Chemodynamic therapy (CDT) is an emerging approach to treat cancer based on the tumor microenvironment (TME), but its limited content of endogenous hydrogen peroxide (H2O2) weakens the anticancer effects. Herein, a multifunctional biomimetic nanozyme (Se@SiO2-Mn@Au/DOX, named as SSMA/DOX) is fabricated, which undergoes TME responsive self-cascade catalysis to facilitate MRI guided enhanced chemo/chemodynamic therapy. The SSMA/DOX nanocomposites (NCs) responsively degrade in acidic conditions of tumor to release Se, DOX, Au and Mn2+. Mn2+ not only enables MRI to guided therapy, but also catalyzes the endogenous H2O2 into hydroxyl radical (˙OH) for CDT. In addition, the Au NPs continuously catalyze glucose to generate H2O2, enhancing CDT by supplementing a sufficiently reactive material and cutting off the energy supply of the tumor by consuming glucose. Simultaneously, Se enhances the chemotherapy of doxorubicin hydrochloride (DOX) and CDT by upregulating ROS in the tumor cells, achieving remarkable inhibition effect towards tumor. Moreover, SSMA/DOX NCs have good biocompatibility and degradability, which avoid long-term toxicity and side effects. Overall, the degradable SSMA/DOX NCs provide an innovative strategy for tumor microenvironment responsive self-cascade catalysis to enhance tumor therapy.
    DOI:  https://doi.org/10.1039/d1tb01891d
  79. Med Oncol. 2022 Jan 04. 39(2): 20
    Novel molecules as the emerging trends in cancer treatment: an update.
    Priyanka Sekar, Raashmi Ravitchandirane, Sofia Khanam, Nethaji Muniraj, Ananda Vayaravel Cassinadane.
      As per World Health Organization cancer remains as a leading killer disease causing nearly 10 million deaths in 2020. Since the burden of cancer increases worldwide, warranting an urgent search for anti-cancer compounds from natural sources. Secondary metabolites from plants, marine organisms exhibit a novel chemical and structural diversity holding a great promise as therapeutics in cancer treatment. These natural metabolites target only the cancer cells and the normal healthy cells are left unharmed. In the emerging trends of cancer treatment, the natural bioactive compounds have long become a part of cancer chemotherapy. In this review, we have tried to compile about eight bioactive compounds from plant origin viz. combretastatin, ginsenoside, lycopene, quercetin, resveratrol, silymarin, sulforaphane and withaferin A, four marine-derived compounds viz. bryostatins, dolastatins, eribulin, plitidepsin and three microorganisms viz. Clostridium, Mycobacterium bovis and Streptococcus pyogenes with their well-established anticancer potential, mechanism of action and clinical establishments are presented.
    Keywords:  Cancer; Combretastatin; Eribulin; Ginsenoside; Mycobacterium bovis; Novel molecules; Plitidepsin
    DOI:  https://doi.org/10.1007/s12032-021-01615-6
  80. J Nanobiotechnology. 2022 Jan 06. 20(1): 20
    Atom-precise fluorescent copper cluster for tumor microenvironment targeting and transient chemodynamic cancer therapy.
    Zhenzhen Yang, Anli Yang, Wang Ma, Kai Ma, Ya-Kun Lv, Peng Peng, Shuang-Quan Zang, Bingjie Li.
       BACKGROUND: Reactive oxygen species (ROS) have been widely studied for cancer therapy. Nevertheless, instability and aspecific damages to cellular biomolecules limit the application effect. Recently, significant research efforts have been witnessed in the flourishing area of metal nanoclusters (NCs) with atomically precise structures for targeted release of ROS but few achieved success towards targeting tumor microenvironment.
    RESULTS: In this work, we reported an atomically precise nanocluster Cu6(C4H3N2S)6 (Cu6NC), which could slowly break and generate ROS once encountered with acidic. The as-prepared Cu6NC demonstrated high biological safety and efficient chemodynamic anti-tumor properties. Moreover, Cu6NC enabled transient release of ROS and contained targeting behavior led by the tumor microenvironment. Both in vitro and in vivo experiments confirmed that Cu6NC demonstrated a low cytotoxicity for normal cells, while presented high cytotoxicity for tumor cells with a concentration-dependent manner.
    CONCLUSIONS: This work not only reported a promising candidate for chemodynamic cancer therapy, but also paved the route to address clinical issues at the atomic level.
    Keywords:  Cancer therapy; Nano clusters; ROS; Sustainable release; Targeting property
    DOI:  https://doi.org/10.1186/s12951-021-01207-6
  81. J Colloid Interface Sci. 2021 Dec 29. pii: S0021-9797(21)02321-3. [Epub ahead of print]612 287-297
    Galactose conjugated boron dipyrromethene and hydrogen bonding promoted J-aggregates for efficiently targeted NIR-II fluorescence assistant photothermal therapy.
    Huiping Dang, Youliang Tian, Quan Cheng, Changchang Teng, Kai Xie, Lifeng Yan.
      It is essential to develop novel multifunctional and easily synthesized stable NIR-II fluorescent probes to guide photothermal therapy for tumors. Here, we propose a new strategy to construct boron dipyrromethene (BODIPY) J-aggregates by intermolecular hydrogen bonding (H-bond) and π-π stacking interactions to achieve fluorescence emission in the second near-infrared window (NIR-II, 1000-1700 nm). A novel meso-benzamide galactose hexanoate-BODIPY (Gal-OH-BDP) amphiphilic small molecular dye was synthesized and it formed nanoparticles spontaneously in aqueous solution with a maximum emission wavelength near 1060 nm, which works as a smart nanomedicine for targeting NIR-II imaging-guided photothermal therapy (PTT) of hepatocellular carcinoma. Galactose not only provided hydrogen bonds to regulate the aggregation pattern of the molecules but also effectively targeted hepatocellular carcinoma cells and promoted the formation of well-dispersed nanoparticles of dye molecules due to their hydrophilicity. Moreover, due to high photothermal conversion efficiency (PCE = 55%), Gal-OH-BDP NPs achieve galactose-targeted NIR-II imaging and PTT, which is important for the precise diagnosis and treatment of tumors (Scheme 1). In the present research work, H-bond was introduced for the first time into BODIPY for building J-aggregates to achieve the NIR-II fluorescence.
    Keywords:  4, 4-difluoro-4-bora-3a, 4a-diazas-indacene (BODIPY); Galactose conjugated; Imaging-guided; NIR-II fluorescence; Photothermal therapy
    DOI:  https://doi.org/10.1016/j.jcis.2021.12.177
  82. Eur Rev Med Pharmacol Sci. 2021 Dec;pii: 27612. [Epub ahead of print]25(24): 7654-7667
    Use of coumarins as complementary medicine with an integrative approach against cervical cancer: background and mechanisms of action.
    B de la Cruz-Concepción, A Gutiérrez-Escobar, H Y Lorenzo-Moran, N Navarro-Tito, D N Martínez-Carrillo, C Ortuño-Pineda, A E Zacapala-Gómez, F I Torres-Rojas, R Dircio-Maldonado, H Jiménez-Wences, C Sotelo Leyva, M A Mendoza-Catalán.
      Cervical cancer is characterized by the cellular transformation caused by Human Papillomavirus (HPV), favoring cell proliferation, migration, invasion, and metastasis. Cervical cancer is conventionally treated with radiation therapy, and chemotherapy focused on the destruction of tumor cells. However, chemoresistance and low selectivity between tumor and non-tumor cells have been reported, causing side effects in patients. Metabolites of natural origin have shown selectivity against tumor cells, suggesting their use for reducing the side effects caused by drugs used in conventional therapy. Among these compounds, several natural coumarins stand out, such as auraptene, scopoletin, osthole, and praeruptorin, of which antiproliferative, anti-migratory, and anti-invasive activity have been reported. Auraptene, scopoletin, osthole, and praeruptorin show a cytotoxic or antiproliferative effect on cervical tumor cells, arresting the cell cycle by inducing the overexpression of negative regulators of the cell cycle, or inducing cell death by increasing the expression of pro-apoptotic proteins and decreasing that of anti-apoptotic proteins. On the other hand, auraptene, scopoletin, and praeruptorin inhibit the capacity for migration, invasion, and metastasis of cervical tumor cells, mainly by inhibiting the expression and activity of matrix metalloproteinase-2 and -9. The PI3K/Akt signal pathway appears to be central to the anti-tumor activity of the coumarins analyzed in this review. In addition, auraptene, osthole, and praeruptorin are useful in sensitizing tumor cells to radiotherapy or chemotherapeutic molecules, such as FOLFOX, cisplatin, or DOX. Coumarins offer an excellent possibility for developing new drugs as complementary medicine with an integrative approach against cervical cancer.
    DOI:  https://doi.org/10.26355/eurrev_202112_27612
  83. Int J Biol Macromol. 2021 Dec 30. pii: S0141-8130(21)02759-8. [Epub ahead of print]
    Recent advances on chitosan as an adjuvant for vaccine delivery.
    Isra Dmour, Nazrul Islam.
      Chitosan (CS) is a natural polymer derived from chitin that has wide applications in drugs, vaccines, and antigen delivery. The distinctive mucoadhesive, biocompatibility, biodegradable, and less toxic properties of chitosan compared to the currently used vaccine adjuvants made it a promising candidate for use as an adjuvant/carrier in vaccine delivery. In addition, chitosan exhibits intrinsic immunomodulating properties making it a suitable adjuvant in preparing vaccines delivery systems. Nanoparticles (NPs) of chitosan and its derivatives loaded with antigen have been shown to induce cellular and humoral responses. Versatility in the physicochemical properties of chitosan can provide an excellent opportunity to engineer antigen-specific adjuvant/delivery systems. This review discusses the recent advances of chitosan and its derivatives as adjuvants in vaccine deliveryand the published literature in the last fifteen years. The impact of physicochemical properties of chitosan on vaccine formulation has been described in detail. Applications of chitosan and its derivatives, their physicochemical properties, and mechanisms in enhancing immune responses have been discussed. Finally, challenges and future aspects of chitosan use has been pointed out.
    Keywords:  Adjuvant; Chitosan; Formulation; Immunization; Infections; Vaccine
    DOI:  https://doi.org/10.1016/j.ijbiomac.2021.12.129
  84. Curr Neuropharmacol. 2022 Jan 03.
    The Role of Natural Products in Treatment of Depressive Disorder.
    Tayebeh Noori, Antoni Sureda, Eduardo Sobarzo-Sánchez, Samira Shirooie.
      Depressive disorder is one of the most common psychiatric syndromes that, if left untreated, can cause many disturbances in a person's functions. Numerous factors are involved in depression, including inflammation, brain-derived neurotrophic factor (BDNF), GABAergic system, hypothalamic-pituitary-adrenal (HPA) Axis, monoamine neurotransmitters (serotonin (5-HT), noradrenaline, and dopamine). Common treatments for depression are selective serotonin reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors, but these drugs have several side effects such as anxiety, diarrhea, constipation, weight loss, and sexual dysfunctions. These agents only reduce the symptoms and temporarily reduce the rate of cognitive impairment associated with depression. As a result, extensive research has recently been conducted on the potential use of antidepressant and sedative herbs. According to the available data, herbs used in traditional medicine can be significantly effective in reducing depression, depressive symptoms and improving patients' performance. The present study provides a summary of biomarkers and therapeutic goals of depression and shows that natural products such as saffron or genipin, have antidepressant effects. Some of the useful natural products and their mechanisms were evaluated. Data on various herbs and natural isolated compounds reported to prevent and reduce depressive symptoms is also discussed.
    Keywords:  BDNF; Depression; HPA Axis; Monoamine Neurotransmitters; Natural products
    DOI:  https://doi.org/10.2174/1570159X20666220103140834
  85. J Enzyme Inhib Med Chem. 2022 Dec;37(1): 542-553
    Inhibitory effect of roburic acid in combination with docetaxel on human prostate cancer cells.
    Xiao Wang, Xu Xuetao, Mengshuo Wu, Panpan Wu, Zhaojun Sheng, Wenfeng Liu, Yan-Yan Ma, Den-Gao Zhao, Kun Zhang, Dongli Li, Xi Zheng, Susan Goodin.
      Roburic acid (ROB) is a naturally occurred tetracyclic triterpenoid, and the anticancer activity of this compound has not been reported. Docetaxel (DOC) is the first-line chemotherapeutic agent for advanced stage prostate cancer but toxic side effects and drug resistance limit its clinical success. In this study, the potential synergistic anticancer effect and the underlying mechanisms of ROB in combination with DOC on prostate cancer were investigated. The results showed that ROB and DOC in combination synergistically inhibited the growth of prostate cancer cells. The combination also strongly induced apoptosis, and suppressed cell migration, invasion and sphere formation. Mechanistic study showed that the combined effects of ROB and DOC on prostate cancer cells were associated with inhibition of NF-κB activation, down regulation of Bcl-2 and up regulation of Bax. Knockdown of NF-κB by small interfering RNA (siRNA) significantly decreased the combined effect of ROB and DOC. Moreover, we found that esomeprazole (ESOM), a proton pump inhibitor (PPI), strongly enhanced the effectiveness of ROB and DOC on prostate cancer cells in acidic culture medium. Since acidic micro environment is known to impair the efficacy of current anticancer therapies, ESOM combined with ROB and DOC may be an effective approach for improving the treatment of prostate cancer patients.
    Keywords:  Prostate cancer; combination; docetaxel; roburic acid
    DOI:  https://doi.org/10.1080/14756366.2021.2018684
  86. Theranostics. 2022 ;12(2): 796-816
    Repurposing ferumoxytol: Diagnostic and therapeutic applications of an FDA-approved nanoparticle.
    Yue Huang, Jessica C Hsu, Hyun Koo, David P Cormode.
      Ferumoxytol is an intravenous iron oxide nanoparticle formulation that has been approved by the U.S. Food and Drug Administration (FDA) for treating anemia in patients with chronic kidney disease. In recent years, ferumoxytol has also been demonstrated to have potential for many additional biomedical applications due to its excellent inherent physical properties, such as superparamagnetism, biocatalytic activity, and immunomodulatory behavior. With good safety and clearance profiles, ferumoxytol has been extensively utilized in both preclinical and clinical studies. Here, we first introduce the medical needs and the value of current iron oxide nanoparticle formulations in the market. We then focus on ferumoxytol nanoparticles and their physicochemical, diagnostic, and therapeutic properties. We include examples describing their use in various biomedical applications, including magnetic resonance imaging (MRI), multimodality imaging, iron deficiency treatment, immunotherapy, microbial biofilm treatment and drug delivery. Finally, we provide a brief conclusion and offer our perspectives on the current limitations and emerging applications of ferumoxytol in biomedicine. Overall, this review provides a comprehensive summary of the developments of ferumoxytol as an agent with diagnostic, therapeutic, and theranostic functionalities.
    Keywords:  drug delivery; ferumoxytol; iron deficiency; magnetic resonance imaging (MRI); nanozyme
    DOI:  https://doi.org/10.7150/thno.67375
  87. J Cancer Res Clin Oncol. 2022 Jan 08.
    Harnessing chlorin e6 loaded by functionalized iron oxide nanoparticles linked with glucose for target photodynamic therapy and improving of the immunogenicity of lung cancer.
    Ting-Ting Yu, Xing-Chun Peng, Mei-Fang Wang, Ning Han, Hua-Zhen Xu, Qi-Rui Li, Liu-Gen Li, Xiang Xu, Qian-Li Ma, Bin Liu, Jue Wang, Li Zhao, Xiao Chen, Tong-Fei Li.
       BACKGROUND: Non-small-cell lung cancer (NSCLC) is the most common malignant lung tumor and is difficult to be eradicated due to its immunosuppressive microenvironment. Chlorin e6 (Ce6)-mediated photodynamic therapy (PDT) could improve immunogenicity while destroying malignant tumor cells. However, the clinic application of Ce6-mediated PDT is limited by Ce6's poor water solubility and insufficient accumulation in lung cancer. To address this issue, Ce6 was loaded onto functionalized iron oxide nanoparticles linked with glucose to improve the distribution of Ce6 in lung cancer.
    MATERIALS AND RESULTS: The results of transmission electron microscopy (TEM), UV-Vis spectrophotometry, dynamic light scattering and near-infrared (NIR) spectroscopy confirmed the successful preparation of the composites. Confocal and flow cytometry showed IO-PG-GLU-Ce6 significantly enhanced the uptake of Ce6 by lung cancer cells and produced more reactive oxygen species (ROS) under NIR light irradiation. In addition, the detection of cell viability, proliferation and apoptosis indicated IO-PG-GLU-Ce6 achieved stronger photo-toxicity to lung cancer cells. Moreover, IO-PG-GLU-Ce6 treatment effectively damaged the DNA of lung cancer cells and thereby activated STING, up-regulated the expression of IFN-β, HMGB1 and HSP90, indicating augmented immunogenicity of lung cancer cells. Further results of in vivo, organ imaging and tissue fluorescence sections demonstrated IO-PG-GLU-Ce6 significantly improved the distribution of Ce6 in tumor tissues of lung cancer-bearing mice as well. Finally, the findings of in vivo study and immunohistochemistry confirmed the better efficacy of IO-PG-GLU-Ce6. HE staining results of vital organs suggested that the composites were less toxic.
    CONCLUSION: In conclusion, Ce6 loaded by functionalized iron oxide nanoparticles linked with glucose exhibited both target photodynamic efficacy and the ability to enhance its immunogenicity in lung cancer. This study provides a promising strategy for augment of the targeting delivery of Ce6 and its mediated photodynamic and immunotherapy.
    Keywords:  Chlorin e6; Glucose; Immunogenicity; Lung cancer; Nano-iron oxide; Photodynamic effect
    DOI:  https://doi.org/10.1007/s00432-021-03879-x
  88. Methods Mol Biol. 2022 ;2423 115-122
    Impact of Nano Preparation of Phytoconstituents in Medulloblastoma.
    Priyanka Mishra, Y B Tripathi.
      The conventional cancer treatment strategies from chemotherapy to surgery often lead to inadequate results which in some cases lead to relapsing of the tumor being treated. Medulloblastoma witness 30% relapse rate which is universally fatal among children. Although the treatment of primary medulloblastoma is well established including surgical excision, postsurgical irradiation, and, more recently, chemotherapy, there is no established treatment for its recurrence. Despite efforts to improve its therapy, frequent long-haul survivors have been recorded in the world's medical literature. In this book chapter, we have attempted to focus light on the nano preparation of phytoconstituents as an alternative approach as it has advantage of providing better bioavailability of the compound in terms of crossing the blood-brain barrier and an additional benefit in terms of limited adverse effects of the natural product over the traditional chemotherapeutic approaches. In recent times, biological methods or green approaches in the case of plants have received immense attention due to its safety and lack of contamination in the process. In this chapter, we will explore some plant products that have been incorporated into nanocarriers to improve their bioavailability in this tumor treatment.
    Keywords:  Green synthesis; Medulloblastoma; Nanomedicine; Phytoconstituent
    DOI:  https://doi.org/10.1007/978-1-0716-1952-0_12
  89. J Inflamm Res. 2021 ;14 7065-7077
    The Potential of Drug Delivery Nanosystems for Sepsis Treatment.
    Yi Shi, Meng-Lu Zhu, Qian Wu, Yi Huang, Xiao-Ling Xu, Wei Chen.
      Sepsis is a major immune response disorder caused by infection, with very high incidence and mortality rates. In the clinic, sepsis and its complications are mainly controlled and treated with antibiotics, anti-inflammatory, and antioxidant drugs. However, these treatments have some shortcomings, such as rapid metabolism and severe side effects. The emergence of drug delivery nanosystems can significantly improve tissue permeability, prolong drugs' circulation time, and reduce side effects. In this paper, we reviewed recent drug delivery nanosystems designed for sepsis treatment based on their mechanisms (anti-bacterial, anti-inflammatory, and antioxidant). Although great progress has been made recently, clinical practice transformation is still very difficult. Therefore, we also discussed key obstacles, including tissue distribution, overcoming bacterial resistance, and single treatment modes. Finally, a rigorous optimization of drug delivery nanosystems is expected to present great potential for sepsis therapy.
    Keywords:  anti-bacterial; anti-inflammatory; anti-oxidative; drug delivery nanosystems; multidrug resistance; sepsis
    DOI:  https://doi.org/10.2147/JIR.S339113
  90. J Clin Invest. 2022 Jan 04. pii: e148550. [Epub ahead of print]132(1):
    Clinical development of metabolic inhibitors for oncology.
    Kathryn M Lemberg, Sadakatali S Gori, Takashi Tsukamoto, Rana Rais, Barbara S Slusher.
      Metabolic inhibitors have been used in oncology for decades, dating back to antimetabolites developed in the 1940s. In the past 25 years, there has been increased recognition of metabolic derangements in tumor cells leading to a resurgence of interest in targeting metabolism. More recently there has been recognition that drugs targeting tumor metabolism also affect the often acidic, hypoxic, immunosuppressive tumor microenvironment (TME) and non-tumor cell populations within it, including immune cells. Here we review small-molecule metabolic inhibitors currently in clinical development for oncology applications. For each agent, we evaluate the preclinical studies demonstrating antitumor and TME effects and review ongoing clinical trials. The goal of this Review is to provide an overview of the landscape of metabolic inhibitors in clinical development for oncology.
    DOI:  https://doi.org/10.1172/JCI148550
  91. ACS Appl Mater Interfaces. 2022 Jan 06.
    A Photothermal Nanoplatform with Sugar-Triggered Cleaning Ability for High-Efficiency Intracellular Delivery.
    Kunyan Lu, Yangcui Qu, Yuancheng Lin, Luohuizi Li, Yan Wu, Yi Zou, Tianqi Chang, Yanxia Zhang, Qian Yu, Hong Chen.
      Intracellular delivery of functional molecules is of great importance in various biomedical and biotechnology applications. Recently, nanoparticle-based photothermal poration has attracted increasing attention because it provided a facile and efficient method to permeabilize cells transiently, facilitating the entry of exogenous molecules into cells. However, this method still has some safety concerns associated with the nanoparticles that bind to the cell membranes or enter the cells. Herein, a nanoplatform with both photothermal property and sugar-triggered cleaning ability for intracellular delivery is developed based on phenylboronic acid (PBA) functionalized porous magnetic nanoparticles (named as M-PBA). The M-PBA particles could bind to the target cells effectively through the specific interactions between PBA groups and the cis-diol containing components on the cell membrane. During a short-term near-infrared irradiation, the bound particles convert absorbed light energy to heat, enabling high-efficiency delivery of various exogenous molecules into the target cells via a photothermal poration mechanism. After delivery, the bound particles could be easily "cleaned" from the cell surface via mild sugar-treatment and collected by a magnet, avoiding the possible side effects caused by the entrance of particles or their fragments. The delivery and cleaning process is short and effective without compromising the viability and proliferation ability of the cells with delivered molecules, suggesting that the M-PBA particles could be used as promising intracellular delivery agents with a unique combination of efficiency, safety, and flexibility.
    Keywords:  intracellular delivery; magnetic nanoparticles; phenylboronic acid; photothermal poration; sugar-responsive
    DOI:  https://doi.org/10.1021/acsami.1c21670
  92. Bioorg Med Chem. 2021 Dec 30. pii: S0968-0896(21)00603-9. [Epub ahead of print]55 116595
    Design, synthesis and bioactivity evaluation of novel N-phenyl-substituted evodiamine derivatives as potent anti-tumor agents.
    Xiangyong Hao, Jiedan Deng, Honghua Zhang, Ziyi Liang, Fang Lei, Yuqing Wang, Xiaoyan Yang, Zhen Wang.
      Natural products are important sources for the development of therapeutic medicine, among which evodia fruit has a wide range of medicinal properties in traditional Chinese medicine. Evodiamine, the main active component of evodia fruit, has various anti-cancer effects and has been proved to be a Topo inhibitor. From our previous attempts of modifying evodiamine, we found that the N14 phenyl substituted derivatives had showed great anti-tumor activity, which prompted us to further explore the novel structures and activities of these compounds. Compound 6f, as a N14 3-fluorinated phenyl substituted evodiamine derivative, showed a certain inhibitory activity against Topo I at 200 μM. By studying its anti-tumor effects in vitro, compound 6f could inhibit proliferation and induce apoptosis, as well as arrest the cell cycle of HGC-27 and HT-29 cell lines at G2/M phase in a concentration-dependent manner. Moreover, compound 6f could inhibit the migration and invasion of HGC-27 cell lines. Meanwhile, compound 6f could induce apoptosis of HGC-27 cells by inhibiting PI3K/AKT pathway. Overall, this work demonstrated that the N14 phenyl-substituted evodiamine derivatives had a good inhibitory effect on tumor cells in vitro, providing a promising strategy for developing potential anticancer agents for the treatment of gastrointestinal tumors.
    Keywords:  Anti-tumor; Evodiamine derivatives; PI3K/AKT
    DOI:  https://doi.org/10.1016/j.bmc.2021.116595
  93. Theranostics. 2022 ;12(1): 59-75
    A hydrogen peroxide economizer for on-demand oxygen production-assisted robust sonodynamic immunotherapy.
    Qinqin Jiang, Bin Qiao, Xiaohong Lin, Jin Cao, Nan Zhang, Huanling Guo, Weiwei Liu, Lingyu Zhu, Xue Xie, Li Wan, Rui Tang, Bing Liang, Dong Wang, Zhigang Wang, Yang Zhou, HaiTao Ran, Pan Li.
      The outcome of sonodynamic immunotherapy is significantly limited by tumor hypoxia. To overcome this obstacle, one common solution is to catalyze the conversion of endogenous H2O2 into O2. However, the effectiveness of this strategy is limited by the insufficient concentration of H2O2 in the tumor microenvironment (TME). Herein, we developed a H2O2 economizer for on-demand O2 supply and sonosensitizer-mediated reactive oxygen species production during ultrasound activation, thereby alleviating hypoxia-associated limitations and augmenting the efficacy of sonodynamic immunotherapy. Methods: The H2O2 economizer is constructed by electrostatic adsorption and π-π interactions between the Fe-doped polydiaminopyridine (Fe-PDAP) nanozyme and chlorin e6. By employing a biomimetic engineering strategy with cancer cell membranes, we addressed the premature leakage issue and increased tumor-site accumulation of nanoparticles (membrane-coated Fe-PDAP/Ce6, MFC). Results: The prepared MFC could significantly attenuate the catalytic activity of Fe-PDAP by reducing their contact with H2O2. Ultrasound irradiation promoted MFC dissociation and the exposure of Fe-PDAP for a more robust O2 supply. Moreover, the combination of MFC-enhanced sonodynamic therapy with anti-programmed cell death protein-1 antibody (aPD-1) immune checkpoint blockade induced a strong antitumor response against both primary tumors and distant tumors. Conclusion: This as-prepared H2O2 economizer significantly alleviates tumor hypoxia via reducing H2O2 expenditure and that on-demand oxygen-elevated sonodynamic immunotherapy can effectively combat tumors.
    Keywords:  cancer cell membrane; focused ultrasound; immunotherapy; nanozyme; sonodynamic therapy
    DOI:  https://doi.org/10.7150/thno.64862
  94. Int J Biol Macromol. 2021 Dec 30. pii: S0141-8130(21)02760-4. [Epub ahead of print]
    Effectiveness of 5-Fluorouracil and Gemcitabine Hydrochloride Loaded Iron‑Based Chitosan-Coated MIL-100 Composite as an Advanced, Biocompatible, pH-Sensitive and Smart Drug Delivery System on Breast Cancer Therapy.
    Ali K Resen, Atheer Atiroğlu, Vesen Atiroğlu, Gamze Guney Eskiler, Ismail H Aziz, Suleyman Kaleli, Mahmut Özacar.
      This study was planned to evolve the bioavailability and therapeutic efficiency of Gemcitabine (GEM) and 5-Fluorouracil with decreased side effects using MIL-100 nano-composite as carrier. Impregnation approach was used for encapsulation of 5-Fluorouracil alone and with GEM inside the MIL-100. The formed 5-Fluorouracil@MIL-100 and 5-Fluorouracil-GEM@MIL-100 were then coated with chitosan, sequentially chelated with iron(III) and conjugated with quercetin, eventually obtaining a multifunctional MIL-100 nanocarrier. The hybrid nanocarrier nascency was verified by different characterization results. pH-sensitive releases of 5-Fluorouracil and GEM were observed because of the inherent pH-dependent stability of MIL-100. Additionally, we evaluated the anti-cancer activity of these nanocarriers through WST-1 analysis and acridine orange staining in MCF-7 human breast cancer and HUVEC control cell lines. Our findings showed that all nanocarriers exhibited anti-cancer activity and induced apoptosis in MCF-7 cells. However, 5-Fluorouracil@MIL-100 and chitosan-coated 5-Fluorouracil@MIL-100 with quercetin were more effective than other nanocarriers in MCF-7 cells (p<0.05). Moreover, we observed cytotoxicity in HUVEC cells due to the adverse side effects of chemotherapy drugs. However, chitosan coated nanocarriers with quercetin were less toxic on HUVEC cells at particularly 1 µg/mL. Therefore, MIL-100 could be used for a promising chemotherapeutic drugs delivery and chitosan coated drugs with quercetin could be useful for reducing toxicity on normal cells.
    Keywords:  5-Fluorouracil; Breast cancer; Drug delivery system; Gemcitabine; MIL-100
    DOI:  https://doi.org/10.1016/j.ijbiomac.2021.12.130
  95. Mater Today (Kidlington). 2021 Nov;50 149-169
    Iron oxide nanoparticle targeted chemo-immunotherapy for triple negative breast cancer.
    Qin Gxin Mu, Guanyou Lin, Mike Jeon, Hui Wang, Fei-Chien Chang, Richard A Revia, John Yu, Miqin Zhang.
      Triple negative breast cancer is difficult to treat effectively, due to its aggressiveness, drug resistance, and lack of the receptors required for hormonal therapy, particularly at the metastatic stage. Here, we report the development and evaluation of a multifunctional nanoparticle formulation containing an iron oxide core that can deliver doxorubicin, a cytotoxic agent, and polyinosinic:polycytidylic acid (Poly IC), a TLR3 agonist, in a targeted and simultaneous fashion to both breast cancer and dendritic cells. Endoglin-binding peptide (EBP) is used to target both TNBC cells and vasculature epithelia. The nanoparticle demonstrates favorable physicochemical properties and a tumor-specific targeting profile. The nanoparticle induces tumor apoptosis through multiple mechanisms including direct tumor cell killing, dendritic cell-initiated innate and T cell-mediated adaptive immune responses. The nanoparticle markedly inhibits tumor growth and metastasis and substantially extends survival in an aggressive and drug-resistant metastatic mouse model of triple negative breast cancer (TNBC). This study points to a promising platform that may substantially improve the therapeutic efficacy for treating metastatic TNBC.
    Keywords:  Iron oxide nanoparticles; doxorubicin; endoglin binding peptide; immunotherapy; metastasis; triple negative breast cancer
    DOI:  https://doi.org/10.1016/j.mattod.2021.08.002
  96. AAPS PharmSciTech. 2022 Jan 05. 23(1): 49
    Transdermal Delivery of Curcumin-Loaded Solid Lipid Nanoparticles as Microneedle Patch: an In Vitro and In Vivo Study.
    Ankitha Prabhu, Jobin Jose, Lalit Kumar, S Salwa, M Vijay Kumar, Seyed Mohammad Nabavi.
      Curcumin is well known for its neuroprotective effect, and also able to alleviate Parkinsonian features. Clinical application of curcumin is limited due to its low bioavailability. Hence, we hypothesized that the microneedles (MN) containing drug-loaded solid lipid nanoparticles (SLNs) may be able to improve its bioavailability and efficacy. The SLNs were prepared with microemulsion technique using glyceryl monostearate as a lipid and tween 80 as a stabilizer. The particle size, polydispersity index, zeta potential, and entrapment efficiency of prepared SLNs were determined. The optimized formulation was incorporated into microneedle arrays using micromolding technique and fabricated microneedle patch were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, optical microscopy, ex vivo permeation studies, histology studies, and fluorescent microscopy. The fabricated microneedle patch was also evaluated for neuroprotective activity and skin irritation potential. Fourier transform infrared spectroscopy studies of SLNs and microneedles confirmed the chemical compatibility of excipients with curcumin. The developed microneedles were also found to be non-irritant with decreased degree of bradykinesia, high motor coordination, and balance ability. The study provided a theoretical basis for the use of novel microneedle containing curcumin-loaded solid lipid nanoparticles as a useful tool for the treatment of Parkinson's disease.
    Keywords:  Curcumin, Solid lipid nanoparticles, Microneedles, Transdermal
    DOI:  https://doi.org/10.1208/s12249-021-02186-5
  97. Curr Med Chem. 2022 Jan 05.
    Nanoparticle mediated gene therapy: a trailblazer armament to fight CNS disorders.
    Annu, Saleha Rehman, Bushra Nabi, Ali Sartaj, Sanjula Baboota, Shadab Md, P K Sahoo, Javed Ali.
      Central nervous system (CNS) disorders account for boundless socioeconomic burdens with devastating effects among the population, especially the elderly. The major symptoms of these disorders are neurodegeneration, neuroinflammation, and cognitive dysfunction caused by inherited genetic mutations or by genetic and epigenetic changes due to injury, environmental factors, and disease-related events. Currently available clinical treatment for CNS diseases, i.e., Alzheimer's disease, Parkinson's disease, stroke, and brain tumor have significant side effects and are largely unable to halt the clinical progression. So, gene therapy displays a new paradigm in the treatment of these disorders with some modalities, varying from suppression of endogenous genes to expression of exogenous genes. Both viral and non-viral vectors are commonly used for gene therapy. Viral vectors are quite effective but associated with immunogenicity and carcinogenicity like severe side effects, and poor target cell specificity. Thus, non-viral vectors, mainly nanotherapeutics like nanoparticles (NPs), opt-out to be a realistic approach in gene therapy in achieving higher efficacy. NPs demonstrate a new avenue in pharmacotherapy for the delivery of drugs or genes to their selective cells or tissue thus providing concentrated and constant drug delivery to targeted tissues, minimizing systemic toxicity and side effects. The current review will emphasize the role of NPs in mediating gene therapy for CNS disorders treatment. Moreover, the challenges and perspectives of NPs in gene therapy will be summarized.
    Keywords:  Alzheimer's disease; Brain tumors; Gene therapy; Nanoparticles; Parkinson's disease; Stroke
    DOI:  https://doi.org/10.2174/0929867329666220105122318
  98. Food Res Int. 2022 Jan;pii: S0963-9969(21)00802-4. [Epub ahead of print]151 110902
    Brazilian tucumã-do-Amazonas (Astrocaryum aculeatum) and tucumã-do-Pará (Astrocaryum vulgare) fruits: bioactive composition, health benefits, and technological potential.
    Ana Paula da Fonseca Machado, Roberto de Paula do Nascimento, Mariana da Rocha Alves, Lívia Mateus Reguengo, Mario Roberto Marostica Junior.
      Latin America has a wide range of native plants spread through its territory. The palms of the Astrocaryum genus are examples of crops occurring in Central and South America, including the large plant life in Brazil. Although not very well known, the Astrocaryum spp. possess edible and non-edible fractions with potential technological and medicinal uses, as evidenced by recent research. Two native Brazilian fruits, tucumã-do-Amazonas (Astrocaryum aculeatum) and tucumã-do-Pará (Astrocaryum vulgare), typically found in the north and northeast of the country, respectively, stand out for their high antioxidant capacity and rich content in bioactive compounds, mainly carotenoids and phenolic compounds. Accordingly, experimental studies indicate their potential to prevent and treat inflammatory and oxidative stress-related conditions, including cancer. The tucumã plants have also been suggested as tools in the industry, for example for biofuel production, activated carbon technology, and as alternative packaging. Considering the importance of bringing light to underestimated yet culturally relevant native crops with potential benefits for small and large communities, this review aims to present and discuss the characteristics, bioactive composition, health effects, and technological potential of tucumã-do-Amazonas and tucumã-do-Pará fruits.
    Keywords:  Cancer; Carotenoids; Inflammation; Oxidative stress; Phenolic compounds
    DOI:  https://doi.org/10.1016/j.foodres.2021.110902
  99. Appl Biochem Biotechnol. 2022 Jan 06.
    Molecular Docking of Phytochemicals Targeting GFRs as Therapeutic Sites for Cancer: an In Silico Study.
    Love Edet Mendie, S Hemalatha.
      Drug delivery in a safe manner is a major challenge in the drug development process. Growth factor receptors (GFRs) are known to have profound roles in the growth and progression of cancerous cells making these receptors a therapeutic target in the effective treatment of cancer. This work focused on exploring bioactive compounds that can target GFRs using in silico method. In this study, 50 bioactive compounds from different plant sources were screened as anticancer agent against GFRs using drug likeness parameters of Lipinski's rule of five. The molecular docking was performed between phytochemicals and GFRs. Ligands with acceptable drug likeness and binding energy comparable to the standard drugs were further screened to determine their pharmacokinetic activities. This study showed phytochemicals with the binding energy comparable with the standard drugs (Dovitinib and Gefitinib), while ADME, bioactivity score, and bioavailability radar analysis gave further insight on these compounds as potent anticancer agents.
    Keywords:  ADMET; Cancer; Drug delivery; GFR; Molecular docking
    DOI:  https://doi.org/10.1007/s12010-021-03791-7
  100. J Nanobiotechnology. 2022 Jan 06. 20(1): 23
    Extracellular matrix-degrading STING nanoagonists for mild NIR-II photothermal-augmented chemodynamic-immunotherapy.
    Meixiao Zhan, Xiangrong Yu, Wei Zhao, Yongjun Peng, Shaojun Peng, Jingchao Li, Ligong Lu.
      Regulation of stimulator of interferon genes (STING) pathway using agonists can boost antitumor immunity for cancer treatment, while the rapid plasma clearance, limited membrane permeability, and inefficient cytosolic transport of STING agonists greatly compromise their therapeutic efficacy. In this study, we describe an extracellular matrix (ECM)-degrading nanoagonist (dNAc) with second near-infrared (NIR-II) light controlled activation of intracellular STING pathway for mild photothermal-augmented chemodynamic-immunotherapy of breast cancer. The dNAc consists of a thermal-responsive liposome inside loading with ferrous sulfide (FeS2) nanoparticles as both NIR-II photothermal converters and Fenton catalysts, 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) as the STING agonist, and an ECM-degrading enzyme (bromelain) on the liposome surface. Mild heat generated by dNAc upon NIR-II photoirradiation improves Fenton reaction efficacy to kill tumor cells and cause immunogenic cell death (ICD). Meanwhile, the generated heat triggers a controlled release of cGAMP from thermal-responsive liposomes to active STING pathway. The mild photothermal activation of STING pathway combined with ICD promotes anti-tumor immune responses, which leads to improved infiltration of effector T cells into tumor tissues after bromelain-mediated ECM degradation. As a result, after treatment with dNAc upon NIR-II photoactivation, both primary and distant tumors in a murine mouse model are inhibited and the liver and lung metastasis are effectively suppressed. This work presents a photoactivatable system for STING pathway and combinational immunotherapy with improved therapeutic outcome.
    Keywords:  Fenton reaction; Immunotherapy; Nanoagonist; Photoactivation; STING pathway
    DOI:  https://doi.org/10.1186/s12951-021-01226-3
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