bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–04–10
107 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Metabolic Intervention Nanoparticles for triple-negative Breast Cancer Therapy Via Overcoming FSP1-mediated Ferroptosis Resistance.
  2. NIR-responsive polydopamine-based calcium carbonate hybrid nanoparticles deliver artesunate for cancer chemo-photothermal therapy.
  3. Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy.
  4. Bioorthogonal chemistry and illumination controlled programmed size-changeable nanomedicine for synergistic photodynamic and hypoxia-activated therapy.
  5. Metabolic profile of the Warburg effect as a tool for molecular prognosis and diagnosis of cancer.
  6. Nanomedicine Tactics in Cancer Treatment: Challenge and Hope.
  7. pH-Responsive Polymer Nanomaterials for Tumor Therapy.
  8. The Influence of Mitochondrial Energy and 1C Metabolism on the Efficacy of Anticancer Drugs - Exploring Potential Mechanisms of Resistance.
  9. An amino acid-defined diet impairs tumour growth in mice by promoting endoplasmic reticulum stress and mTOR inhibition.
  10. KRAS Addiction Promotes Cancer Cell Adaptation in Harsh Microenvironment Through Macropinocytosis.
  11. Disruption of dual homeostasis by a metal-organic framework nanoreactor for ferroptosis-based immunotherapy of tumor.
  12. Synthesis, characterization, and evaluation of chloroaluminium phthalocyanine incorporated in poly(ε-caprolactone) nanoparticles for photodynamic therapy.
  13. Metabolic Reservoir Cycles in Cancer.
  14. A Dual-locked Activatable Phototheranostic Probe for Biomarkers Regulated Photodynamic and Photothermal Cancer Therapy.
  15. Avenaciolide Induces Apoptosis in Human Malignant Meningioma Cells through the Production of Reactive Oxygen Species.
  16. Programmed self-assembly of enzyme activity-inhibited nanomedicine for augmenting chemodynamic tumor nanotherapy.
  17. Curcumin and Paclitaxel co-Loaded Heparin and Poloxamer P403 Hybrid Nanocarrier for Improved Synergistic Efficacy in Breast Cancer.
  18. Degradable Tumor-Responsive Iron-Doped Phosphate-Based Glass Nanozyme for H2O2 Self-Supplying Cancer Therapy.
  19. On-demand assembly of polymeric nanoparticles for longer-blood-circulation and disassembly in tumor for boosting sonodynamic therapy.
  20. Heterojunction engineered bioactive chlorella for cascade promoted cancer therapy.
  21. Classification of KRAS-Activating Mutations and the Implications for Therapeutic Intervention.
  22. Brain-targeting, acid-responsive antioxidant nanoparticles for stroke treatment and drug delivery.
  23. Nanoreactor activated in situ for starvation-chemodynamic therapy of breast cancer.
  24. Combined Prussian Blue Nanozyme Carriers Improve Photodynamic Therapy and Effective Interruption of Tumor Metastasis.
  25. Recent advances in nanoparticle-based targeting tactics for antibacterial photodynamic therapy.
  26. Major Constituents From Brucea javanica and Their Pharmacological Actions.
  27. The potential applications of traditional Chinese medicine in Parkinson's disease: A new opportunity.
  28. Characterization of Novel Paclitaxel Nanoparticles Prepared by Laser Irradiation.
  29. The golden spice curcumin in cancer: A perspective on finalized clinical trials during the last 10 years.
  30. pH-Responsive Hyaluronic Acid Nanoparticles for Enhanced Triple Negative Breast Cancer Therapy.
  31. Engineered exosomes as a photosensitizer delivery platform for cancer photodynamic therapy.
  32. Association of Hypertension and Breast Cancer: Antihypertensive Drugs as an Effective Adjunctive in Breast Cancer Therapy.
  33. Dark Dynamic Therapy: Photosensitization without Light Excitation Using Chemiluminescence Resonance Energy Transfer in a Dioxetane-Erythrosin B Conjugate.
  34. Polymeric nanoparticles for the delivery of Sonoran desert propolis: Synthesis, characterization and antiproliferative activity on cancer cells.
  35. Recent advances of antitumor shikonin/alkannin derivatives: A comprehensive overview focusing on structural classification, synthetic approaches, and mechanisms of action.
  36. Curcumin doped zeolitic imidazolate framework nanoplatforms as multifunctional nanocarriers for tumor chemo/immunotherapy.
  37. KRASG12R-Independent Macropinocytosis in Pancreatic Cancer.
  38. Dietary phytochemicals targeting Nrf2 for chemoprevention in breast cancer.
  39. Enhancement of anti-neoplastic effects of cuminaldehyde against breast cancer via mesoporous silica nanoparticle based targeted drug delivery system.
  40. Light-triggered multifunctional nanoplatform for efficient cancer photo-immunotherapy.
  41. Epidermal growth factor-labeled liposomes as a way to target the toxicity of silver nanoparticles into EGFR-overexpressing cancer cells in vitro.
  42. Safety issues of nanomaterials for dermal pharmaceutical products.
  43. Bioactivity of Natural Polyphenols as Antiparasitic Agents and their Biochemical Targets.
  44. A review: Pharmacology and pharmacokinetics of Schisandrin A.
  45. Lipid Metabolism Regulation Based on Nanotechnology for Enhancement of Tumor Immunity.
  46. Daylight-PDT: everything under the sun.
  47. Nano-traditional Chinese medicine: a promising strategy and its recent advances.
  48. Dietary Phytochemicals Targeting Nrf2 to Enhance the Radiosensitivity of Cancer.
  49. Sonosensitizer nanoplatform-mediated sonodynamic therapy induced immunogenic cell death and tumor immune microenvironment variation.
  50. Fabrication of Curcumin@Ag Loaded Core/Shell Nanofiber Membrane and its Synergistic Antibacterial Properties.
  51. Supramolecular nanotherapeutics enable metabolic reprogramming of tumor-associated macrophages to inhibit tumor growth.
  52. Cascade-responsive nanobomb with domino effect for anti-tumor synergistic therapies.
  53. A Hybrid Supramolecular Polymeric Nanomedicine for Cascade-Amplified Synergetic Cancer Therapy.
  54. Preparation of PEG/ZIF-8@HF drug delivery system for melanoma treatment via oral administration.
  55. Vesicular Approach Review on Nanocarriers bearing Curcumin and Applications.
  56. Induction of p53 mediated mitochondrial apoptosis and cell cycle arrest in human breast cancer cells by plant mediated synthesis of silver nanoparticles from Bergenia ligulata (Whole plant).
  57. Combining Doxorubicin-Conjugated Polymeric Nanoparticles and 5-Aminolevulinic Acid for Enhancing Radiotherapy against Lung Cancer.
  58. Ultrasound-triggered reactive oxygen species effector nanoamplifier for enhanced combination therapy of mutant p53 tumors.
  59. Targeting mTOR in the context of diet and whole-body metabolism.
  60. In vivo self-assembled drug nanocrystals for metastatic breast cancer all-stage targeted therapy.
  61. Saponins in Cancer Treatment: Current Progress and Future Prospects.
  62. Biomedical features and therapeutic potential of rosmarinic acid.
  63. Intelligent Micro/nanorobot for Cancer Theragnostic.
  64. Harpephyllum caffrum fruit (wild plum) facilitates glucose uptake and modulates metabolic activities linked to neurodegeneration in isolated rat brain: An in vitro and in silico approach.
  65. Eichhornia crassipes (Mart.) Solms: A Comprehensive Review of Its Chemical Composition, Traditional Use, and Value-Added Products.
  66. Methotrexate-Lactoferrin Targeted Exemestane Cubosomes for Synergistic Breast Cancer Therapy.
  67. Targeting transforming growth factor-β signalling for cancer prevention and intervention: Recent advances in developing small molecules of natural origin.
  68. Advances in Photodynamic Therapy Based on Nanotechnology and Its Application in Skin Cancer.
  69. 4'-Nitrobiphenyl thioglucoside as the Smallest, fluorescent photosensitizer with cancer targeting ligand.
  70. Macropinocytosis and Cancer: From Tumor Stress to Signaling Pathways.
  71. Nanogels loading curcumin in situ through microemulsion photopolymerization for enhancement of antitumor effects.
  72. Partial ligand shielding nanoparticles improve pancreatic ductal adenocarcinoma treatment via a multifunctional paradigm for tumor stroma reprogramming.
  73. The Potential Oncostatic Effects of Melatonin against Prostate Cancer.
  74. Regulation of Glucose, Fatty Acid and Amino Acid Metabolism by Ubiquitination and SUMOylation for Cancer Progression.
  75. Homogenous multifunctional microspheres induce ferroptosis to promote the anti-hepatocarcinoma effect of chemoembolization.
  76. Beneficial effects of intermittent fasting: a narrative review.
  77. Interplay between the Cannabinoid System and microRNAs in Cancer.
  78. Microfluidic Nanoparticles for Drug Delivery.
  79. The role of TBK1 in cancer pathogenesis and anticancer immunity.
  80. Graphene oxide induces autophagy and apoptosis via ROS-dependent AMPK/mTOR/ULK-1 pathway in colorectal cancer cells.
  81. A nanotherapy responsive to the inflammatory microenvironment for the dual-targeted treatment of atherosclerosis.
  82. Formulation of pH-responsive PEGylated nanoparticles with high drug loading capacity and programmable drug release for enhanced antibacterial activity.
  83. An Overview of the Pharmacological Activities of Scopoletin against Different Chronic Diseases.
  84. Design, Characterization, and Evaluation of Diosmetin-Loaded Solid Self-microemulsifying Drug Delivery System Prepared by Electrospray for Improved Bioavailability.
  85. Exploring nose to brain nano delivery for effective management of migraine.
  86. Wirelessly Activated Nanotherapeutics for In Vivo Programmable Photodynamic-Chemotherapy of Orthotopic Bladder Cancer.
  87. Bioresponsive Nanomaterials: Recent Advances in Cancer Multimodal Imaging and Imaging-Guided Therapy.
  88. Metaboloepigenetics in cancer, immunity and cardiovascular disease.
  89. Fabrication of tumor targeting rare-earth nanocrystals for real-time NIR-IIb fluorescence imaging-guided breast Cancer precise surgery.
  90. Cholesterol-Lowering Phytochemicals: Targeting the Mevalonate Pathway for Anticancer Interventions.
  91. Epigenetic drugs induce the potency of classic chemotherapy, suppress post-treatment re-growth of breast cancer, but preserve the wound healing ability of stem cells.
  92. Flavored Food Additives on the Leaves of Piper betle L.: A Human Health Perspective.
  93. In vitro and in vivo characterization of Entacapone-loaded nanostructured lipid carriers developed by quality-by-design approach.
  94. Gallium containing bioactive materials: A review of anticancer, antibacterial, and osteogenic properties.
  95. Getting into the Brain: Are We in Yet or Just Knocking at the Door?
  96. Evodiamine suppresses the progression of non-small cell lung carcinoma via endoplasmic reticulum stress-mediated apoptosis pathway in vivo and in vitro.
  97. Vitamin A fortification: Recent advances in encapsulation technologies.
  98. Biomimetic nanoparticles directly remodel immunosuppressive microenvironment for boosting glioblastoma immunotherapy.
  99. Isolation of Natural Prodrug-Like Metabolite by Simulating Human Prodrug Activation in Filamentous Fungus.
  100. Antitumor Effects of 10058-F4 and Curcumin in Combination Therapy for Pancreatic Cancer In Vitro and In Vivo.
  101. Synthesis of novel dual target inhibitors of PARP and EGFR and their antitumor activities in triple negative breast cancers.
  102. Application of chitosan/alginate nanoparticle in oral drug delivery systems: prospects and challenges.
  103. Cancer combination therapies by angiogenesis inhibitors; a comprehensive review.
  104. Rethinking Breast Cancer Chemoprevention: Technological Advantages and Enhanced Performance of a Nanoethosomal-Based Hydrogel for Topical Administration of Fenretinide.
  105. Black Mn-containing layered double hydroxide coated magnesium alloy for osteosarcoma therapy, bacteria killing, and bone regeneration.
  106. Pectin coated Nanostructured Lipid Carriers for Targeted Piperine Delivery to Hepatocellular Carcinoma.
  107. Preliminary Study on the Therapeutic Effect of Doxorubicin-Loaded Targeting Nanoparticles on Glioma.
  1. Adv Healthc Mater. 2022 Apr 08. e2102799
    Metabolic Intervention Nanoparticles for triple-negative Breast Cancer Therapy Via Overcoming FSP1-mediated Ferroptosis Resistance.
    Jie Yang, Zengguang Jia, Jun Zhang, Xiuhua Pan, Yawen Wei, Siyu Ma, Ning Yang, Zengyi Liu, Qi Shen.
      Triple-negative breast cancer (TNBC) patients have a predisposition to poor prognosis due to the strong malignancy. Ferroptosis, a new forms of cell death, is a candidate treatment for TNBC owing to its effectiveness in killing cancer cells. However, some TNBC cells exhibit an abnormal tumor metabolism, especially the ferroptosis suppressor protein 1 (FSP1)-mediated ubiquinone redox metabolism, which could promote ferroptosis resistance. Here, rosuvastatin (RSV) was encapsulated in silk fibroin (SF) nanoparticle (designated as Cu-SF(RSV) NPs) for TNBC inhibition by overcoming FSP1-mediated ferroptosis resistance. RSV intervened in metabolic mevalonate pathway to disturb the redox homeostasis regulated by CoQ/FSP1 axis, thereby overcoming ferroptosis resistance. Besides, Cu-SF(RSV) NPs could generate reactive oxygen species (ROS) and deplete glutathione (GSH) to facilitate redox stress, thereby amplifying ferroptosis effect. Thus, we anticipate that the metabolic intervention nanoparticles, Cu-SF(RSV) NPs, could be exploited as a promising therapeutic platform for clinical TNBC treatment. This article is protected by copyright. All rights reserved.
    Keywords:  ferroptosis resistance; metabolic intervention; metastasis; statins-loaded silk fibroin nanoparticles; triple-negative breast cancer
    DOI:  https://doi.org/10.1002/adhm.202102799
  2. Acta Biomater. 2022 Apr 02. pii: S1742-7061(22)00190-8. [Epub ahead of print]
    NIR-responsive polydopamine-based calcium carbonate hybrid nanoparticles deliver artesunate for cancer chemo-photothermal therapy.
    Wenzhao Zhong, Ka Hong Wong, Fujian Xu, Nana Zhao, Meiwan Chen.
      Artesunate (AS), the first-line treatment of malaria with satisfied safety profile, has been repurposed as a potential anticancer candidate as it mainly generates reactive oxygen species (ROS) through its intrinsic endoperoxide bridge reacting with ferrous-based catalysts to suppress cancer cell growth. However, further clinical translation of AS is hindered by the attenuated anticancer efficacy due to insufficient ROS generation. Herein, we rationally integrated hydrophobic-modified AS (hAS) with biomimetic polydopamine (PDA) and biomineral calcium carbonate to fabricate high AS-loaded nanomedicine (Ca-PDA/hAS@PEG) for cancer chemo-photothermal therapy, which exerted anticancer effects in the following ways: (1) the heat was generated when PDA was irradiated by near-infrared (NIR) light for photothermal therapy. In the meanwhile, the increased temperature accelerated the production of ROS from hAS, thus enhancing the anticancer efficacy of hAS-based chemotherapy; (2) hAS-mediated chemotherapy boosted the cancer inhibition effect of photothermal therapy by arousing the intracellular ROS levels in the presence of endogenous ferrous ions and sensitizing cancer cells to thermal ablation; (3) the integration of calcium carbonate into the nanoparticle facilitated the pH-responsive drug release for precise treatment. Such hybrid nanoparticles exhibited a combinational antitumor effect of photothermal therapy and chemotherapy in vivo with no systemic toxicity. Taken together, our work presents a facile strategy to improve the anticancer efficacy of AS by combining chemical modification and photothermal therapy-assisted endoperoxide bridge cleavage, which may offer opportunities to pave the way for clinical translation of AS-based nanomedicines. STATEMENT OF SIGNIFICANCE: The clinical translation of artesunate (AS) is hindered by the attenuated anticancer efficacy due to insufficient ROS generation. Herein, we rationally integrated hydrophobic-modified AS (hAS) with biomimetic polydopamine (PDA) and biomineral calcium carbonate to fabricate high AS-loaded nanomedicine (Ca-PDA@hAS) for improved cancer chemo-photothermal therapy. The heat generated from PDA in response to near-infrared light irradiation could locally ablate tumor as well as accelerate the production of ROS by hAS, aiming to enhance the anticancer efficacy of hAS-based chemotherapy. On the other hand, hAS-based chemotherapy amplified the intracellular oxidative stress, sensitizing cancer cells to thermal ablation. Our work presents a facile strategy to improve the anticancer efficacy of AS by combining chemical modification and photothermal therapy-assisted endoperoxide bridge cleavage.
    Keywords:  Artesunate; Cancer chemo-photothermal therapy; Polydopamine-based calcium carbonate hybrid nanoparticles
    DOI:  https://doi.org/10.1016/j.actbio.2022.03.051
  3. J Nanobiotechnology. 2022 Apr 02. 20(1): 177
    Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy.
    Ting Zhao, Ce Liang, Yanrong Zhao, Xiangdong Xue, Zhao Ma, Jinlong Qi, Haitao Shen, Shaokun Yang, Jia Zhang, Qingzhong Jia, Qing Du, Deying Cao, Bai Xiang, Hailin Zhang, Xianrong Qi.
       BACKGROUND: Small interfering RNA (siRNA) is utilized as a potent agent for cancer therapy through regulating the expression of genes associated with tumors. While the widely application of siRNAs in cancer treatment is severely limited by their insufficient biological stability and its poor ability to penetrate cell membranes. Targeted delivery systems hold great promise to selectively deliver loaded drug to tumor site and reduce toxic side effect. However, the elevated tumor interstitial fluid pressure and efficient cytoplasmic release are still two significant obstacles to siRNA delivery. Co-delivery of chemotherapeutic drugs and siRNA represents a potential strategy which may achieve synergistic anticancer effect. Herein, we designed and synthesized a dual pH-responsive peptide (DPRP), which includes three units, a cell-penetrating domain (polyarginine), a polyanionic shielding domain (ehG)n, and an imine linkage between them. Based on the DPRP surface modification, we developed a pH-responsive liposomal system for co-delivering polo-like kinase-1 (PLK-1) specific siRNA and anticancer agent docetaxel (DTX), D-Lsi/DTX, to synergistically exhibit anti-tumor effect.
    RESULTS: In contrast to the results at the physiological pH (7.4), D-Lsi/DTX lead to the enhanced penetration into tumor spheroid, the facilitated cellular uptake, the promoted escape from endosomes/lysosomes, the improved distribution into cytoplasm, and the increased cellular apoptosis under mildly acidic condition (pH 6.5). Moreover, both in vitro and in vivo study indicated that D-Lsi/DTX had a therapeutic advantage over other control liposomes. We provided clear evidence that liposomal system co-delivering siPLK-1 and DTX could significantly downregulate expression of PLK-1 and inhibit tumor growth without detectable toxic side effect, compared with siPLK-1-loaded liposomes, DTX-loaded liposomes, and the combinatorial administration.
    CONCLUSION: These results demonstrate great potential of the combined chemo/gene therapy based on the multistage pH-responsive codelivery liposomal platform for synergistic tumor treatment.
    Keywords:  Cancer therapy; Co-delivery system; Docetaxel; Liposome; Small interfering RNA; pH-responsive
    DOI:  https://doi.org/10.1186/s12951-022-01383-z
  4. Biomaterials. 2022 Apr 01. pii: S0142-9612(22)00119-3. [Epub ahead of print]284 121480
    Bioorthogonal chemistry and illumination controlled programmed size-changeable nanomedicine for synergistic photodynamic and hypoxia-activated therapy.
    Maolin Jiang, Ye Liu, Yansong Dong, Kewei Wang, Youyong Yuan.
      Photodynamic therapy (PDT) can aggravate the hypoxia aggravation and be further utilized for the activation of hypoxia-activated prodrug (HAP). Ideally, photosensitizers (PSs) are mainly administrated to tumor vasculatures adjacent to regions with high oxygen to effectively generate reactive oxygen species (ROS) effectively and further aggravate tumor hypoxia, while the HAP is delivered to the inner tumor as far as possible for efficient activation. However, a delivery system capable of transporting PSs and HAP to the desired region respectively for the optimum effect is urgently needed. Here, we developed a bioorthogonal click chemistry and illumination controlled programmed size-changeable nanomedicine for synergistic photodynamic and hypoxia-activated therapy. It utilized tumor acidity responsive bioorthogonal click reaction for crosslinking nanoparticles to construct a drug depot with tumor vasculatures adjacent region retention for PDT in normoxia. Under laser illumination, cleavage of the ROS-responsive thioketal (TK) crosslinker to release small sized poly(amidoamine) (PAMAM) dendrimer conjugated with HAP for enhanced tumor penetration into the hypoxic region. Therefore, this strategy could differentially deliver PSs and HAP in desired spatial distribution, eventually achieving the enhanced synergistic enhancement in the combined PDT and hypoxia-activated therapy.
    Keywords:  Bioorthogonal chemistry; Combination therapy; Hypoxia-activated prodrug; Photodynamic therapy; Tumor penetration
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121480
  5. Expert Rev Mol Diagn. 2022 Apr 08.
    Metabolic profile of the Warburg effect as a tool for molecular prognosis and diagnosis of cancer.
    Gerardo M Nava, Luis Alberto Madrigal Perez.
       INTRODUCTION: Adaptations of eukaryotic cells to environmental changes are important for their survival. However, under some circumstances, microenvironmental changes promote that eukaryotic cells utilize a metabolic signature resembling a unicellular organism named the Warburg effect. Most cancer cells share the Warburg effect displaying lactic fermentation and high glucose uptake. The Warburg effect also induces a metabolic rewiring stimulating glutamine consumption and lipid synthesis, also considered cancer hallmarks. Amino acid metabolism alteration due to the Warburg effect increases plasma levels of proline and branched-chain amino acids in several cancer types. Proline and lipids are probably used as electron transfer molecules in carcinogenic cells. In addition, branched-chain amino acids fuel the Krebs cycle, protein synthesis, and signaling in cancer cells.
    AREAS COVERED: This review covers how metabolomics studies describe changes in some metabolites and proteins associated with the Warburg effect and related metabolic pathways.
    EXPERT OPINION: In this review, we analyze the metabolic signature of the Warburg effect and related phenotypes and propose some Warburg effect-related metabolites and proteins (lactate, glucose uptake, glucose transporters, glutamine, branched-chain amino acids, proline, and some lipogenic enzymes) as promising cancer biomarkers.
    Keywords:  Biomarker; Warburg effect; cancer; diagnosis; metabolism; molecular prognosis
    DOI:  https://doi.org/10.1080/14737159.2022.2065196
  6. Crit Rev Oncol Hematol. 2022 Apr 03. pii: S1040-8428(22)00101-9. [Epub ahead of print] 103677
    Nanomedicine Tactics in Cancer Treatment: Challenge and Hope.
    Mazhar Salim Al-Zoubi, Raed M Al-Zoubi.
      Defeating cancer is the ultimate challenge and goal of oncologists, facing various obstacles along with finding effective anti-cancer therapies and understanding drug delivery mechanisms. Additionally, the translation of the experimental findings to the clinical outcomes such as specificity, delivery, toxicity, clearance, and bioavailability is another health concern. Nanomedicine is a branch of nanotechnology that has been drastically developed in the last decades. Due to the fact of various nanomaterial formulas, different nanomedicine drug delivery tactics have been developed as anti-cancer therapies. The most effective and less toxic approaches involved the active targeting drug delivery tactic, which relies on the recognition of the drug nanoparticle carriers and the cell surface marker. Accordingly, FDA approved such a group of nanomedicine drug delivery systems while other formulas are still under the clinical trial phases. Nanomedicine is showing a bright future in the treatment of cancer. Oncologists learned from cancer research the possible drug resistance that could be developed. Consequently, researchers need to be prepared for the possible adverse effect of the nanomedicine approach.
    Keywords:  Anti-Cancer; Cytotoxicity; Liposomal Nanoparticles; Nanomedicine
    DOI:  https://doi.org/10.1016/j.critrevonc.2022.103677
  7. Front Oncol. 2022 ;12 855019
    pH-Responsive Polymer Nanomaterials for Tumor Therapy.
    Shunli Chu, Xiaolu Shi, Ye Tian, Fengxiang Gao.
      The complexity of the tumor microenvironment presents significant challenges to cancer therapy, while providing opportunities for targeted drug delivery. Using characteristic signals of the tumor microenvironment, various stimuli-responsive drug delivery systems can be constructed for targeted drug delivery to tumor sites. Among these, the pH is frequently utilized, owing to the pH of the tumor microenvironment being lower than that of blood and healthy tissues. pH-responsive polymer carriers can improve the efficiency of drug delivery in vivo, allow targeted drug delivery, and reduce adverse drug reactions, enabling multifunctional and personalized treatment. pH-responsive polymers have gained increasing interest due to their advantageous properties and potential for applicability in tumor therapy. In this review, recent advances in, and common applications of, pH-responsive polymer nanomaterials for drug delivery in cancer therapy are summarized, with a focus on the different types of pH-responsive polymers. Moreover, the challenges and future applications in this field are prospected.
    Keywords:  drug delivery; nanomaterials; pH-responsive polymer; tumor; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.855019
  8. Curr Med Chem. 2022 Apr 01.
    The Influence of Mitochondrial Energy and 1C Metabolism on the Efficacy of Anticancer Drugs - Exploring Potential Mechanisms of Resistance.
    Marika Franczak, Isabel Toenshoff, Gerrit Jansen, Ryszard T Smolenski, Elisa Giovannetti, Godefridus J Peters.
      Mitochondria are the main energy factory in living cells. To rapidly proliferate and metastasize, neoplastic cells increase their energy requirements. Thus, mitochondria become one of the most important organelles for them. Indeed, much research shows the interplay between cancer chemoresistance and altered mitochondrial function. In this review we focus on the differences in energy metabolism between cancer and normal cells, to better understand their resistance and how to develop drugs targeting energy metabolism and nucleotide synthesis. One of the differences between cancer and normal cells is the higher nicotinamide adenine dinucleotide (NAD+) level, a cofactor for the tricarboxylic acid cycle (TCA), which enhances their proliferation and helps cancer cells survive under hypoxic conditions. An important change is a metabolic switch, called the Warburg effect. This effect is based on the change of energy harvesting from oxygen-dependent transformation to oxidative phosphorylation (OXPHOS), adapt them to the tumor environment. Another mechanism is the high expression of one carbon (1C) metabolism enzymes. Again, this allows cancer cells to increase proliferation by producing precursors for the synthesis of nucleotides and amino acids. We reviewed drugs in clinical practice and in development targeting NAD+, OXPHOS, and 1C metabolism. Combinations of novel drugs with conventional antineoplastic agents may prove to be a promising new way of anticancer treatment.
    Keywords:  1C Metabolism; Cancer; Mitochondria; NAD+; Oxidative Phosphorylation (OXPHOS); Resistance
    DOI:  https://doi.org/10.2174/0929867329666220401110418
  9. Mol Metab. 2022 Mar 30. pii: S2212-8778(22)00047-3. [Epub ahead of print] 101478
    An amino acid-defined diet impairs tumour growth in mice by promoting endoplasmic reticulum stress and mTOR inhibition.
    Maurizio Ragni, Chiara Ruocco, Laura Tedesco, Michele O Carruba, Alessandra Valerio, Enzo Nisoli.
       OBJECTIVE: Profound metabolic alterations characterize cancer development and, beyond glucose addiction, amino acid (AA) dependency is now recognized as a hallmark of tumour growth. Therefore, targeting the metabolic addiction of tumours by reprogramming their substrate utilization is an attractive therapeutic strategy. We hypothesized that a dietary approach targeted to stimulate oxidative metabolism could reverse the metabolic inflexibility of tumours and represent a proper adjuvant therapy.
    METHODS: We measured tumour development in xenografted mice fed with a designer, casein-deprived diet enriched in free essential amino acids (EAAs; SFA-EAA diet), or two control isocaloric, isolipidic, and isonitrogenous diets, identical to the SFA-EAA diet except for casein presence (SFA diet), or casein replacement by the free AA mixture designed on the AA profile of casein (SFA-CAA diet). Moreover, we investigated the metabolic, biochemical, and molecular effects of two mixtures that reproduce the AA composition of the SFA-EAA diet (i.e., EAAm) and SFA-CAA diet (i.e., CAAm) in diverse cancer and non-cancer cells.
    RESULTS: The SFA-EAA diet reduced tumour growth in vivo, promoted endoplasmic reticulum (ER) stress, and inhibited mechanistic/mammalian target of rapamycin (mTOR) activity in the tumours. Accordingly, in culture, the EAAm, but not the CAAm, activated apoptotic cell death in cancer cells without affecting the survival and proliferation of non-cancer cells. The EAAm increased branched-chain amino acid (BCAA) oxidation and decreased glycolysis, ATP levels, redox potential, and intracellular content of selective non-essential amino acids (NEAA) in cancer cells. The EAAm-induced NEAA starvation activated the GCN2-ATF4 stress pathway, leading to ER stress, mTOR inactivation, and apoptosis in cancer cells, unlike non-cancer cells.
    CONCLUSION: Together, these results confirm the efficacy of specific EAA mixtures in promoting cancer cells' death and suggest that manipulation of dietary EAA content and profile could be a valuable support to the standard chemotherapy for specific cancers.
    Keywords:  Branched-chain amino acids; Cancer metabolism; Essential amino acids; Glycolysis; Mechanistic/mammalian target of rapamycin; Mitochondria
    DOI:  https://doi.org/10.1016/j.molmet.2022.101478
  10. Subcell Biochem. 2022 ;98 189-204
    KRAS Addiction Promotes Cancer Cell Adaptation in Harsh Microenvironment Through Macropinocytosis.
    Laetitia Seguin.
      KRAS is the most frequently mutated oncogene in cancer and despite intensive studies, attempts to develop effective therapies targeting KRAS or its downstream signaling have failed mostly due to the complexity of KRAS activation and function in cancer initiation and progression. Over the years, KRAS has been involved in several biological processes including cell survival, proliferation, and metabolism by promoting not only a favorable tumor environment but also a cell-microenvironment dialog to allow cancer cells to adapt to tumor microenvironment scarcity. One of the mechanisms involved in this adaption is KRAS-mediated macropinocytosis. Macropinocytosis is an evolutionarily conserved, large-scale, and nonselective form of endocytosis involving actin-driven cell membrane remodeling to engulf large amounts of extracellular fluids and proteins from the local environment. While macropinocytosis process has been known for decades, recent gain interest due to its regulation of KRAS-driven tumor growth in adverse microenvironments. By promoting extracellular protein and other macromolecules internalization, macropinocytosis provides a survival mechanism under nutrient scarce conditions and the potential for unrestricted tumor growth. Thus, a better understanding of macropinocytotic process is needed to develop alternative therapeutic strategies.
    Keywords:  Integrin; KRAS addiction; Macropinocytosis; Microenvironment sensing
    DOI:  https://doi.org/10.1007/978-3-030-94004-1_10
  11. Biomaterials. 2022 Mar 31. pii: S0142-9612(22)00141-7. [Epub ahead of print]284 121502
    Disruption of dual homeostasis by a metal-organic framework nanoreactor for ferroptosis-based immunotherapy of tumor.
    Kai Zhang, Zhaoyu Ma, Shuting Li, Yang Wu, Jin Zhang, Weiyun Zhang, Yanli Zhao, Heyou Han.
      Ferroptosis, a newfound non-apoptotic cell death pathway that is iron- and reactive oxygen species (ROS)-dependent, has shown a promise for tumor treatment. However, engineering ferroptosis inducers with sufficient hydrogen peroxide (H2O2) and iron supplying capacity remains a great challenge. To address this issue, herein, we report a powerful nanoreactor by modifying MnO2, glucose oxidase, and polyethylene glycol on iron-based metal-organic framework nanoparticles for disrupting redox and iron metabolism homeostasis, directly providing the Fenton reaction-independent downstream ferroptosis for tumor therapy. By consuming glutathione and oxidizing glucose to increase the H2O2 level in cancer cells and downregulating ferroportin 1 to accumulate intracellular iron ions, the homeostasis disruptor could effectively enhance the ferroptosis. Subsequently, the ferroptosis cells release tumor immune-associated antigens, which combine with in situ injected aptamer-PD-L1 to further strengthen the tumor treatment efficiency. This work not only paves a way to enhance the efficacy of ferroptosis-based cancer therapy by associating intracellular redox homeostasis with the iron metabolism system in tumor cells but also offers an engineered nanoreactor as a promising mimetic antigen for activating immunotherapy.
    Keywords:  Aptamer-PD-L1; Dual homeostasis; Ferroptosis; Immune checkpoint blockade; Metal-organic frameworks
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121502
  12. Photodiagnosis Photodyn Ther. 2022 Apr 05. pii: S1572-1000(22)00138-7. [Epub ahead of print] 102850
    Synthesis, characterization, and evaluation of chloroaluminium phthalocyanine incorporated in poly(ε-caprolactone) nanoparticles for photodynamic therapy.
    Bruna C S Pinto, Jéssica A R Ambrósio, Vitor Luca Moura Marmo, Juliana G Pinto, Leandro José Raniero, Juliana Ferreira-Strixino, Andreza R Simioni, Milton Beltrame Junior.
       BACKGROUND: The use of nanotechnology has been widely used in biomedical science, which consists of orthopedic implants, tissue engineering, cancer therapy and drug elution from nanoparticle systems, such as poly-caprolactone (PCL) nanoparticles, which stand out mainly for their biocompatibility, being considered as effective carriers for photosensitizing drugs (PS) in photodynamic therapy (PDT) protocols.
    METHODS: This manuscript describes the synthesis and characterization of PCL nanoparticles for controlled release of the drug chloro-aluminum phthalocyanine (ClAlPc) as a photosensitizer for application in PDT. The PCL-ClAlPc nanoparticles were developed by the nanoprecipitation process. The structure and morphology of the nanoparticles were studied with scanning electron microscopy (SEM) and with Fourier transform infrared (FTIR). The size of nanomaterials was studied using the Dynamic Light Scattering (DLS) method. Photophysical and photochemical characterizations were performed. Subsequently, photobiological studies were also used to characterize the system.
    RESULTS: The nanoparticles had an average diameter of 384.7 ± 138.6 nm and a polydispersity index of 0.153. SEM analysis revealed that the system formed a spherical shape typical of these delivery systems. Charging efficiency was 82.1% ± 1.2%. The phthalocyanine-loaded PCL nanoparticles maintained their photophysical behavior after encapsulation. Cell viability was determined after the dark toxicity test, and it was possible to observe that there was no evidence of toxicity in the dark, for all concentrations tested. The assay also revealed that adenocarcinoma cells treated with free ClAlPc and in the nanoformulation showed 100% cell death when subjected to PDT protocols. The intracellular location of the photosensitizer indicated a high potential for accumulation in the cytoplasm and nucleus.
    CONCLUSIONS: From the photophysical, photochemical and photobiological analyzes obtained, it was possible to observe that the development of PCL nanoparticles encapsulated with ClAlPc, by the nanoprecipitation method was adequate and that the in vivo release study is efficient to reduce the release rate and attenuate the burst of PS loaded on PCL nanoparticles. The results reinforce that the use of this system as drug delivery systems is useful in PDT protocols.
    Keywords:  characterization; chloro-aluminum phthalocyanine; photodynamic therapy; poly-caprolactone
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.102850
  13. Semin Cancer Biol. 2022 Apr 04. pii: S1044-579X(22)00079-7. [Epub ahead of print]
    Metabolic Reservoir Cycles in Cancer.
    Cissy Zhang, Addison Quinones, Anne Le.
      Cancer cells possess various biological processes to ensure survival and proliferation even under unfavorable conditions such as hypoxia, nutrient deprivation, and oxidative stress. One of the defining hallmarks of cancer cells is their ability to reprogram their metabolism to suit their needs. Building on over a decade of research in the field of cancer metabolism, numerous unique metabolic capabilities are still being discovered in the present day. One recent discovery in the field of cancer metabolism that was hitherto unexpected is the ability of cancer cells to store vital metabolites in forms that can be readily converted to glucose and glutamine for later use. We called these forms "metabolic reservoirs." While many studies have been conducted on storage molecules such as glycogen, triglyceride, and phosphocreatine (PCr), few have explored the concept of "metabolic reservoirs" for cancer as a whole. In this review, we will provide an overview of this concept, the previously known reservoirs including glycogen, triglyceride, and PCr, and the new discoveries made including the newly discovered reservoirs such as N-acetyl-aspartyl-glutamate (NAAG), lactate, and γ- aminobutyric acid (GABA). We will also discuss whether disrupting these reservoir cycles may be a new avenue for cancer treatment.
    Keywords:  Metabolic reservoir; N-acetyl-aspartyl-glutamate (NAAG); cancer metabolism; gamma aminobutyric acid (GABA); lactate
    DOI:  https://doi.org/10.1016/j.semcancer.2022.03.023
  14. Angew Chem Int Ed Engl. 2022 Apr 09.
    A Dual-locked Activatable Phototheranostic Probe for Biomarkers Regulated Photodynamic and Photothermal Cancer Therapy.
    Xin Wei, Chi Zhang, Shasha He, Jiaguo Huang, Jingsheng Huang, Si Si Liew, Ziling Zeng, Kanyi Pu.
      Activatable phototheranostics holds promise for precision cancer treatment owing to the "turn-on" signals and therapeutic effects. However, most activatable phototheranostic probes only possess photodynamic therapy (PDT) or photothermal therapy (PTT), which suffer from poor therapeutic efficacy due to deficient cellular oxygen and complex tumor microenvironment. We herein report a dual-locked activatable phototheranostic probe that activates near-infrared fluorescence (NIRF) signals in tumor, triggers PDT in response to a tumor-periphery biomarker, and switches from PDT to PTT upon detecting a tumor-core-hypoxia biomarker. This PDT-PTT auto-regulated probe exhibits complete tumor ablation under the photoirradiation of a single laser source by producing cytotoxic singlet oxygen at the tumor periphery and generating hyperthermia at tumor-core where is too hypoxic for PDT. This dual-locked probe represents a promising molecular design approach towards precise cancer phototheranostics.
    Keywords:  activatable phototheranostic probes; cancer phototherapy; near-infrared fluorescence probes
    DOI:  https://doi.org/10.1002/anie.202202966
  15. Biol Pharm Bull. 2022 ;45(4): 517-521
    Avenaciolide Induces Apoptosis in Human Malignant Meningioma Cells through the Production of Reactive Oxygen Species.
    Takumi Katsuzawa, Kohei Kujirai, Shinji Kamisuki, Yo Shinoda.
      Malignant meningioma has a poor prognosis and there are currently no effective therapies. Avenaciolide is water-insoluble natural organic product produced by Aspergillus avenaceus G. Smith that can inhibit mitochondrial function. In the present study, we investigated the anti-cancer effects of avenaciolide in an isolated human malignant meningioma cell line, HKBMM. In addition, to assess the specificity of avenaciolide, its effects on normal human neonatal dermal fibroblast HDFn cells were also examined. Avenaciolide showed effective anti-cancer activity, and its cytotoxicity in HKBMM cells was greater than that in HDFn cells. The anti-cancer effects of avenaciolide were mediated by reactive oxygen species (ROS)-induced apoptosis, which may have been caused by mitochondrial disfunction. These results suggest that avenaciolide has potential as a therapeutic drug for malignant meningioma.
    Keywords:  apoptosis; avenaciolide; malignant meningioma; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1248/bpb.b21-01039
  16. Nanoscale. 2022 Apr 07.
    Programmed self-assembly of enzyme activity-inhibited nanomedicine for augmenting chemodynamic tumor nanotherapy.
    Ling Chang, Hui Huang, Wei Feng, Hao Fu, Fenggang Qi, Jianjun Liu, Yu Chen.
      The satisfactory therapeutic effects of chemodynamic therapy (CDT) dependent solely on endogenous hydrogen peroxide (H2O2) from tumor cells are difficult to achieve. This is closely attributed to the high metabolic activity of malignant cancer cells, prompting the rapid self-protection and proliferation. Here, we report a programmed self-assembly multilayered nanostructure, thioglycolic acid (TGA)-Cu coordination nanoparticles with rapid GSH-response characteristics, for intensifying the CDT efficiency and comprehensively inhibiting the tumor metabolic activity via exchanging the TGA ligand with glutathione (GSH) in the tumor cell. In the formulation, TGA, a small toxic molecule, was combined with Cu ions and securely delivered to the destination for inactivating the functional protein by depriving their spatial structure, then inducing the inhibition of metabolism and meiosis. Simultaneously, the oxidative stress that originated from the oxidized glutathione (GSSG)-Cu complex triggering H2O2 compels the cancer cells to perform active and passive death processes in concert with the inhibition of intracellular enzyme activities. Thus, this work is not only expected to be a heuristic strategy for amplifying the therapeutic effect of CDT together with the inhibition of enzyme activity, but also may advance the construction of stimulus-response bio-functional materials.
    DOI:  https://doi.org/10.1039/d2nr00165a
  17. Curr Drug Deliv. 2022 Apr 01.
    Curcumin and Paclitaxel co-Loaded Heparin and Poloxamer P403 Hybrid Nanocarrier for Improved Synergistic Efficacy in Breast Cancer.
    Ngoc The Nguyen, Quynh Anh Bui, Phuong Duy Huynh, Quang Huy Nguyen, Ngoc Quyen Tran, Nguyen Thanh Viet, Dinh Trung Nguyen.
      Introduction- Multi-drug nanosystem has been employed in several therapeutic models due to the synergistic effect of the drugs and/or bioactive compounds, which help in tumor-targeting and limit usual side effects of chemotherapy. Methods- In this research, we developed the amphiphilic Heparin-Poloxamer P403 (HSP) nanogel that can load curcumin (CUR) and Paclitaxel (PTX) through the hydrophobic core of Poloxamer P403. The features of HSP nanogel are assessed through Fourier-transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), differential light scattering (DLS), and critical micelle concentration (CMC). Nanogel and its duel-loaded platform show high stability and spherical morphology. Results- The drug release profile indicates fast release at pH 5.5, suggesting effective drug distribution at the tumor site. In vitro research confirms lower cytotoxicity of HSP@CUR@PTX compared with free PTX and higher inhibition effect with MCF-7 than HSP@PTX. These results support the synergism between PTX and CUR. Conclusion, HSP@CUR@PTX suggests a prominent strategy for achieving the synergistic effect of PTX and CUR to circumvent undesirable effects in breast cancer treatment.
    Keywords:  Heparin; MCF-7; Paclitaxel; Poloxamer; curcumin; nanogel.
    DOI:  https://doi.org/10.2174/1567201819666220401095923
  18. ACS Appl Mater Interfaces. 2022 Apr 08.
    Degradable Tumor-Responsive Iron-Doped Phosphate-Based Glass Nanozyme for H2O2 Self-Supplying Cancer Therapy.
    Yuan Yao, Zhongqiang Wang, Qiannan Cao, Hui Li, Shufang Ge, Jinjian Liu, Penghui Sun, Zhihao Liu, Yuanhao Wu, Wei Wang, Jianfeng Liu.
      Tumor microenvironment (TME)-responsive chemodynamic therapy (CDT) mediated by nanozymes has been extensively studied both experimentally and theoretically, but the low catalytic efficiency due to insufficient H2O2 in the TME and the poor biodegradability of the nanozymes are still main challenges for clinical translation of nanozymes. Herein, we designed a H2O2 self-supplying nanozyme bearing glucose oxidase (GOX) and polyethyleneimine based on a degradable iron-doped phosphate-based glass (FePBG) nanomimic (FePBG@GOX), which can convert endogenous glucose into toxic hydroxyl radicals. The GOX loaded on the nanozyme can effectively consume glucose in tumor cells to produce a large amount of H2O2 to make up for the lack of H2O2 in the TME. Thereafter, enormous hydroxyl radicals, based on a Fenton reaction of FePBG without any exogenous H2O2, are generated to induce severe apoptosis of tumor cells. The nanozyme exhibits enhanced in vitro cytotoxicity in a high-glucose medium than in a low-glucose medium, illustrating sufficient generation of H2O2 by GOX. The excellent in vivo antitumor efficacy is manifested by a high tumor growth inhibition ratio of 94.65% in model mice. Excellent intrinsic biodegradability owing to its phosphate-based glass nature is a remarkable advantage of the prepared FePBG nanozyme over most other reported nanozymes. Big concerns about side effects caused by long-time residence in living organisms are eliminated since it degrades not only in an acid medium but also in a neutral physiological environment. Therefore, this novel strategy of the TME-responsive H2O2 self-supplying nanozyme based on an endogenous cascade catalytic reaction opens up an avenue for designing degradable nanozymes in CDT.
    Keywords:  H2O2 self-supplying Fenton reaction; biodegradable; cancer therapy; nanocascade catalysis; nanozyme
    DOI:  https://doi.org/10.1021/acsami.2c02669
  19. Bioact Mater. 2022 Dec;18 242-253
    On-demand assembly of polymeric nanoparticles for longer-blood-circulation and disassembly in tumor for boosting sonodynamic therapy.
    Mei Wen, Nuo Yu, Shiwen Wu, Mengmeng Huang, Pu Qiu, Qian Ren, Meifang Zhu, Zhigang Chen.
      Sonodynamic therapy (SDT) is one of the promising strategies for tumor therapy, but its application is usually hindered by fast clearance in blood-circulation, abnormal tumor microenvironment, and inefficient generation of reactive oxygen species. To solve these problems, we proposed an on-demand assembly-disassembly strategy, where the assembly is favorable for longer-blood-circulation and then the disassembly in tumor is favorable for boosting SDT. Hematoporphyrin monomethyl ether (HMME) as the model of organic sonosensitizers were conjugated with hyaluronic acid (HA). Then HA-HMME was mixed with catalase (CAT) and assembled into polymeric nanoparticles (CAT@HA-HMME NPs) with size of ∼80 nm. CAT@HA-HMME NPs exhibit good biocompatibility and a longer blood half-time (t1/2 = 4.17 h) which is obviously longer than that (∼0.82 h) of HMME molecules. After HA receptor-mediated endocytosis of cancer cells, CAT@HA-HMME NPs can be cleaved by endogenous hyaluronidase, resulting in the on-demand disassembly in tumor to release HA-HMME molecules and CAT. The CAT catalyzes the endogenous H2O2 into O2 to relieve the hypoxic microenvironment, and the released HA-HMME exhibits a higher ROS generation ability, greatly boosting SDT for the inhibition of tumor growth. Therefore, the on-demand assembly-disassembly strategy may provide some insight in the design and development of nanoagents for tumor therapy.
    Keywords:  Longer-blood-circulation; On-demand assembly; On-demand disassembly; Polymeric nanoparticles; Sonodynamic therapy
    DOI:  https://doi.org/10.1016/j.bioactmat.2022.03.009
  20. J Control Release. 2022 Apr 02. pii: S0168-3659(22)00193-6. [Epub ahead of print]
    Heterojunction engineered bioactive chlorella for cascade promoted cancer therapy.
    Meitong Ou, Chuchu Lin, Ying Wang, Yuting Lu, Wenyan Wang, Zimu Li, Weiwei Zeng, Xiaowei Zeng, Xiaoyuan Ji, Lin Mei.
      The hypoxic tumor microenvironment is one of most major hurdles restraining the anti-tumor efficiency of photodynamic therapy (PDT). Herein, active photosynthetic Chlorophyceae (Chlorella, Chl) functionalized with black phosphorus nanosheets (BPNSs) through polyaspartic acid (PASP) and Fe3+ mediating "Lego building method" are utilized for photocatalyzed oxygen-evolving to realize photosynthesis enhanced synergistic photodynamic/chemodynamic/immune therapy. The Chl cells with inherent photosynthesis and distinct metabolites are able to ameliorate tumor hypoxia, enhance immune cells infiltration, and stimulate the proliferation and maturation of immune cells. BPNSs loaded on the surface of Chl cells construct a type-II heterojunction with the chlorophyll in Chl cells, which improves the conversion efficiency of light through thoroughly separating photo-excited electrons and holes for 1O2 generation and O2 evolution, respectively. Additionally, the lock between "Lego bricks", Fe3+, can both consume glutathione (GSH) and catalyze Fenton reaction with H2O2 to generate ·OH, mediating chemodynamic therapy (CDT). Moreover, Chl@BP-Fe also exhibited high biocompatibility and potential biodegradability, guaranteeing high potential for clinic applications of this synergistic photodynamic/chemodynamic/immune therapy.
    Keywords:  Chemodynamic therapy; Hypoxia alleviation; Immunotherapy; Photodynamic therapy; Photosynthesis
    DOI:  https://doi.org/10.1016/j.jconrel.2022.03.059
  21. Cancer Discov. 2022 Apr 01. 12(4): 913-923
    Classification of KRAS-Activating Mutations and the Implications for Therapeutic Intervention.
    Christian Johnson, Deborah L Burkhart, Kevin M Haigis.
      Members of the family of RAS proto-oncogenes, discovered just over 40 years ago, were among the first cancer-initiating genes to be discovered. Of the three RAS family members, KRAS is the most frequently mutated in human cancers. Despite intensive biological and biochemical study of RAS proteins over the past four decades, we are only now starting to devise therapeutic strategies to target their oncogenic properties. Here, we highlight the distinct biochemical properties of common and rare KRAS alleles, enabling their classification into functional subtypes. We also discuss the implications of this functional classification for potential therapeutic avenues targeting mutant subtypes.
    SIGNIFICANCE: Efforts in the recent past to inhibit KRAS oncogenicity have focused on kinases that function in downstream signal transduction cascades, although preclinical successes have not translated to patients with KRAS-mutant cancer. Recently, clinically effective covalent inhibitors of KRASG12C have been developed, establishing two principles that form a foundation for future efforts. First, KRAS is druggable. Second, each mutant form of KRAS is likely to have properties that make it uniquely druggable.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0035
  22. Bioact Mater. 2022 Oct;16 57-65
    Brain-targeting, acid-responsive antioxidant nanoparticles for stroke treatment and drug delivery.
    Shenqi Zhang, Bin Peng, Zeming Chen, Jiang Yu, Gang Deng, Youmei Bao, Chao Ma, Fengyi Du, Wendy C Sheu, W Taylor Kimberly, J Marc Simard, Daniel Coman, Qianxue Chen, Fahmeed Hyder, Jiangbing Zhou, Kevin N Sheth.
      Stroke is the leading cause of death and disability. Currently, there is no effective pharmacological treatment for this disease, which can be partially attributed to the inability to efficiently deliver therapeutics to the brain. Here we report the development of natural compound-derived nanoparticles (NPs), which function both as a potent therapeutic agent for stroke treatment and as an efficient carrier for drug delivery to the ischemic brain. First, we screened a collection of natural nanomaterials and identified betulinic acid (BA) as one of the most potent antioxidants for stroke treatment. Next, we engineered BA NPs for preferential drug release in acidic ischemic tissue through chemically converting BA to betulinic amine (BAM) and for targeted drug delivery through surface conjugation of AMD3100, a CXCR4 antagonist. The resulting AMD3100-conjugated BAM NPs, or A-BAM NPs, were then assessed as a therapeutic agent for stroke treatment and as a carrier for delivery of NA1, a neuroprotective peptide. We show that intravenous administration of A-BAM NPs effectively improved recovery from stroke and its efficacy was further enhanced when NA1 was encapsulated. Due to their multifunctionality and significant efficacy, we anticipate that A-BAM NPs have the potential to be translated both as a therapeutic agent and as a drug carrier to improve the treatment of stroke.
    Keywords:  A-BAM NPs, A-BAM NPs; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Acid-triggered release; Antioxidant nanoparticles; BA, betulinic acid; BAM, betulinic amine; BBB, blood brain barrier; BIRDS, biosensor imaging of redundant deviation in shifts; BT, ß-sitosterol; DLS, dynamic light scattering; DTA, dehydrotrametenolic acid; DYDA, diketohydrindylidene diketohydrindamine; Drug delivery; GA, glycyrrhetic acid; Ischemic stroke; LCMS, liquid chromatography mass spectrometry; LP, lupeol; MCAO, middle cerebral artery occlusion; NA1; NMR, nuclear magnetic resonance; NP, nanoparticle; OA, oleanolic acid; PAA, poricoic acid; PEG, polyethylene glycol; SA, sumaresinolic acid; SEM, scanning electron microscopy; ST, stigmasterol; TEM, transmission electron microscope; TTC, triphenyltetrazolium chloride; UA, ursolic acid; tPA, tissue-type plasminogen activator
    DOI:  https://doi.org/10.1016/j.bioactmat.2022.02.033
  23. J Drug Target. 2022 Apr 05. 1-27
    Nanoreactor activated in situ for starvation-chemodynamic therapy of breast cancer.
    Linyu Gao, Xiangyang Xuan, Mingli Sui, Jingjing Wang, Yaping Wang, Huijuan Zhang.
      The nano-drug delivery system activated by tumor microenvironment (TME) can effectively treat tumors with low-toxicity. Based on high level of reductive GSH in TME and different coordination properties of Fe ions, this project intended to prepare a GSH-activated cascade catalytic nanoreactor for breast cancer treatment using Fe3+/Fe2+ as the molecular switch. In this study, the glucose oxidase (GOx) loaded iron alginate nano hydrogel (FeAlg/GOx) was prepared by the simple one-step titration method. Results showed that FeAlg/GOx could remain stable during in vivo circulation to avoid hypoglycaemia. When it reached targeted tumor site, reductive GSH can reduce Fe3+ to Fe2+. Thereafter, FeAlg/GOx nanogel was broken and GOx was released to consume the essential nutrient glucose (Glu) to achieve tumor starvation therapy. Next, the substrate H2O2 generated by the reaction between GOx and Glu can be catalyzed by Fe2+ to produce highly cytotoxic •OH in situ, which could further kill tumor cells. The in vivo pharmacodynamics results demonstrated that compared with the control group (V/V0 = 8.36 ± 1.73), FeAlg/GOx group showed the most significant anti-tumor effect with V/V0 of 3.08 ± 1.06. In conclusion, this "inactivated" FeAlg/GOx nanogel can be converted into "activated" therapeutic substances in situ to achieve starvation-chemodynamic combined treatment for breast cancer.
    Keywords:  TME-responsive; cascade catalytic nanoreactor; nano hydrogel; phase transition; starvation treatment; •OH
    DOI:  https://doi.org/10.1080/1061186X.2022.2062598
  24. Int J Nanomedicine. 2022 ;17 1397-1408
    Combined Prussian Blue Nanozyme Carriers Improve Photodynamic Therapy and Effective Interruption of Tumor Metastasis.
    Wenhao Shen, Gaohua Han, Lei Yu, Song Yang, Xiangyi Li, Wei Zhang, Pei Pei.
       Introduction: Photodynamic therapy (PDT) as a new technique for theranostics is to kill tumor cells by activating photosensitizer and interacting with oxygen (O2) to produce reactive oxygen species (ROS). However, the hypoxic tumor microenvironment (TME) may constrain the efficacy of PDT. Moreover, the lack of O2 in TME also up-regulates the expression of HIF-1α and promotes tumor metastasis, which is also a leading cause of death for terminal cancer patients.
    Methods: Prussian blue (PBs) was firstly synthesized by hydrothermal method, which was then etched by hydrochloric acid to obtained hollow Prussian blue nanoparticles (HPBs). Afterwards, Au-Pt nanozymes were in situ growing on the HPBs by reduction method to prepare Au-Pt@HPBs (APHPBs). Owing to the hollow structure of APHPBs, photosensitizer Ce6 can be easily and efficiently loaded into it to obtain Ce6-Au-Pt@HPBs (Ce6-APHPBs). After ce6-APHPBS regulation, photoacoustic imaging and hypoxic fluorescence imaging were then used to evaluate changes in hypoxic TME in vivo. Finally, under the assistant of Ce6-APHPBs, we evaluated the inhibitory effect of enhanced PDT on primary and metastatic tumors.
    Results: We first designed and synthesized Ce6 loaded hollow prussian blue nanoparticles with Au-Pt nanozymes grown in situ on it. Both in vitro and in vivo experiments show that the prepared Ce6-APHPBs have good biosafety and could effectively degrade the overexpressed H2O2 in TME to generate O2, further relieve the hypoxic TME and thus enhance the effect of PDT. At the same time, the increasing O2 content could also reduce the expression of HIF-1α at the tumor site, which could reduce lung metastasis.
    Conclusion: Ce6-APHPBs designed by us could not only efficiently enhance PDT but also regulate TME to reduce tumor metastasis and prolong survival of mice, which provide a novel idea and strategy for clinical PDT and metastatic tumor.
    Keywords:  Au-Pt nanozymes; HIF-1α; TME; enhanced PDT; prussian blue; tumor metastasis
    DOI:  https://doi.org/10.2147/IJN.S359156
  25. Photochem Photobiol Sci. 2022 Apr 06.
    Recent advances in nanoparticle-based targeting tactics for antibacterial photodynamic therapy.
    Brydie A Thomas-Moore, Carla Arnau Del Valle, Robert A Field, María J Marín.
      The rise of antibacterial drug resistance means treatment options are becoming increasingly limited. We must find ways to tackle these hard-to-treat drug-resistant and biofilm infections. With the lack of new antibacterial drugs (such as antibiotics) reaching the clinics, research has switched focus to exploring alternative strategies. One such strategy is antibacterial photodynamic therapy (aPDT), a system that relies on light, oxygen, and a non-toxic dye (photosensitiser) to generate cytotoxic reactive oxygen species. This technique has already been shown capable of handling both drug-resistant and biofilm infections but has limited clinical approval to date, which is in part due to the low bioavailability and selectivity of hydrophobic photosensitisers. Nanotechnology-based techniques have the potential to address the limitations of current aPDT, as already well-documented in anti-cancer PDT. Here, we review recent advances in nanoparticle-based targeting tactics for aPDT.
    Keywords:  Antibacterial photodynamic therapy; Bacteria; Nanoparticles; Targeting; aPDT
    DOI:  https://doi.org/10.1007/s43630-022-00194-3
  26. Front Pharmacol. 2022 ;13 853119
    Major Constituents From Brucea javanica and Their Pharmacological Actions.
    Juan Zhang, Hong-Xi Xu, Yao-Xing Dou, Qiong-Hui Huang, Yan-Fang Xian, Zhi-Xiu Lin.
      Brucea javanica (Ya-dan-zi in Chinese) is a well-known Chinese herbal medicine, which is traditionally used in Chinese medicine for the treatment of intestinal inflammation, diarrhea, malaria, and cancer. The formulation of the oil (Brucea javanica oil) has been widely used to treat various types of cancer. It has also been found that B. javanica is rich in chemical constituents, including quassinoids, triterpenes, alkaloids and flavonoids. Pharmacological studies have revealed that chemical compounds derived from B. javanica exhibit multiple bioactivities, such as anti-cancer, anti-bacterial, anti-diabetic, and others. This review provides a comprehensive summary on the pharmacological properties of the main chemical constituents presented in B. javanica and their underlying molecular mechanisms. Moreover, the review will also provide scientific references for further research and development of B. javanica and its chemical constituents into novel pharmaceutical products for disease management.
    Keywords:  Brucea javanica; anti-cancer; chemical constituents; molecular mechanism; pharmacological activities
    DOI:  https://doi.org/10.3389/fphar.2022.853119
  27. Biomed Pharmacother. 2022 Mar 31. pii: S0753-3322(22)00255-4. [Epub ahead of print]149 112866
    The potential applications of traditional Chinese medicine in Parkinson's disease: A new opportunity.
    Jiaxue Chen, Jingke Xu, Ping Huang, Yining Luo, Yuanshu Shi, Ping Ma.
      Parkinson's disease (PD) presents a common challenge for people all over the world and has become a major research hotspot due to the large population affected by the illness and the difficulty of clinical treatment. The prevalence of PD is increasing every year, the pathogenesis is complex, and the current treatment is ineffective. Therefore, it has become imperative to find effective drugs for PD. With the advantages of low cost, high safety and high biological activity, Chinese medicine has great advantages in the prevention and treatment of PD. This review systematically summarizes the potential of Chinese medicine for the treatment of PD, showing that Chinese medicine can exert anti-PD effects through various pathways, such as anti-inflammatory and antioxidant pathways, reducing mitochondrial dysfunction, inhibiting endoplasmic reticulum stress and iron death, and regulating intestinal flora. These mainly involve HMGB1/TLR4, PI3K/Akt, NLRP3/ caspase-1/IL-1β, Nrf2/HO-1, SIRT1/Akt1, PINK1/parkin, Bcl-2/Bax, BDNF-TrkB and other signaling pathways. In sum, based on modern phytochemistry, pharmacology and genomic proteomics, Chinese medicine is likely to be a potential candidate for PD treatment, which requires more clinical trials to further elucidate its importance in the treatment of PD.
    Keywords:  Mechanism of action; Neuroprotection; Parkinson's disease; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.biopha.2022.112866
  28. Chem Pharm Bull (Tokyo). 2022 ;70(4): 269-276
    Characterization of Novel Paclitaxel Nanoparticles Prepared by Laser Irradiation.
    Masumi Suzuki, Gen Takebe, Tokio Takagi, Hideo Tsukada.
      The antitumor drug paclitaxel has low water solubility, and its bioavailability is limited by the dissolution rate. To overcome this low water solubility, the currently marketed drug, Taxol, is formulated in a vehicle including Cremophor EL and ethanol mixture (1/1, v/v). However, Cremophor EL has been shown to have serious adverse side effects, such as hypersensitivity reactions and neurotoxicity. Improving the solubility of paclitaxel makes it possible to reduce side effects and enhance drug efficacy during antitumor therapy. One way to improve the solubility of poorly soluble drugs is to decrease their particle size to the nano-range to increase the surface area and dissolution rate. In the present study, we aimed to develop a new method for paclitaxel nanoparticle production. Polymeric nanoparticles of paclitaxel were prepared by laser irradiation at 1064 nm, which is the wavelength in the near-IR region. The prepared nanoparticles had a mean size of 57.9 nm and were spherical in shape. X-ray powder diffraction analysis showed that paclitaxel in the nanoparticles was in an amorphous state. These results demonstrate that the preparation of nanoparticles by laser irradiation is effective in improving the solubility of paclitaxel. Furthermore, the nanoparticles had an equivalent efficacy to Taxol in cell growth inhibition against breast cancer MCF-7 cells and drug efficacy in MCF-7 tumor-bearing mice as determined using positron emission tomography. Our method for preparing paclitaxel nanoparticles may be more effective in treating tumors with fewer adverse side effects than conventional Taxol.
    Keywords:  laser irradiation; nanoparticle; paclitaxel
    DOI:  https://doi.org/10.1248/cpb.c21-00994
  29. J Cancer Res Ther. 2022 Jan-Mar;18(1):18(1): 19-26
    The golden spice curcumin in cancer: A perspective on finalized clinical trials during the last 10 years.
    Ayse Kubra Karaboga Arslan, Ebru Uzunhisarcıklı, Mükerrem Betül Yerer, Anupam Bishayee.
      Curcumin, the key bioactive phytochemical present in turmeric (Curcuma longa L.), is the most studied natural compound in cancer. Preclinical studies (in vitro and in vitro) and clinical trials have demonstrated curcumin's effectiveness as an anti-inflammatory agent. The existing evidence supports that curcumin inhibits the proliferation of many types of cancer cells and can play an important role in cancer therapy. This study analyses the existing evidence in the literature on finalized clinical trials (2010-2020) related to the effect of curcumin and turmeric-derived products that focused on different types of cancers, such as chronic myeloid leukemia, multiple myeloma, prostate, colorectal and pancreatic cancer as well as cancer therapy-related complications, including oral mucositis and radiation dermatitis. Original English language articles and clinical trials published between 2010 and 2020 were searched using mainstream scholarly databases, such as PubMed, ScienceDirect, Google Scholar, and ClinicalTrials.gov. The keywords, such as "curcumin," "turmeric," "cancer," "anti-inflammatory," and "clinical trials," were used in various combinations. A total of 21 clinical trials were selected, reviewed, and included in this study. Sixteen out of 21 clinical trials were associated with the effectiveness of curcumin or turmeric on various types of cancer, and the other five clinical trials were related to the evaluation of the efficacy of curcumin or turmeric in relieving the side effects of cancer chemotherapy and radiotherapy. The emerging data from the clinical trials confirm that curcumin has the potential for cancer prevention and intervention. However, it is not yet clear whether long-term curcumin supplementation has similar benefits.
    Keywords:  Adjuvant therapy; bioavailability; cancer; clinical trials; curcumin; efficacy; turmeric
    DOI:  https://doi.org/10.4103/jcrt.JCRT_1017_20
  30. Int J Nanomedicine. 2022 ;17 1437-1457
    pH-Responsive Hyaluronic Acid Nanoparticles for Enhanced Triple Negative Breast Cancer Therapy.
    Xiangle Zeng, Hairong Wang, Yawen Zhang, Xue Xu, Xinyi Yuan, Jianchun Li.
       Purpose: This study emphasized that dasatinib (DAS) and olaparib (OLA) have synergistic effects on triple negative breast cancer, by inducing DNA damage and inhibiting DNA damage repair. However, poor water solubility, short half-life of drugs, and low drug concentration in tumor tissue limit the clinical application.
    Methods: In this research, acid-sensitive ester bonds were used to connect hydrophobic DAS and hydrophilic hyaluronic acid (HA) to form the amphiphilic polymer prodrug HA-DAS, and then OLA was added as the core, the HA-DAS was used as the carrier to form nanomicelles (HDO-NPs) in aqueous. The characterization and drug release of HDO-NPs were studied, and the cytotoxicity, targeting effect, and intracellular transport behavior of HDO-NPs were evaluated in MDA-MB-231. In addition, the pharmacokinetic and therapeutic effect of HDO-NPs were further verified in vivo.
    Results: In vitro characterizations showed that HDO-NPs were spherical with uniform particle size, good stability and anti-dilution ability, and displayed favorable pH-responsive drug release behavior. In addition, the cell experiments showed that HDO-NPs could be effectively taken up by binding to the overexpressed CD44 proteins of MDA-MB-231 cells, resulting in increased intracellular drug concentration. In vivo experiments showed that HDO-NPs can effectively target tumor tissues, have excellent therapeutic effects on tumor, significantly prolong the circulation time of drugs in vivo, and effectively improved the bioavailability of drugs.
    Conclusion: DAS and OLA were designed into micelles, the efficacy of HDO-NPs was higher than that of free drugs. Therefore, HDO-NPs have good application prospects in the treatment of triple negative breast cancer.
    Keywords:  combination therapy; dasatinib; hyaluronic acid; olaparib; polymeric prodrug micelles
    DOI:  https://doi.org/10.2147/IJN.S360500
  31. ChemMedChem. 2022 Apr 05.
    Engineered exosomes as a photosensitizer delivery platform for cancer photodynamic therapy.
    Anyi Dao, Rajesh Kushwaha, Ashish Kumar, Huaiyi Huang, Samya Banerjee.
      Photodynamic therapy (PDT), a non/minimally invasive cancer treatment method, has the advantages of low side effects, high selectivity, and low drug resistance. It is currently a popular cancer treatment method. However, the shortcomings of photosensitizers such as poor photostability, poor water solubility, and short half-life in vivo when used alone, the development of photosensitizer nano-delivery platforms have always been a research hotspot. In the human body, various types of cells generally release exosomes, the bilayer extracellular vesicles. Compared with traditional materials, exosomes are currently an ideal drug delivery platform due to their homology, low immunogenicity, easy modification, high biocompatibility, and natural carrying capacity. Therefore, in this concept, we focus on the research status and prospects of engineered exosome-based photosensitizer nano-delivery platforms in cancer PDT.
    Keywords:  Engineered exosomes · Photosensitizer delivery · Photodynamic therapy · Anti-tumor
    DOI:  https://doi.org/10.1002/cmdc.202200119
  32. Cancer Manag Res. 2022 ;14 1323-1329
    Association of Hypertension and Breast Cancer: Antihypertensive Drugs as an Effective Adjunctive in Breast Cancer Therapy.
    Yuanyuan Fan, Nazeer Hussain Khan, Muhammad Farhan Ali Khan, M D Faysal Ahammad, Tayyaba Zulfiqar, Razia Virk, Enshe Jiang.
      Breast cancer (BC) is the most common malignancy affecting women, and its incidence in younger women is rising worldwide. Early-onset of BC is a multi-step process involving various biological aggressive tumors such as triple negative and human epidermal growth factor 2 (HER2)-positive cancers. BC prevention is still arduous across the globe. A series of observational studies have established a conclusive non-genetic clinical link between hypertension (HTN) and the development of invasive BC. Those clinical associations have driven a pharmacological seek to use the anti-hypertension (AHTN) drugs as an effective adjunctive in BC therapy. The use of AHTN, especially beta-blockers and thiazides, has been recognized as a potent anti-tumor drug to mitigate BC progression, reduce the side effects of cancer treatment, and stop the reoccurrence of cancer in the survivors. Considering the dire need to disseminate the research on how AHTN drugs can be opted as the effective adjunctive therapy to cure the BC, the current review aimed to provide an update on novel understandings on association and mechanisms of AHTN-drugs against BC as an additional cancer therapy.
    Keywords:  beta blockers; breast cancer; hypertension; hypertensive drugs; thiazides
    DOI:  https://doi.org/10.2147/CMAR.S350854
  33. ACS Chem Biol. 2022 Apr 08.
    Dark Dynamic Therapy: Photosensitization without Light Excitation Using Chemiluminescence Resonance Energy Transfer in a Dioxetane-Erythrosin B Conjugate.
    Elyse M Digby, Matthew T Tung, Husain N Kagalwala, Lucas S Ryan, Alexander R Lippert, Andrew A Beharry.
      Reactive oxygen species (e.g., singlet oxygen) are the primary cytotoxic agents used in the clinically approved technique photodynamic therapy (PDT). Although singlet oxygen has high potential to effectively kill tumor cells, its production via light excitation of a photosensitizer has been limited by the penetration depth and delivery of light in tissue. To produce singlet oxygen without light excitation, we describe the use of Schaap's chemiluminescent scaffold comprising an adamantylidene-dioxetane motif. Functionalizing this scaffold with a photosensitizer, Erythrosin B, resulted in spontaneous chemiluminescence resonance energy transfer (CRET) leading to the production of singlet oxygen. We show that this compound is cell permeable and that the singlet oxygen produced via CRET is remarkably efficient in killing cancer cells at low micromolar concentrations. Moreover, we demonstrate that protection of the phenol on the chemiluminescent scaffold with a nitroreductase-responsive trigger group allows for cancer-selective dark dynamic cell death. Here, we present the concept of dark dynamic therapy using a small cell-permeable molecule capable of producing the effects of PDT in cells, without light.
    DOI:  https://doi.org/10.1021/acschembio.1c00925
  34. Colloids Surf B Biointerfaces. 2022 Mar 23. pii: S0927-7765(22)00158-8. [Epub ahead of print]215 112475
    Polymeric nanoparticles for the delivery of Sonoran desert propolis: Synthesis, characterization and antiproliferative activity on cancer cells.
    Pablo Mendez-Pfeiffer, Josue Juarez, Javier Hernandez, Pablo Taboada, Claudia Virués, Efrain Alday, Dora Valencia, Carlos Velazquez.
      Sonoran propolis (SP) exerts remarkable biological activities attributed to its polyphenolic composition, mostly described as poplar-type flavonoids. It is known that polyphenols present low bioavailability derived of their molecular weight, glycosylation level, metabolic conversion, as well as interaction with the intestinal microbiota, affording limitations for possible in vivo applications. The aim of this work was to synthesize Poly-(lactide-co-glycolide) acid (PLGA) nanoparticles for encapsulation of SP, as a matrix to increase solubility of their polyphenolic compounds and improve delivery, for the evaluation of its antiproliferative activity on cancer cells. The Sonoran propolis-loaded PLGA nanoparticles (SP-PLGA NPs) were synthesized (by nanoprecipitation), and their physicochemical parameters were determined (size, morphology, zeta potential, stability, and drug release). Additionally, the antiproliferative activity of SP-PLGA nanoparticles was evaluated in vitro against murine (M12.C3.F6) and human (HeLa) cancer cell lines, including a non-cancer human cell line (ARPE-19) as control. SP-PLGA NPs presented a mean size of 152.6 ± 7.1 nm with an average negative charge of - 21.2 ± 0.7 mV. The encapsulation yield of SP into PLGA system was approximately 68.2 ± 6.0% with an in vitro release of 45% of propolis content at 48 h. SP-PLGA NPs presented antiproliferative activity against both cancer cell lines tested, with lower IC50 values in M12.C3.F6 and HeLa cell lines (7.8 ± 0.4 and 3.8 ± 0.4 μg/mL, respectively) compared to SP (24.0 ± 4.3 and 7.4 ± 0.4 μg/mL, respectively). In contrast, the IC50 of SP-PLGA NPs and SP against ARPE-19 was higher than 50 µg/mL. Cancer cells treated with SP and SP-PLGA NPs presented morphological features characteristic of apoptosis (cellular shrinkage and membrane blebs), as well as elongated cells, effect previously reported for SP, meanwhile, no morphological changes were observed with ARPE-19 cells. The obtained delivery system demonstrates appropriate encapsulation characteristics and antiproliferative activity to be used in the field of nanomedicine, therefore SP could be potentially used in antitumoral in vivo assays upon its encapsulation into PLGA nanoparticles.
    Keywords:  Drug delivery; Propolis PLGA nanoparticles; Propolis encapsulation; Sonoran Desert propolis
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112475
  35. Eur J Med Chem. 2022 Mar 27. pii: S0223-5234(22)00216-1. [Epub ahead of print]235 114314
    Recent advances of antitumor shikonin/alkannin derivatives: A comprehensive overview focusing on structural classification, synthetic approaches, and mechanisms of action.
    Mehdi Valipour.
      Shikonin and its enantiomeric analogue, alkaninn, are prevailing natural lead compounds in the drug discovery and development of anticancer agents. Despite having numerous biological effects, the most important activity reported for shikonin derivatives is the antitumor effect which is exerted through various mechanisms such as induction of apoptosis and autophagy. The design, synthesis, and development of new shikonin derivatives are continuously performed with the aim of promoting therapeutic effects through increasing cytotoxicity against cancer cells and simultaneously reducing toxicity on normal cells. In spite of significant advances in the development of shikonin derivatives in recent years and the publication of some reviews in this regard, the structural classification, synthesis methods, as well as the diversity of the anti-tumor mechanism of action of these compounds have not been well considered. This review aims to provide comprehensive data in this regard by reviewing studies conducted over the last two decades (from 2000 until now).
    Keywords:  Alkannin; Anticancer; Mechanism of action; Shikonin; Structural classifications; Synthesis methods
    DOI:  https://doi.org/10.1016/j.ejmech.2022.114314
  36. Biomater Sci. 2022 Apr 06.
    Curcumin doped zeolitic imidazolate framework nanoplatforms as multifunctional nanocarriers for tumor chemo/immunotherapy.
    Jingjin Liu, Suwan Liu, Yunchao Wu, Xiao Xu, Qianzhe Li, Mengyu Yang, Aihua Gong, Miaomiao Zhang, Rongzhu Lu, Fengyi Du.
      Curcumin as a hydrophobic polyphenol has great potential for tumor therapy, yet its rapid degradation and hydrophobicity severely impair its therapeutic effect in the clinic. Herein, we report a novel strategy for the formation of curcumin doped zeolitic imidazolate framework nanoparticles (Cur-ZIF NPs) by zinc ion driven simultaneous coordination of curcumin and 2-methylimidazole. The resultant Cur-ZIF NPs with a uniform nanosize exhibit favorable stability and dispersibility in water, as well as high drug-loading capacities. The pH and redox sensitivity of ZIF NPs enable the controlled release of curcumin in vivo. Moreover, Cur-ZIF NPs serve as nanocarriers that can load the toll-like-receptor-7 agonist (imiquimod, IQ) and be coated by homotypic cancer cell membranes to enhance tumor-targeted delivery. This study provides an attractive nanoplatform to effectively utilize curcumin and integrate multiple therapeutic modalities into a single system for tumor treatment.
    DOI:  https://doi.org/10.1039/d2bm00149g
  37. Subcell Biochem. 2022 ;98 205-221
    KRASG12R-Independent Macropinocytosis in Pancreatic Cancer.
    G Aaron Hobbs, Channing J Der.
      Macropinocytosis is a critical route of nutrient acquisition in pancreatic cancer cells. Constitutive macropinocytosis is promoted by mutant KRAS, which activates the PI3Kα lipid kinase and RAC1, to drive membrane ruffling, macropinosome uptake and processing. However, our recent study on the KRASG12R mutant indicated the presence of a KRAS-independent mode of macropinocytosis in pancreatic cancer cell lines, thereby increasing the complexity of this process. We found that KRASG12R-mutant cell lines promote macropinocytosis independent of KRAS activity using PI3Kγ and RAC1, highlighting the convergence of regulation on RAC signaling. While macropinocytosis has been proposed to be a therapeutic target for the treatment of pancreatic cancer, our studies have underscored how little we understand about the activation and regulation of this metabolic process. Therefore, this review seeks to highlight the differences in macropinocytosis regulation in the two cellular subtypes while also highlighting the features that make the KRASG12R mutant atypical.
    Keywords:  KRAS; Macropinocytosis; Metabolism; Mutant-specific signaling; PI3K; Pancreatic cancer
    DOI:  https://doi.org/10.1007/978-3-030-94004-1_11
  38. Food Funct. 2022 Apr 04.
    Dietary phytochemicals targeting Nrf2 for chemoprevention in breast cancer.
    Pinghan Wang, Fangyi Long, Hong Lin, Ting Wang.
      Breast cancer accounts for 11.7% of all newly diagnosed cancer cases and has become the leading cause of cancer worldwide. Currently, more effective and less toxic chemopreventive strategies for breast cancer are urgently needed. Notably, naturally occurring dietary phytochemical compounds, such as curcumin and resveratrol, are generally considered to be the most promising breast cancer preventive agents. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a key regulatory role in the expression of multiple antioxidant and anti-inflammatory enzymes, which can effectively suppress the excessive accumulation of carcinogens and their metabolites. Therefore, modulation of Nrf2 by dietary phytochemicals appears to be a promising approach for breast cancer prevention, which further removes excessive carcinogenic metabolites by inducing Phase II cytoprotective enzymes such as heme oxygenase-1 (HO-1) and NAD(P)H quinine oxidoreductase 1 (NQO1). In this review, we summarize recently published findings on the prevention of breast cancer with potential natural phytochemical compounds targeting Nrf2, as well as a mechanistic discussion of Nrf2 activation and its contribution in inhibiting breast cancer carcinogenesis. The epigenetic regulation of Nrf2 by phytochemicals is also explored.
    DOI:  https://doi.org/10.1039/d2fo00186a
  39. Life Sci. 2022 Apr 01. pii: S0024-3205(22)00225-9. [Epub ahead of print] 120525
    Enhancement of anti-neoplastic effects of cuminaldehyde against breast cancer via mesoporous silica nanoparticle based targeted drug delivery system.
    Sumit Ghosh, Mousumi Kundu, Sayanta Dutta, Sushweta Mahalanobish, Noyel Ghosh, Joydeep Das, Parames C Sil.
       AIMS: Synthesis of novel drug delivery system for targeted delivery of cuminaldehyde to breast cancer cells and the subsequent analyses of anti-neoplastic potential of the drug.
    MAIN METHODS: 3-carboxy-phenyl boronic acid (PBA) conjugated and polyacrylic acid (PAA) gated mesoporous silica nanoparticles (MSNs) were synthesized for the targeted delivery of cuminaldehyde (CUM) to breast cancer cells. Enhancement of anti-neoplastic effects of cuminaldehyde (4-isopropylbenzaldehyde) by the nanoconjugates was assessed.
    KEY FINDINGS: The anti-cancer effects of non-targeted and targeted drug-nanoconjugates were examined in vitro and in vivo. The targeted drug-nanoconjugates caused cell cycle arrest at G1 phase and induced the intrinsic pathway of apoptosis in MCF-7 cells through mitochondrial damage. In vivo intravenous injection of the targeted drug-nanoconjugates led to effective reduction in growth of 4 T1 induced mammary pad tumor in female BALB/c mice via augmented accumulation of cuminaldehyde. The drug-nanoconjugates did not exhibit any systemic toxicity.
    SIGNIFICANCE: Therefore, MSN-PBA-CUM-PAA represents a potent therapeutic model for breast cancer treatment.
    Keywords:  Breast cancer; Controlled release; Cuminaldehyde; Mesoporous silica nanoparticle; Targeted drug delivery
    DOI:  https://doi.org/10.1016/j.lfs.2022.120525
  40. J Nanobiotechnology. 2022 Apr 07. 20(1): 181
    Light-triggered multifunctional nanoplatform for efficient cancer photo-immunotherapy.
    Juan Yue, Qian Mei, Panyong Wang, Peng Miao, Wen-Fei Dong, Li Li.
      Cancer immunotherapy is limited by the immune escape of tumor cells and adverse effects. Photo-immunotherapy, the combination of immunotherapy and phototherapy (such as photodynamic therapy (PDT) and photothermal therapy (PTT)), can improve the effectiveness of immunotherapy in cancer treatment. Here, we first explored mesoporous hexagonal core-shell zinc porphyrin-silica nanoparticles (MPSNs), which are composed of a zinc porphyrin core and a mesoporous silica shell, and exhibit high laser-triggered photodynamic and photothermal activity, as well as outstanding drug loading capacity. In other words, MPSNs can be used not only as excellent photosensitizers for photo-immunotherapy, but also as an ideal drug carrier to achieve more efficient synergy. After loading with R837 (imiquimod, a toll-like receptor-7 agonist), MPSNs@R837 will elicit high-efficiency immunogenic cell death via PDT and PTT, and promote dendritic cell maturation after the PH-responsive release of R837, thereby, inducing tumor-specific immune responses. When combined with a programmed death ligand-1 checkpoint blockade, the photo-immunotherapy system markedly restrains primary tumors and metastatic tumors with negligible systemic toxicity. Therefore, the therapeutic strategy of integrating PTT, PDT and checkpoint blockade, shows great potential for suppressing cancer metastasis.
    Keywords:  Dendritic cell; Hexahedron zinc porphyrin mesoporous nanoparticles; Immune response; PD-L1 checkpoint blockade; Photo-immunotherapy
    DOI:  https://doi.org/10.1186/s12951-022-01388-8
  41. Toxicol Appl Pharmacol. 2022 Apr 03. pii: S0041-008X(22)00154-5. [Epub ahead of print] 116009
    Epidermal growth factor-labeled liposomes as a way to target the toxicity of silver nanoparticles into EGFR-overexpressing cancer cells in vitro.
    Bartosz Skóra, Tomasz Piechowiak, Konrad A Szychowski.
      Silver nanoparticles (AgNPs) are the most toxic nanostructures for both cancer and healthy cells. Thus, their usefulness in the anticancer therapy is limited. Interestingly, the epidermal growth factor receptor (EGFR) is overexpressed in many cancer cells, e.g. in lung and tongue cancers. Therefore, the aim of this study was to develop a way to direct the cytotoxic effect of AgNPs against cancer cells, saving healthy ones by entrapping these NPs inside liposomes labeled with the epidermal growth factor (EGF-LipoAgNPs) and directing these structures into EGFR-overexpressing cancer cells. The obtained results showed spherical structures with a 107.9 nm size and - 16.60 mV zeta-potential. The UV-Vis scan and TEM images did not show free AgNPs in the solution. The obtained complexes were able to decrease the metabolic activity in the A549 and SCC-15 cells more effectively than native AgNPs. Furthermore, the ROS production, lactate dehydrogenase release, and caspase-9 and -3 activity were significantly increased after the treatment with EGF-LipoAgNPs for 24 and 48 h. The expression of genes encoding catalase, superoxide dismutase, and p53 protein increased significantly, while the Ki67 gene expression decreased, especially in the A549 and SCC-15 cells. Moreover, the Ki67 protein expression was lower than in the cells treated with native AgNPs, while catalase activity was decreased significantly after the treatment with the obtained complexes. In turn, SOD activity increased more efficiently in the EGFR-overexpressing cancer cells. In all tested parameters, EGF-LipoAgNPs exerted a lower toxic effect on the BJ cells than native AgNPs. Summarizing, the created liposomal system reduces the toxicity of AgNPs against normal human fibroblasts and enhances the toxic and proapoptotic effect of these NPs, which may be caused by improvement of their uptake by EGFR-overexpressing cancer cells.
    Keywords:  Anticancer treatment; Drug delivery system; EGFR; Epidermal growth factor; Liposomes; Oxidative stress; Silver nanoparticles
    DOI:  https://doi.org/10.1016/j.taap.2022.116009
  42. Pharm Nanotechnol. 2022 Apr 05.
    Safety issues of nanomaterials for dermal pharmaceutical products.
    Farzaneh Lotfipour, Shahriar Shahi, Khadijeh Khezri, Sara Salatin, Solmaz Maleki Dizaj.
      Nanomaterials (NMs) have favorable application in the medicine area, specifically in regard to the carry of pharmaceutical ingredients to provide targeted drug delivery systems. The skin is an excellent route for the delivery of pharmaceutical nano-transporters for skin-related applications. The physicochemical properties of nanomaterials such as size, hydrophobicity, loading capacity, charge and weight are vital for a skin penetrating system. Many nanocarriers such as polymeric nanoparticles, inorganic nanomaterials and, lipid nanostructures have been utilized for dermal delivery of active ingredients and others such as carbon nanotubes and fullerenes require more examination for future application in the skin-related area. Some negative side effects and nano-cytotoxicity of nanomaterials require special attention while investigating different nanomaterials for medicinal applications. Then, in the current review, we had a view on the safety issues of nanomaterials for dermal pharmaceutical products.
    Keywords:  Dermal pharmaceutical products; Nano-medicine; Nanomaterials; Nnano-carrier; Safety issues
    DOI:  https://doi.org/10.2174/1871520622666220405093811
  43. Mini Rev Med Chem. 2022 Apr 04.
    Bioactivity of Natural Polyphenols as Antiparasitic Agents and their Biochemical Targets.
    Jacqueline Soto-Sánchez.
       BACKGROUND: Leishmaniasis and trypanosomiasis are diseases that affect public health worldwide due to their high incidence, morbidity, and mortality. Available treatments are costly, prolonged, and toxic, not to mention the problem of parasite resistance. The development of alternative treatments is justified and polyphenols show promising activity.
    OBJECTIVE: The main aim of this mini-review was to analyze the most promising phenolic compounds with reported antileishmanial and antitrypanosomal activity as well as their mechanisms of action.
    RESULTS: We found that the mode of action of these natural compounds mainly lignans, neolignans, and flavonoids depends on the organism they act on and includes, macrophage activation, induction of morphological changes such as chromatin condensation, DNA fragmentation, accumulation of acidocalcisomes, and glycosomes, Golgi damage and mitochondrial dysfunction as well as negative regulation of mitochondrial enzymes and other essential enzymes for parasite survival such as arginase. This gives a wide scope for future research towards the rational development of anti-kinetoplastid drugs.
    CONCLUSION: Although the specific molecular targets, bioavailability, route of administration, and dosages of some of these natural compounds need to be determined, polyphenols and their combinations represent a very promising and safe strategy to be considered for use against Leishmania spp and Trypanosoma spp. In addition, these compounds may provide a scaffold for developing new, more potent, and more selective antiprotozoal agents.
    Keywords:  Polyphenols; biological activity; flavonoids; leishmaniasis; molecular targets; trypanosomiasis
    DOI:  https://doi.org/10.2174/1389557522666220404090429
  44. Phytother Res. 2022 Apr 05.
    A review: Pharmacology and pharmacokinetics of Schisandrin A.
    Ke Fu, Honglin Zhou, Cheng Wang, Lihong Gong, Cheng Ma, Yafang Zhang, Yunxia Li.
      Schisandrin A (SA) is a bioactive lignan isolated from the traditional Chinese medicine Fructus schisandrae chinensis. In recent years, it has attracted extensive attention because of its multiple pharmacological activities. This review is the first to provide an overview of SA-related pharmacological effects and pharmacokinetic characteristics. The results showed that SA had many pharmacological effects, such as antiinflammation, anticancer, hepatoprotection, antioxidation, neuroprotection, antidiabetes mellitus, and musculoskeletal protection. Among them, NF-κB, Nrf2, MAPK, NLRP3, PI3K/AKT, Wnt, miRNA, P-gp, CYP450, PXR, and other signal transduction pathways are involved. Pharmacokinetic studies showed that SA had good pharmacokinetic characteristics, but these were affected by other factors, such as drugs or hepatic fibrosis. Thus, SA has a variety of pharmacological effects and good pharmacokinetic characteristics, which is worthy of further research and development in the future.
    Keywords:  Schisandrin A; anticancer; antiinflammatory; hepatoprotective; pharmacokinetics; pharmacological activities
    DOI:  https://doi.org/10.1002/ptr.7456
  45. Front Pharmacol. 2022 ;13 840440
    Lipid Metabolism Regulation Based on Nanotechnology for Enhancement of Tumor Immunity.
    Bin Tu, Yanrong Gao, Feifei Sun, Mingjie Shi, Yongzhuo Huang.
      The hallmarks of cancer include dysregulated metabolism and immune evasion. As a basic way of metabolism, lipid metabolism is reprogrammed for the rapid energy and nutrient supply in the occurrence and development of tumors. Lipid metabolism alterations that occur in the tumor microenvironment (TME) affect the antitumor responses of immune cells and cause immune evasion. Therefore, targeting lipid metabolism in the TME for enhancing the antitumor effect of immune cells is a promising direction for cancer treatment. Cancer nanomedicine has great potential in regulating tumor metabolism and tumor immunity. This review summarizes the nanotechnology-based strategies for lipid metabolism regulation in the TME for enhanced anticancer immune responses.
    Keywords:  cancer nanomedicine; lipid metabolism; nanotechnology; tumor immunity; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2022.840440
  46. Biochem Soc Trans. 2022 Apr 06. pii: BST20200822. [Epub ahead of print]
    Daylight-PDT: everything under the sun.
    Dana Beiki, Ian M Eggleston, Charareh Pourzand.
      5-Aminolevulinic acid-based photodynamic therapy (ALA-PDT) was first implemented over three decades ago and has since been mainly part of clinical practice for the management of pre-cancerous and cancerous skin lesions. Photodynamic therapy relies on the combination of a photosensitizer, light and oxygen to cause photo-oxidative damage of cellular components. 5-Aminolevulinic acid (ALA) is a natural precursor of the heme biosynthetic pathway, which when exogenously administered leads to the accumulation of the photoactivatable protoporphyrin IX. Although, effective and providing excellent cosmetic outcomes, its use has been restricted by the burning, stinging, and prickling sensation associated with treatment, as well as cutaneous adverse reactions that may be induced. Despite intense research in the realm of drug delivery, pain moderation, and light delivery, a novel protocol design using sunlight has led to some of the best results in terms of treatment response and patient satisfaction. Daylight PDT is the protocol of choice for the management of treatment of multiple or confluent actinic keratoses (AK) skin lesions. This review aims to revisit the photophysical, physicochemical and biological characteristics of ALA-PDT, and the underlying mechanisms resulting in daylight PDT efficiency and limitations.
    Keywords:  ALA; PDT; cancer; daylight; skin; sun
    DOI:  https://doi.org/10.1042/BST20200822
  47. J Mater Chem B. 2022 Apr 05.
    Nano-traditional Chinese medicine: a promising strategy and its recent advances.
    Daohe Wei, Han Yang, Yue Zhang, Xinhui Zhang, Jian Wang, Xiaoli Wu, Jin Chang.
      Traditional Chinese Medicine (TCM) has been applied to the prevention and treatment of numerous diseases and has an irreplaceable role in rehabilitation and health care. However, the application of TCMs is drastically limited by their defects, such as single administration, poor water solubility, low bioavailability, and weak targeting capability. Recently, nanoparticles have been extensively used in resolving pharmaceutical obstacles in consideration of their large specific surface area, strong targeting capability, good sustained-release effect, etc. In this review, we first describe the limitations of TCM ingredients and two significant forms of nanotechnology applied in TCM, nanometerization of TCMs and nano-drug delivery systems for TCMs. Then, we discuss the preparation methods of nanometerization: mechanical crushing, spray drying, and high-pressure homogenization, which have been utilized to conquer the various weaknesses of TCMs. Then, recent advances in nano-drug delivery systems for TCM ingredients are discussed, including lipid-based nanocarriers, polymeric nanoparticles, inorganic nanocarriers, hybrid nanoparticles, and TCM self-assembled nanoparticles. Finally, the future challenges and perspectives of TCM formula complexity and the limitations of nanocarriers are also discussed. Better understanding the function of nanotechnology in TCM will help to modernize Chinese medicine and broaden the application of nano-TCM in the clinic.
    DOI:  https://doi.org/10.1039/d2tb00225f
  48. Oxid Med Cell Longev. 2022 ;2022 7848811
    Dietary Phytochemicals Targeting Nrf2 to Enhance the Radiosensitivity of Cancer.
    Pinghan Wang, Fangyi Long, Hong Lin, Song Wang, Ting Wang.
      Nowadays, cancer has become the second leading cause of death worldwide. Radiotherapy (RT) is the mainstay in management of carcinoma; however, overcoming radioresistance remains a great challenge to successfully treat cancer. Nrf2 is a key transcription factor that is responsible for maintaining cellular redox homeostasis. Activation of Nrf2 signaling pathway could upregulate multifarious antioxidant and detoxifying enzymes, further scavenging excessive reactive oxygen species (ROS). Despite its cytoprotective roles in normal cells, it could also alleviate oxidative stress and DNA damage caused by RT in cancer cells, thus promoting cancer cell survival. Accumulating evidence indicates that overactivation of Nrf2 is associated with radioresistance; therefore, targeting Nrf2 is a promising strategy to enhance radiosensitivity. Dietary phytochemicals coming from natural products are characterized by low cost, low toxicity, and general availability. Numerous phytochemicals are reported to regulate Nrf2 and intensify the killing capability of RT through diverse mechanisms, including promoting oxidative stress, proapoptosis, and proautophagy as well as inhibiting Nrf2-mediated cytoprotective genes expression. This review summarizes recent advances in radiosensitizing effects of dietary phytochemicals by targeting Nrf2 and discusses the underlying mechanisms, including N6-methyladenosine (m6A) modification of Nrf2 mediated by phytochemicals in cancer.
    DOI:  https://doi.org/10.1155/2022/7848811
  49. Drug Deliv. 2022 Dec;29(1): 1164-1175
    Sonosensitizer nanoplatform-mediated sonodynamic therapy induced immunogenic cell death and tumor immune microenvironment variation.
    Jing Zheng, Yixuan Sun, Tengfei Long, Dong Yuan, Song Yue, Ni Zhang, Zhu Yang.
      Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic malignancies, and effective treatments are still lacking due to drug tolerance and tumor recurrence. In this study, we aimed to investigate the effects of sonodynamic therapy (SDT) on ovarian cancer and its potential mechanism. Folate receptor-targeted and ultrasound-responsive nanoparticles (NPs) were constructed using PLGA-PEG-FA (PLGA: poly (lactic-co-glycolic) acid, polyethylene glycol (PEG), FA: folate), the reactive oxygen species (ROS)-generating sonosensitizer IR780 and the oxygen-carrying material perfluorohexane (PFH), termed IRO@FA NPs. The antitumor effect of NPs triggered by ultrasound (US) was measured by an apoptosis assay in a C57/BL6 mouse model. Immunochemistry and flow cytometry were used to detect the proportion of CD3+ T, CD4+ T, CD8+ T cells and activated dendritic cells (DCs) in spleens and tumor tissues to assess variation in the immune response. Moreover, endoplasmic reticulum (ER) stress and immunogenic cell death (ICD) markers (high mobility group protein box-1, ATP and calreticulin) were detected to identify potential mechanisms. The results showed that IRO@FA NP-mediated SDT promoted ID8 cell apoptosis both in vitro and in vivo. The densities of CD3+ and CD8+ T lymphocytes and inflammatory markers were upregulated in tumor tissues. IRO@FA NP-mediated SDT prompted DC maturation and T lymphocyte infiltration by inducing ID8 cell ICD.
    Keywords:  ER stress; Epithelial ovarian cancer; immunogenic cell death; sonodynamic therapy; tumor microenvironment
    DOI:  https://doi.org/10.1080/10717544.2022.2058653
  50. Front Chem. 2022 ;10 870666
    Fabrication of Curcumin@Ag Loaded Core/Shell Nanofiber Membrane and its Synergistic Antibacterial Properties.
    Qiuxiang Wang, Songlin Liu, Wenjuan Lu, Pingping Zhang.
      The core/shell structure nanofiber membrane loaded with curcumin and silver nanoparticles was prepared by coaxial electrospinning technology, which is a high-efficiency combined antibacterial material composed of photodynamic antibacterial agent and metal nanoparticle. As a photosensitizer, curcumin could generate singlet oxygen under laser irradiation. Silver nanoparticles have antibacterial properties, and could also enhance the singlet oxygen production of curcumin due to the metal-enhanced singlet oxygen effect, thereby producing a synergistic antibacterial effect. Compared with the antibacterial rate of uniaxial curcumin fiber membrane (45.65%) and uniaxial silver nanoparticle-loaded fiber membrane (66.96%), the antibacterial rate of curcumin@Ag core/shell structure fiber membrane against Staphylococcus aureus is as high as 93.04%. In addition, the antibacterial experiments show that the core/shell fiber membrane also has excellent antibacterial effects on Escherichia coli.
    Keywords:  core/shell fibers; curcumin; electrospinning; photodynamic antibacterial; silver nanoparticles; synergistic antibacterial properties
    DOI:  https://doi.org/10.3389/fchem.2022.870666
  51. J Biomed Mater Res A. 2022 Apr 07.
    Supramolecular nanotherapeutics enable metabolic reprogramming of tumor-associated macrophages to inhibit tumor growth.
    Anujan Ramesh, Vaishali Malik, Anthony Brouillard, Ashish Kulkarni.
      Tumor-associated macrophages (TAMs) exist in multiple phenotypes across the spectrum, defined by an M1 antitumorigenic phenotype and an M2 pro-tumorigenic phenotype on two ends of the spectrum. A largely immunosuppressive tumor-microenvironment aids the polarization of the infiltrating macrophages to a pro-tumorigenic M2 phenotype that promotes tumor progression and metastasis. Recent developments in macrophage immunotherapy have focused on strategies to re-educate TAMs from an M2 to M1 phenotype. Recent findings in the realm of immuno-metabolism have indicated that distinct metabolic signatures accompany macrophages based on their polarization states (M1-Glycolysis and M2-TCA cycle). These metabolites are important drivers of cellular signaling responsible for acquiring these polarization states, with evidence showing that metabolism is essential to facilitate the energy requirements of immune cells and regulate immune cell response. We hypothesized that TAMs could be reprogrammed metabolically by co-delivery of drugs using a supramolecular nanoparticle system that could effectively rewire macrophage metabolism by simultaneous inhibition of the TCA cycle and upregulation of the glycolytic metabolic pathway. TLR7/8 agonist and Fatty Acid Oxidation (FAO) inhibitor loaded metabolic supramolecular nanoparticles (MSNPs) were synthesized. In vitro assays showed macrophages treated with MSNPs were reprogrammed from an M2 phenotype to an M1 phenotype while significantly upregulating phagocytosis. When injected in 4T1 tumor-bearing mice, MSNPs treatment reduced tumor growth progression more than other treatments. Hence, the delivery of TLR7/8 agonist combined with an FAO inhibitor can enhance antitumor efficacy through metabolic reprogramming of tumor-associated macrophages.
    Keywords:  cancer; combination; immunotherapy; macrophage; metabolic reprogramming
    DOI:  https://doi.org/10.1002/jbm.a.37391
  52. Natl Sci Rev. 2022 Mar;9(3): nwab139
    Cascade-responsive nanobomb with domino effect for anti-tumor synergistic therapies.
    Yang Liu, Yinghui Wang, Shuyan Song, Hongjie Zhang.
      The development of reactive oxygen species (ROS) generation agents that can selectively produce sufficient ROS at the tumor site without external energy stimulation is of great significance for the further clinical application of ROS-based therapies. Herein, we designed a cascade-responsive ROS nanobomb (ZnO2@Ce6/CaP@CPPO/BSA, designated as Z@Ce6/CaP@CB) with domino effect and without external stimulation for the specific generation of multiple powerful ROS storms at the tumor site. The calcium phosphate shell and ZnO2 core gradually degrade and release Ca2+, Zn2+ and hydrogen peroxide (H2O2) under acid stimulation. On the one hand, Zn2+ can enhance the generation of endogenous superoxide anions (·O2 -) and H2O2 through the inhibition of the mitochondrial electron transport chain. On the other hand, the generation of large amounts of exogenous H2O2 can cause oxidative damage to tumor cells and further activate bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] oxalate (CPPO)-mediated chemiexcited photodynamic therapy. In addition, the oxidative stress caused by the generated ROS can lead to the uncontrolled accumulation of Ca2+ in cells and further result in Ca2+ overload-induced cell death. Therefore, the introduction of Z@Ce6/CaP@CB nanobombs triggered the 'domino effect' that caused multiple heavy ROS storms and Ca2+ overload in tumors and effectively activated anti-tumor immune response.
    Keywords:  biodegradable; chemiexcited photodynamic therapy; immunotherapy; ion interference therapy; reactive oxygen species
    DOI:  https://doi.org/10.1093/nsr/nwab139
  53. Angew Chem Int Ed Engl. 2022 Apr 05.
    A Hybrid Supramolecular Polymeric Nanomedicine for Cascade-Amplified Synergetic Cancer Therapy.
    Kai Yang, Shaolong Qi, Xinyang Yu, Bing Bai, Xueyan Zhang, Zhengwei Mao, Feihe Huang, Guocan Yu.
      Supramolecular nanomedicines have shown unparalleled merits in cancer therapy, but their clinical translation is greatly hampered by monotonous therapeutic modality and unsatisfactory antitumor performance. Herein, a hybrid supramolecular polymeric nanomedicine (SNPs) is developed based on β-cyclodextrin/camptothecin (CPT) host-guest molecular recognition and iron-carboxylate coordination. Iron ions stabilizing SNPs catalyze the conversion of intracellular hydrogen peroxide into highly toxic hydroxyl radical through a Fenton reaction, which further cleaves thioketal linker of the supramolecular monomer to release potent CPT, thus synergistically amplifying the therapeutic efficacy by combining chemodynamic therapy and chemotherapy. The combination therapy stimulates antitumor immunity and promotes intratumoral infiltration of cytotoxic T lymphocytes by triggering immunogenic cell death. In synergy with PD-L1 checkpoint blockade, SNPs enables enhanced immune therapy and a long-term tumor remission.
    Keywords:  cancer theranostics * chemodynamic therapy * host−guest systems * immunotherapy * supramolecular chemistry
    DOI:  https://doi.org/10.1002/anie.202203786
  54. Drug Deliv. 2022 Dec;29(1): 1075-1085
    Preparation of PEG/ZIF-8@HF drug delivery system for melanoma treatment via oral administration.
    Luxi Peng, Jiajun Qiu, Lidan Liu, Xiaoyu Li, Xuanyong Liu, Yongjun Zhang.
      Melanoma is one of the highly malignant tumors whose incidence and fatality rates have been increased year by year. However, in addition to early surgical resection, there still lacks specific targeted drugs and treatment strategies. In this study, it was discovered that hinokiflavone (HF) encapsulated in zeolitic imidazolate framework-8 (ZIF-8) exhibited a superior anti-melanoma effect in vitro and in vivo. HF was encapsulated in ZIF-8 through a one-step synthesis method, and polyethylene glycol (PEG-2000) was used to optimize the size and dispersion of the drug-loaded complex (PEG/ZIF-8@HF). The results show that the prepared PEG/ZIF-8@HF has a high encapsulation efficiency (92.12%) and can achieve selective drug release in an acidic microenvironment. The results of in vitro anti-melanoma experiments indicate that PEG/ZIF-8@HF shows up-regulation of reactive oxygen species (ROS) levels and can restrain the migration and invasion of B16F10 cells. Moreover, in vivo animal experiments further confirm that PEG/ZIF-8@HF shows anti-tumor effect by up-regulating the pro-apoptotic proteins caspase-3 and caspase-8, and down-regulating the migration-promoting invasion protein MMP-9. This study developed a safe and effective oral administration of HF based on the high-efficiency delivery ZIF-8 system, which provides an effective treatment strategy for melanoma.
    Keywords:  Hinokiflavone; antitumor; cytocompatibility; melanoma; zeolitic imidazolate framework-8
    DOI:  https://doi.org/10.1080/10717544.2022.2058649
  55. Recent Adv Drug Deliv Formul. 2022 Apr 04.
    Vesicular Approach Review on Nanocarriers bearing Curcumin and Applications.
    Prashant Upadhyay, Deepak Singh, Sukirti Upadhyay.
      Phytoconstituents have been used to treat a variety of human diseases for a long time, but their use in pharmaceuticals is limited because of their low aqueous solubility. Researchers have created vesicular systems to address many of the issues associated with the bioavailability and therapeutic efficacy of poorly water-soluble drugs and target the drug to the desired location in the body. Several vesicular nanocarrier systems have been developed. Review contrasts various vesicular drug delivery systems, including liposomes, sphingosomes, emulsomes, niosomes, ethosomes, virosomes, phytosomes, aquasomes, proniosomes, transfersomes, pharmacosomes. Vesicular drug delivery systems have caused a scientific revolution, which has resulted in the development of novel dosage forms. This review aims to illustrate the applications, advantages, and disadvantages of the vesicular approach as nanocarriers bearing curcumin and widely used in gene delivery, tumor-targeting to the brain, oral formulations, and resolving various problems associated with drug stability and permeability issues. Nanocarriers also has wide application as green nanocomposites and for antitubercular drugs depending on their physical properties.
    Keywords:  Curcumin; Liposomes; Nanocarriers; Niosomes; Phytosomes; Vesicular; Virosomes
    DOI:  https://doi.org/10.2174/2667387816666220404092415
  56. Int J Pharm. 2022 Mar 30. pii: S0378-5173(22)00265-4. [Epub ahead of print]619 121710
    Induction of p53 mediated mitochondrial apoptosis and cell cycle arrest in human breast cancer cells by plant mediated synthesis of silver nanoparticles from Bergenia ligulata (Whole plant).
    Mir Mohd Faheem, Madhulika Bhagat, Pooja Sharma, Rythem Anand.
      The biological synthesis of nanoparticles is a growing research trend because it has numerous pharmaceutical and biomedical applications. The present study describes the preparation, characterization and anti-cancer evaluation of silver nanoparticles synthesized using an aqueous extract of Bergenia ligulata whole plant as a reducing agent. The physiochemical properties of the Bergenia ligulata silver nanoparticles (BgAgNPs) were measured by ultraviolet-visible spectrophotometry, Fourier transform infrared spectrophotmetry (FTIR), X-ray powder diffraction (XRD) and Scanning electron microscopy (SEM) analysis for identifying functional groups, crystallinity, structural and morphological features, respectively. Further, BgAgNps, along with the Bergenia ligulata aqueous extract (BgAE), were investigated for their effects on cell proliferation and apoptosis through MTT, colony-forming assay, wound-healing assay and flow cytometry-based approaches. The cytotoxic effects were more pronounced in cells treated with BgAgNps in comparison to BgAE. These effects were evidenced by the decreasing cell viability, migration capacity and loss of characteristic morphological features. In addition, BgAgNps unveiled significant induction of apoptosis in human breast cancer (MCF-7) cells, possibly through oxidative stress-mediated reactive oxygen species (ROS) generation and loss of mitochondrial membrane potential (MMP). Moreover, molecular mechanism-based studies revealed that BgAgNps robustly augmented p53 levels and pro-apoptotic downstream targets of p53 like Bax and cleaved caspase 3 in MCF-7 cells. Of note, BgAgNps had little or no cytotoxic effect on p53-deficient cancer cells (Mda-mb-231 and SW-620). These findings confirm that the BgAgNPs exhibited superior anti-cancer potential and could be exploited as a promising, cost-effective, and environmentally benign strategy in treating this disease in the future.
    Keywords:  Apoptosis; Bergenia ligulata; Breast cancer cells; Cell cycle arrest; Silver nanoparticles; p53
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121710
  57. Bioconjug Chem. 2022 Apr 06.
    Combining Doxorubicin-Conjugated Polymeric Nanoparticles and 5-Aminolevulinic Acid for Enhancing Radiotherapy against Lung Cancer.
    Jinghua Han, Wei Yang, Yuanke Li, Jianwen Li, Fangchao Jiang, Jin Xie, Xinglu Huang.
      Radiation therapy (RT) concurrent with chemotherapy improves local lung cancer control but may cause systemic toxicity. There is an unmet clinical need of treatments that can selectively sensitize cancer cells to RT. Herein, we explored a radiosensitizing strategy that combines doxorubicin (DOX)-encapsulated polyaspartamide nanoparticles and 5-aminolevulinic acid (5-ALA). The DOX-polyaspartamide nanoparticles were coupled with NTSmut, a ligand specific to neurotensin receptor type 1 (NTSR1), for lung cancer targeting. DOX was coupled to the polymer backbone through a pH-sensitive hydrazone linker, which allows for controlled release of the drug in an acidic tumor micromovement. Meanwhile, 5-ALA accumulates in the cancer cell's mitochondria, forming protoporphyrin (PpIX) that amplifies RT-induced oxidative stress. When tested in vitro in H1299 cells, DOX-encapsulated nanoparticles in conjugation with 5-ALA enhanced cancer cell killing owing to the complementary radiosensitizing effects of DOX and 5-ALA. In vivo studies confirmed that the combination improved tumor suppression relative to RT alone without causing toxicity to normal tissues. Overall, our study suggests an effective and selective radiosensitizing approach.
    DOI:  https://doi.org/10.1021/acs.bioconjchem.2c00066
  58. Colloids Surf B Biointerfaces. 2022 Apr 04. pii: S0927-7765(22)00172-2. [Epub ahead of print]215 112489
    Ultrasound-triggered reactive oxygen species effector nanoamplifier for enhanced combination therapy of mutant p53 tumors.
    Xiang Wang, Kang Song, Yan Fan, Jun Du, Jinliang Liu, Jiayu Xu, Lulu Zheng, Ruizhuo Ouyang, Yuhao Li, Yuqing Miao, Dawei Zhang.
      Reactive oxygen species (ROS) damage is a crucial method with which to inhibit tumor cell proliferation; however, tumor cells can reduce ROS damage by modulating multiple repair mechanisms, thus, reducing the efficacy of ROS damage in tumor therapy. In this study, we built an ultrasound-triggered ROS damage nanoamplifier using a synergistic strategy consisting of ROS damage and decreased tumor self-protection capability to enhance the treatment efficacy of mutant p53 tumors. A ROS damage nanoamplifier (PT@PTGA) was fabricated using amphiphilic polyglutamic acid (PTGA) to load with a sonosensitizer (protoporphyrin IX, PpIX) and an MTH1 inhibitor (TH287). Under ultrasonic excitation, PpIX catalyzes oxygen to produce singlet oxygen and release TH287 to inhibit MTH1 activity, thereby causing the accumulation of 8-oxo-dGTP, which enhances DNA damage and further induces cell apoptosis. In addition, TH287 allies with ROS to eliminate the mutated p53 protein in tumor cells, thus reducing the self-protective capacity of tumor cells. As a result, the "internal and external" aspects were combined to enhance sensitization for mutant p53 tumor therapy. The construction of a ROS nanoamplifier not only provides an effective strategy for the treatment of mutant p53 tumors but also supplies an integrated platform for tumor diagnosis and therapy.
    Keywords:  Amphiphilic polyglutamic acid; Mutant p53 protein; ROS damage; Sonodynamic therapy; Synergistic therapy
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112489
  59. Endocrinology. 2022 Apr 02. pii: bqac041. [Epub ahead of print]
    Targeting mTOR in the context of diet and whole-body metabolism.
    Nikos Koundouros, John Blenis.
      The mechanistic target of rapamycin (mTOR) signaling pathway is the central regulator of cell growth and proliferation by integrating growth factor and nutrient availability. Under healthy physiological conditions, this process is tightly coordinated and essential to maintain whole-body homeostasis. Not surprisingly, dysregulated mTOR signaling underpins several diseases with increasing incidence worldwide, including obesity, diabetes and cancer. Consequently, there is significant clinical interest in developing therapeutic strategies that effectively target this pathway. The transition of mTOR inhibitors from the bench to bedside, however, has largely been marked with challenges and shortcomings, such as the development of therapy resistance and adverse side effects in patients. In this review, we discuss the current status of first, second and third generation mTOR inhibitors as a cancer therapy in both pre-clinical and clinical settings, with a particular emphasis on the mechanisms of drug resistance. We focus especially on the emerging role of diet as an important environmental determinant of therapy response, and posit a conceptual framework that links nutrient availability and whole-body metabolic states such as obesity with many of the previously defined processes that drive resistance to mTOR-targeted therapies. Given the role of mTOR as a central integrator of cell metabolism and function, we propose that modulating nutrient inputs through dietary interventions may influence the signaling dynamics of this pathway and compensatory nodes. In doing so, new opportunities for exploiting diet/drug synergies are highlighted that may unlock the therapeutic potential of mTOR inhibitors as a cancer treatment.
    Keywords:  diet; drug resistance; mTOR; metabolism
    DOI:  https://doi.org/10.1210/endocr/bqac041
  60. J Control Release. 2022 Apr 01. pii: S0168-3659(22)00192-4. [Epub ahead of print]
    In vivo self-assembled drug nanocrystals for metastatic breast cancer all-stage targeted therapy.
    Zimiao Luo, Linwei Lu, Weixia Xu, Nana Meng, Sunyi Wu, Jianfen Zhou, Qianzhu Xu, Cao Xie, Yu Liu, Weiyue Lu.
      Chemotherapy is still the mainstay treatment for metastatic triple-negative breast cancers (TNBC) currently in clinical practice. The unmet needs of chemotherapy for metastatic TNBC are mainly from the insufficient drug delivery and unavailable targeting strategy that thwart the whole progression of metastatic TNBC. The in vivo ligands-mediated active targeting efficiency is usually affected by protein corona. While, the protein corona-bridged natural targeting, in turn, provides a new way for specific drug delivery. Herein, we develop a novel metastatic progression-oriented in vivo self-assembled Cabazitaxel nanocrystals (CNC) delivery system (PC/CNC) through the CNC automatically absorbing functional plasma proteins (transferrin, apolipoprotein A-IV and apolipoprotein E) in vivo, aiming to achieve the simultaneously targeted delivery to primary tumors, circulating tumor cells and metastatic lesions. With the unique advantages of superhigh drug-loading and protein corona empowered active targeting properties to tumor cells, HUVECs, active-platelets and blood-brain barrier/blood-tumor barrier, the PC/CNC exhibits a significantly improved therapeutic effect in metastatic TNBC therapy compared with free drug and CNC-loaded liposomes.
    Keywords:  All-stage targeted therapy; Drug nanocrystals; In vivo self-assembly; Metastatic breast cancer
    DOI:  https://doi.org/10.1016/j.jconrel.2022.03.058
  61. Pathophysiology. 2021 Jun 05. 28(2): 250-272
    Saponins in Cancer Treatment: Current Progress and Future Prospects.
    Olusola Olalekan Elekofehinti, Opeyemi Iwaloye, Femi Olawale, Esther Opeyemi Ariyo.
      Saponins are steroidal or triterpenoid glycoside that is distinguished by the soap-forming nature. Different saponins have been characterized and purified and are gaining attention in cancer chemotherapy. Saponins possess high structural diversity, which is linked to the anticancer activities. Several studies have reported the role of saponins in cancer and the mechanism of actions, including cell-cycle arrest, antioxidant activity, cellular invasion inhibition, induction of apoptosis and autophagy. Despite the extensive research and significant anticancer effects of saponins, there are currently no known FDA-approved saponin-based anticancer drugs. This can be attributed to a number of limitations, including toxicities and drug-likeness properties. Recent studies have explored options such as combination therapy and drug delivery systems to ensure increased efficacy and decreased toxicity in saponin. This review discusses the current knowledge on different saponins, their anticancer activity and mechanisms of action, as well as promising research within the last two decades and recommendations for future studies.
    Keywords:  anticancer activities; apoptosis; cell-cycle arrest; chemopreventive; future cancer research; mechanism of action; saponins; traditional plants
    DOI:  https://doi.org/10.3390/pathophysiology28020017
  62. Arch Pharm Res. 2022 Apr 07.
    Biomedical features and therapeutic potential of rosmarinic acid.
    Saba Noor, Taj Mohammad, Malik Abdul Rub, Ali Raza, Naved Azum, Dharmendra Kumar Yadav, Md Imtaiyaz Hassan, Abdullah M Asiri.
      For decades, the use of secondary metabolites of various herbs has been an attractive strategy in combating human diseases. Rosmarinic acid (RA) is a bioactive phenolic compound commonly found in plants of Lamiaceae and Boraginaceae families. RA is biosynthesized using amino acids tyrosine and phenylalanine via enzyme-catalyzed reactions. However, the chemical synthesis of RA involves an esterification reaction between caffeic acid and 3,4-dihydroxy phenyl lactic acid contributing two phenolic rings to the structure of RA. Several studies have ascertained multiple therapeutic benefits of RA in various diseases, including cancer, diabetes, inflammatory disorders, neurodegenerative disorders, and liver diseases. Many previous scientific papers indicate that RA can be used as an anti-plasmodic, anti-viral and anti-bacterial drug. In addition, due to its high anti-oxidant capacity, this natural polyphenol has recently gained attention for its possible application as a nutraceutical compound in the food industry. Here we provide state-of-the-art, flexible therapeutic potential and biomedical features of RA, its implications and multiple uses. Along with various valuable applications in safeguarding human health, this review further summarizes the therapeutic advantages of RA in various human diseases, including cancer, diabetes, neurodegenerative diseases. Furthermore, the challenges associated with the clinical applicability of RA have also been discussed.
    Keywords:  Anti-cancer therapy; Bioactive phenolic compounds; Drug discovery; Natural products; Rosmarinic acid
    DOI:  https://doi.org/10.1007/s12272-022-01378-2
  63. Adv Mater. 2022 Apr 06. e2201051
    Intelligent Micro/nanorobot for Cancer Theragnostic.
    Jie Wang, Yue Dong, Peng Ma, Yu Wang, Fangyu Zhang, Bocheng Cai, Peng Chen, Bi-Feng Liu.
      Cancer is one of the most intractable diseases owing to its high mortality rate and lack of effective diagnostic and treatment tools. Advancements in micro/nanorobot (MNR)-assisted sensing, imaging, and therapeutics offer unprecedented opportunities to develop MNR-based cancer theragnostic platforms. Unlike ordinary nanoparticles which exhibit Brownian motion in biofluids, MNRs overcome viscous resistance in an ultralow Reynolds number (Re<<1) environment by effective self-propulsion. This unique locomotion property has motivated the advanced design and functionalization of MNRs as a basis for next-generation cancer therapy platforms, which offer the potential for precise distribution and improved permeation of therapeutic agents. Enhanced barrier penetration, imaging-guided operation, and biosensing have additionally been studied to enable the promising cancer-related applications of MNRs. This review comprehensively addresses recent advances in MNR-based cancer therapy, including in actuation engines, diagnostics, medical imaging, and targeted drug delivery; we highlight promising research opportunities that could have a profound impact on cancer therapy over the next decade. This article is protected by copyright. All rights reserved.
    Keywords:  drug delivery; medical imaging; micro/nano robotic; tumor diagnosis; tumor therapy
    DOI:  https://doi.org/10.1002/adma.202201051
  64. J Food Biochem. 2022 Apr 09. e14177
    Harpephyllum caffrum fruit (wild plum) facilitates glucose uptake and modulates metabolic activities linked to neurodegeneration in isolated rat brain: An in vitro and in silico approach.
    Kolawole A Olofinsan, Veronica F Salau, Ochuko L Erukainure, Md Shahidul Islam.
      Alteration in brain glucose metabolism due to glucose uptake reduction has been described in the onset of certain neurodegenerative disorders. This study determined Harpephyllum caffrum fruit's potential ability to improve glucose uptake and its modulatory effects on intrinsic antioxidant, glucogenic, cholinergic, and nucleotide-hydrolyzing enzyme activities in isolated rat brain. Consequently, the bioactive compounds of the fruits were identified with LC-MS. The fruit significantly improved brain glucose uptake following coincubation with glucose and brain tissue. The fruit extract also elevated GSH level, SOD, catalase, glycogen phosphorylase, and ENTPDase activities while simultaneously suppressing NO and malonaldehyde levels and fructose-1,6-bisphosphatase, ATPase, acetylcholinesterase and butyrylcholinesterase activities. LC-MS analysis revealed S-methylcysteine sulfoxide, dihydroquercetin, 3,4-dimethyl-2,5-bis(3,4,5-trimethoxyphenyl) tetrahydrofuran (MTHF), nobiletin, puerarin, quercetin 3-rutinoside, 8-D-glucosyl-4',5,7-trihydroxyflavone, asperulosidic acid, 1,2,4,6-tetragalloylglucose, and phellamurin. This study suggests the neuroprotective effects of H. caffrum fruit due to its ability to enhance glucose uptake, attenuate glucose-induced oxidative stress while modulating glucogenic, cholinergic, and nucleotide-hydrolyzing enzyme activities in normal brain tissues. PRACTICAL APPLICATIONS: Available scientific evidence describes oxidative stress as one of the physiological processes contributing to aging-associated neurodegeneration in humans. In this regard, commonly consumed natural products from plants have attracted much interest due to their ability to mitigate redox imbalance-related pathologies that affect various organs in the body such as the brain. Harpephyllum caffrum or bush mango is an evergreen plant native to the South African vegetation. The fruit from the plant is consumed locally as food or specifically for improving the nutritional quality of meals as deserts or condiments. While previous findings described the high antioxidant properties of the fruits, this study reported possible mechanisms via which the plant may exhibit ameliorative effects against oxidative stress-related neurological disorders in the brain. Hence, findings from the current work present another justification for the significance of fruits as a safer nutraceutical alternative for therapy in neurological disease management.
    Keywords:   Harpephyllum caffrum ; antioxidant; brain glucose uptake; neurodegeneration
    DOI:  https://doi.org/10.1111/jfbc.14177
  65. Front Pharmacol. 2022 ;13 842511
    Eichhornia crassipes (Mart.) Solms: A Comprehensive Review of Its Chemical Composition, Traditional Use, and Value-Added Products.
    Widad Ben Bakrim, Amine Ezzariai, Fadoua Karouach, Mansour Sobeh, Mulugeta Kibret, Mohamed Hafidi, Lamfeddal Kouisni, Abdelaziz Yasri.
      Eichhornia crassipes (Mart.) Solms, commonly known as water hyacinth, is one of the world's most invasive aquatic plants of the Pontederiaceae family occurring in tropical and subtropical regions of the world. Although, E. crassipes causes significant ecological and socioeconomic issues such as a high loss in water resources, it has multipurpose applications since it is famous for many industrial applications such as bioenergy, biofertilizer production, wastewater treatment (absorption of heavy metals), and animal feed. Furthermore, E. crassipes is rich in diverse bioactive secondary metabolites including sterols, alkaloids, phenolics, flavonoids, tannins, and saponins. These secondary metabolites are well known for a wide array of therapeutic properties. The findings of this review suggest that extracts and some isolated compounds from E. crassipes possess some pharmacological activities including anticancer, antioxidant, anti-inflammatory, antimicrobial, skin whitening, neuroprotective, and hepatoprotective activities, among other biological activities such as allelopathic, larvicidal, and insecticidal activities. The present review comprehensively summarizes the chemical composition of E. crassipes, reported to date, along with its traditional uses and pharmacological and biological activities.
    Keywords:  Eichhornia crassipes (mart.) Solms; biological activities; pharmacology; phytochemistry; value–added products
    DOI:  https://doi.org/10.3389/fphar.2022.842511
  66. Front Chem. 2022 ;10 847573
    Methotrexate-Lactoferrin Targeted Exemestane Cubosomes for Synergistic Breast Cancer Therapy.
    Sarah Mokhtar, Sherine N Khattab, Kadria A Elkhodairy, Mohamed Teleb, Adnan A Bekhit, Ahmed O Elzoghby, Marwa A Sallam.
      While the treatment regimen of certain types of breast cancer involves a combination of hormonal therapy and chemotherapy, the outcomes are limited due to the difference in the pharmacokinetics of both treatment agents that hinders their simultaneous and selective delivery to the cancer cells. Herein, we report a hybrid carrier system for the simultaneous targeted delivery of aromatase inhibitor exemestane (EXE) and methotrexate (MTX). EXE was physically loaded within liquid crystalline nanoparticles (LCNPs), while MTX was chemically conjugated to lactoferrin (Lf) by carbodiimide reaction. The anionic EXE-loaded LCNPs were then coated by the cationic MTX-Lf conjugate via electrostatic interactions. The Lf-targeted dual drug-loaded LCNPs exhibited a particle size of 143.6 ± 3.24 nm with a polydispersity index of 0.180. It showed excellent drug loading with an EXE encapsulation efficiency of 95% and an MTX conjugation efficiency of 33.33%. EXE and MTX showed synergistic effect against the MCF-7 breast cancer cell line with a combination index (CI) of 0.342. Furthermore, the Lf-targeted dual drug-loaded LCNPs demonstrated superior synergistic cytotoxic activity with a combination index (CI) of 0.242 and a dose reduction index (DRI) of 34.14 and 4.7 for EXE and MTX, respectively. Cellular uptake studies demonstrated higher cellular uptake of Lf-targeted LCNPs into MCF-7 cancer cells than non-targeted LCNPs after 4 and 24 h. Collectively, the targeted dual drug-loaded LCNPs are a promising candidate offering combinational hormonal therapy/chemotherapy for breast cancer.
    Keywords:  breast cancer; cubosomes; exemestane; lactoferrin; methotrexate
    DOI:  https://doi.org/10.3389/fchem.2022.847573
  67. Clin Transl Med. 2022 Apr;12(4): e795
    Targeting transforming growth factor-β signalling for cancer prevention and intervention: Recent advances in developing small molecules of natural origin.
    Devesh Tewari, Anu Priya, Anusha Bishayee, Anupam Bishayee.
       BACKGROUND: Cancer is the world's second leading cause of death, but a significant advancement in cancer treatment has been achieved within the last few decades. However, major adverse effects and drug resistance associated with standard chemotherapy have led towards targeted treatment options.
    OBJECTIVES: Transforming growth factor-β (TGF-β) signaling plays a key role in cell proliferation, differentiation, morphogenesis, regeneration, and tissue homeostasis. The prime objective of this review is to decipher the role of TGF-β in oncogenesis and to evaluate the potential of various natural and synthetic agents to target this dysregulated pathway to confer cancer preventive and anticancer therapeutic effects.
    METHODS: Various authentic and scholarly databases were explored to search and obtain primary literature for this study. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria was followed for the review.
    RESULTS: Here we provide a comprehensive and critical review of recent advances on our understanding of the effect of various bioactive natural molecules on the TGF-β signaling pathway to evaluate their full potential for cancer prevention and therapy.
    CONCLUSION: Based on emerging evidence as presented in this work, TGF-β-targeting bioactive compounds from natural sources can serve as potential therapeutic agents for prevention and treatment of various human malignancies.
    Keywords:  TGF-β signalling; apoptosis; cancer; in vitro; in vivo; natural products; proliferation; treatment
    DOI:  https://doi.org/10.1002/ctm2.795
  68. Front Oncol. 2022 ;12 836397
    Advances in Photodynamic Therapy Based on Nanotechnology and Its Application in Skin Cancer.
    Ping Zhang, Ting Han, Hui Xia, Lijie Dong, Liuqing Chen, Li Lei.
      Comprehensive cancer treatments have been widely studied. Traditional treatment methods (e.g., radiotherapy, chemotherapy), despite ablating tumors, inevitably damage normal cells and cause serious complications. Photodynamic therapy (PDT), with its low rate of trauma, accurate targeting, synergism, repeatability, has displayed great advantages in the treatment of tumors. In recent years, nanotech-based PDT has provided a new modality for cancer treatment. Direct modification of PSs by nanotechnology or the delivery of PSs by nanocarriers can improve their targeting, specificity, and PDT efficacy for tumors. In this review, we strive to provide the reader with a comprehensive overview, on various aspects of the types, characteristics, and research progress of photosensitizers and nanomaterials used in PDT. And the application progress and relative limitations of nanotech-PDT in non-melanoma skin cancer and melanoma are also summarized.
    Keywords:  metastatic melanoma; nanoparticle; nanotechnology; nonmelanoma skin cancer; photodynamic therapy; photosensitizer
    DOI:  https://doi.org/10.3389/fonc.2022.836397
  69. Bioorg Med Chem. 2022 Mar 29. pii: S0968-0896(22)00129-8. [Epub ahead of print] 116737
    4'-Nitrobiphenyl thioglucoside as the Smallest, fluorescent photosensitizer with cancer targeting ligand.
    Takashi Kanamori, Yuto Miki, Masataka Katou, Shun-Ichiro Ogura, Hideya Yuasa.
      We have previously developed a glucose-linked biphenyl photosensitizer that can pass through glucose transporters, aiming for cancer-selective photodynamic therapy (PDT). Its small size (MW: 435) will allow oral administration and a fast clearance avoiding photosensitivity. However, its fluorescence efficiency was quite low, causing difficulty in monitoring cellular uptake. We thus synthesized a series of monosaccharide-linked biphenyl derivatives with a sulfur atom replacing an oxygen atom, in search of a photosensitizer with a brighter fluorescence. Among them, 4'-nitrobiphenyl thioglucoside showed a fluorescence emission extending to near infra-red region with a strength three times greater than that of the previous compound. This compound was found to have a higher 1O2-producing efficiency (ΦΔ: 0.75) than the previous compound (ΦΔ: 0.65). The thioglucoside indicated a significant photodamaging effect (IC50: 250 μM) against cancer cells. Although the galactose and mannose analogs exerted similar photodamaging effects, they were moderately toxic in the dark at a concentration of 300 μM. The thioglucoside and thiomannoside were at least partially uptaken through glucose transporters as demonstrated by inhibition with cytochalasin B, whereas no inhibition was observed for the galactoside. The behavior of d-glucose toward the cellular uptakes of these photosensitizers was bipolar: inhibitory at a low concentration and recovery or acceleratory at a higher concentration. These results indicate that 4'-nitrobiphenyl thioglucoside is the smallest (MW: 393) cancer-targeting photosensitizer with a trackable fluorescence property.
    Keywords:  Biphenyl; Glucose Transporter; Photodynamic Therapy; Photosensitizer
    DOI:  https://doi.org/10.1016/j.bmc.2022.116737
  70. Subcell Biochem. 2022 ;98 15-40
    Macropinocytosis and Cancer: From Tumor Stress to Signaling Pathways.
    Guillem Lambies, Cosimo Commisso.
      Macropinocytosis is an evolutionarily conserved endocytic pathway that mediates the nonselective acquisition of extracellular material via large endocytic vesicles known as macropinosomes. In addition to other functions, this uptake pathway supports cancer cell metabolism through the uptake of nutrients. Cells harboring oncogene or tumor suppressor mutations are known to display heightened macropinocytosis, which confers to the cancer cells the ability to survive and proliferate despite the nutrient-scarce conditions of the tumor microenvironment. Thus, macropinocytosis is associated with cancer malignancy. Macropinocytic uptake can be induced in cancer cells by different stress stimuli, acting as an adaptive mechanism for the cells to resist stresses in the tumor milieu. Here, we review the cellular stresses that are known to promote macropinocytosis, as well as the underlying molecular mechanisms that drive this process.
    Keywords:  Cancer malignancy; Cell metabolism; Macropinocytosis; Nutrient scarcity; Nutrient uptake; Stress stimuli
    DOI:  https://doi.org/10.1007/978-3-030-94004-1_2
  71. J Mater Chem B. 2022 Apr 05.
    Nanogels loading curcumin in situ through microemulsion photopolymerization for enhancement of antitumor effects.
    Yuanyuan Peng, Siyuan Yu, Zhen Wang, Pingsheng Huang, Weiwei Wang, Jinfeng Xing.
      Drug-loaded nanogels for cancer treatment can limit the free diffusion and distribution of drug molecules in the whole body to reduce undesirable side effects and improve the drug absorption efficiency of the tumor. In this study, curcumin as a model drug was encapsulated into nanogels in situ through microemulsion photopolymerization at 532 nm. Nanogels loaded with curcumin (NG-C) displayed a diameter of around 150 nm with good stability and a low polydispersity index of around 0.1. NG-C had a drug-loading capacity of 8.96 ± 1.16 wt%. The cumulative release of curcumin from NG-C was around 25%, 34% and 55% within 90 h in pH 7.4, 6.8 and 5.0 PBS buffer, respectively. NG-C presented prominent cytotoxicity toward Hep G2 and HeLa cancer cells in vitro. Moreover, NG-C exhibited much a stronger inhibition of tumor growth, necrosis, apoptosis, and the suppression of proliferation compared with curcumin on Hep G2 tumor-bearing nude mice.
    DOI:  https://doi.org/10.1039/d2tb00035k
  72. Acta Biomater. 2022 Apr 02. pii: S1742-7061(22)00189-1. [Epub ahead of print]
    Partial ligand shielding nanoparticles improve pancreatic ductal adenocarcinoma treatment via a multifunctional paradigm for tumor stroma reprogramming.
    Ting Zhao, Rongping Zhang, Qin He, Hongli Zhou, Xu Song, Tao Gong, Zhirong Zhang.
      The dense stroma that acts as a physical and biological barrier in the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) leads to the failure of chemotherapeutic drug delivery. Cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) mainly constitute the refuge for cancer cells in PDAC. Herein, a CAF targeting drug delivery system (TDDS) based on RBC vesicles partial protection (RBC-Fn-NP) was established and investigated for reprogramming stroma, as well as enhancing tumor penetration and antitumor efficacy in PDAC. RBC vesicles were firstly used for partial protection of peptide from external influences. The exposed FnBPA5 peptide showed high affinity with both CAFs and the major components as Collagen I and relaxed-fibronectin of ECM. Retinoic acid (RA) could disturb Golgi of CAFs, resulting in the reduction of protein secretion from the headstream. As expected, the strategy of RBC vesicles protected FnBPA5 targeting and RA-induced protein reduction was confirmed to reprogram the dense stroma and improve the penetration of Doxorubicin (Dox) in PDAC. RBC-Fn-NP inhibited tumor growth in both Pan02-orthotopic bearing model and Pan02-subcutaneous mice model. Hence, these partial ligand shielding nanoparticles offer a multifunctional and efficient approach to overcome penetration barriers and enhance the antitumor efficacy of chemotherapy in PDAC. STATEMENT OF SIGNIFICANCE: A partial ligand shielding nanoparticle platform (RBC-Fn-NP), which has the function of an RBC vesicle "shell" and thetargeting properties of a "core" to achieve superior therapeutic effects against PDAC, was established. The targeted ligand was modified on the surface of the nanoparticles instead of the RBC membranes. Three-dimensional PDAC stroma-rich spheroids were established to evaluate the penetration and tumor stroma remodeling. The targeting properties of FnBPA5 peptide, the effect of RA-induced Golgi disruption on the reduction of protein secretion, and the incomplete "camouflage" of the RBC vesicles were confirmed both in vitro and in vivo. As expected, our nanoplatform may provide a promising strategy for remolding dense stroma and enhancing the permeability in PDAC.
    Keywords:  Cancer-associated fibroblasts; Golgi disturbing; Pancreatic ductal adenocarcinoma; Penetration; Stroma reprogramming
    DOI:  https://doi.org/10.1016/j.actbio.2022.03.050
  73. Crit Rev Oncog. 2021 ;26(3): 53-67
    The Potential Oncostatic Effects of Melatonin against Prostate Cancer.
    Saptadip Samanta.
      Melatonin is an endogenous indolamine, synthesized and secreted from the pineal gland. The environmental light-dark cycle is the primary regulator of melatonin synthesis. Darkness during the subjective night induces noradrenaline secretion, which stimulates pinealocytes for melatonin production. Melatonin exhibits anticancer effects and different physiological functions through the membrane-bound G-protein-coupled MT1 and MT2 receptors. Impaired circadian activity, indoor or outdoor light pollution, shift work, night work, and jet lag suppress normal melatonin synthesis. Decreased melatonin concentration causes impaired anticancer effects that adversely affect the progression of different cancers, including prostate. Melatonin differentially regulates the cell cycle, cell survival, and metabolism in malignant cells in contrast to normal prostate epithelial cells. Melatonin promotes the nuclear exclusion of androgen receptors without suppressing the expression of this receptor. This indirect effect blocks the androgenic response in prostate cancer cells. It acts as a cytostatic and cytotoxic agent, prevents cell proliferation, and activates an apoptotic response. Melatonin also inhibits HIF-1α activity and the expression of vascular endothelial growth factors to suppress angiogenesis. This indolamine restricts alteration of metabolic activity, invasion, and metastasis. Melatonin has therapeutic importance. It decreases the side effects of anticancer treatment and mitigates adverse effects after prostatectomy and radiotherapy. Melatonin blocks the recurrence of prostate cancer as well as hormone-refractory effects during androgen deprivation therapy. The present review discusses the multifaceted effects of melatonin against prostate cancer.
    DOI:  https://doi.org/10.1615/CritRevOncog.2021041260
  74. Front Cell Dev Biol. 2022 ;10 849625
    Regulation of Glucose, Fatty Acid and Amino Acid Metabolism by Ubiquitination and SUMOylation for Cancer Progression.
    Shunqin Zhu, Hongyu Gu, Cheng Peng, Fanwei Xia, Huan Cao, Hongjuan Cui.
      Ubiquitination and SUMOylation, which are posttranslational modifications, play prominent roles in regulating both protein expression and function in cells, as well as various cellular signal transduction pathways. Metabolic reprogramming often occurs in various diseases, especially cancer, which has become a new entry point for understanding cancer mechanisms and developing treatment methods. Ubiquitination or SUMOylation of protein substrates determines the fate of modified proteins. Through accurate and timely degradation and stabilization of the substrate, ubiquitination and SUMOylation widely control various crucial pathways and different proteins involved in cancer metabolic reprogramming. An understanding of the regulatory mechanisms of ubiquitination and SUMOylation of cell proteins may help us elucidate the molecular mechanism underlying cancer development and provide an important theory for new treatments. In this review, we summarize the processes of ubiquitination and SUMOylation and discuss how ubiquitination and SUMOylation affect cancer metabolism by regulating the key enzymes in the metabolic pathway, including glucose, lipid and amino acid metabolism, to finally reshape cancer metabolism.
    Keywords:  SUMOylation; cancer; glucose metabolism; lipid metabolism; metabolic reprogramming; ubiquitination
    DOI:  https://doi.org/10.3389/fcell.2022.849625
  75. J Nanobiotechnology. 2022 Apr 02. 20(1): 179
    Homogenous multifunctional microspheres induce ferroptosis to promote the anti-hepatocarcinoma effect of chemoembolization.
    Minjiang Chen, Jie Li, Gaofeng Shu, Lin Shen, Enqi Qiao, Nannan Zhang, Shiji Fang, Xiaoxiao Chen, Zhongwei Zhao, Jianfei Tu, Jingjing Song, Yongzhong Du, Jiansong Ji.
      Transcatheter arterial chemoembolization (TACE) is one of the main palliative therapies for advanced hepatocellular carcinoma (HCC), which is also regarded as a promising therapeutic strategy for cancer treatment. However, drug-loaded microspheres (DLMs), as commonly used clinical chemoembolization drugs, still have the problems of uneven particle size and unstable therapeutic efficacy. Herein, gelatin was used as the wall material of the microspheres, and homogenous gelatin microspheres co-loaded with adriamycin and Fe3O4 nanoparticles (ADM/Fe3O4-MS) were further prepared by a high-voltage electrospray technology. The introduction of Fe3O4 nanoparticles into DLMs not only provided excellent T2-weighted magnetic resonance imaging (MRI) properties, but also improved the anti-tumor effectiveness under microwave-induced hyperthermia. The results showed that ADM/Fe3O4-MS plus microwave irradiation had significantly better antitumor efficacy than the other types of microspheres at both cell and animal levels. Our study further confirmed that ferroptosis was involved in the anti-tumor process of ADM/Fe3O4-MS plus microwave irradiation, and ferroptosis marker GPX4 was significantly decreased and ACSL4 was significantly increased, and ferroptosis inhibitors could reverse the tumor cell killing effect caused by ADM/Fe3O4-MS to a certain extent. Our results confirmed that microwave mediated hyperthermia could amplify the antitumor efficacy of ADM/Fe3O4-MS by activating ferroptosis and the introduction of Fe3O4 nanoparticles can significantly improve TACE for HCC. This study confirmed that it was feasible to use uniform-sized gelatin microspheres co-loaded with Fe3O4 nanoparticles and adriamycin to enhance the efficacy of TACE for HCC.
    Keywords:  Fe3O4 nanoparticles; Ferroptosis; Hepatocellular carcinoma; Homogenous drug-loaded microspheres; Transcatheter arterial chemoembolization
    DOI:  https://doi.org/10.1186/s12951-022-01385-x
  76. J Yeungnam Med Sci. 2022 Apr 04.
    Beneficial effects of intermittent fasting: a narrative review.
    Dae-Kyu Song, Yong-Woon Kim.
      Caloric restriction is a popular approach to treat obesity and its associated chronic illnesses but is difficult to maintain for a long time. Intermittent fasting is an alternative and easily applicable dietary intervention for caloric restriction. Moreover, intermittent fasting has beneficial effects equivalent to those of caloric restriction in terms of body weight control, improvements in glucose homeostasis and lipid profiles, and anti-inflammatory effects. In this review, the beneficial effects of intermittent fasting are discussed.
    Keywords:  Caloric restriction; Diet therapy; Fasting; Obesity
    DOI:  https://doi.org/10.12701/jyms.2022.00010
  77. ACS Omega. 2022 Mar 29. 7(12): 9995-10000
    Interplay between the Cannabinoid System and microRNAs in Cancer.
    Julia M Salamat, Kodye L Abbott, Patrick C Flannery, Elizabeth L Ledbetter, Satyanarayana R Pondugula.
      Cancer patients often use cannabinoids for alleviating symptoms induced by cancer pathogenesis and cancer treatment. This use of cannabinoids can have unexpected effects in cancer patients depending on the cancer type, resulting in either beneficial (e.g., anticancer) or adverse (e.g., oncogenic) effects. While cannabinoids can enhance the growth and progression of some cancers, they can also suppress the growth and progression of other cancers. However, the underlying mechanisms of such differential effects are poorly understood. miRNAs have been shown to be involved in driving the hallmarks of cancer, affecting cancer growth and progression as well as cancer therapy response. Although the understanding of the effects of cannabinoids and miRNAs as they relate to cancer continues to improve, the interplay between cannabinoid system and miRNAs in cancer pathogenesis and cancer treatment response is poorly understood. Investigation of such interactions between the cannabinoid system and miRNAs could provide novel insights into the underlying mechanisms of the differential effects of cannabinoids in cancer and can help predict and improve the prognosis of cancer patients.
    DOI:  https://doi.org/10.1021/acsomega.2c00635
  78. Small. 2022 Apr 09. e2106580
    Microfluidic Nanoparticles for Drug Delivery.
    Yun Liu, Guangze Yang, Yue Hui, Supun Ranaweera, Chun-Xia Zhao.
      Nanoparticles (NPs) have attracted tremendous interest in drug delivery in the past decades. Microfluidics offers a promising strategy for making NPs for drug delivery due to its capability in precisely controlling NP properties. The recent success of mRNA vaccines using microfluidics represents a big milestone for microfluidic NPs for pharmaceutical applications, and its rapid scaling up demonstrates the feasibility of using microfluidics for industrial-scale manufacturing. This article provides a critical review of recent progress in microfluidic NPs for drug delivery. First, the synthesis of organic NPs using microfluidics focusing on typical microfluidic methods and their applications in making popular and clinically relevant NPs, such as liposomes, lipid NPs, and polymer NPs, as well as their synthesis mechanisms are summarized. Then, the microfluidic synthesis of several representative inorganic NPs (e.g., silica, metal, metal oxide, and quantum dots), and hybrid NPs is discussed. Lastly, the applications of microfluidic NPs for various drug delivery applications are presented.
    Keywords:  drug delivery; lipids; microfluidics; nanomedicine; nanoparticles; polymers
    DOI:  https://doi.org/10.1002/smll.202106580
  79. J Exp Clin Cancer Res. 2022 Apr 09. 41(1): 135
    The role of TBK1 in cancer pathogenesis and anticancer immunity.
    Austin P Runde, Ryan Mack, Peter Breslin S J, Jiwang Zhang.
      The TANK-binding kinase 1 (TBK1) is a serine/threonine kinase belonging to the non-canonical inhibitor of nuclear factor-κB (IκB) kinase (IKK) family. TBK1 can be activated by pathogen-associated molecular patterns (PAMPs), inflammatory cytokines, and oncogenic kinases, including activated K-RAS/N-RAS mutants. TBK1 primarily mediates IRF3/7 activation and NF-κB signaling to regulate inflammatory cytokine production and the activation of innate immunity. TBK1 is also involved in the regulation of several other cellular activities, including autophagy, mitochondrial metabolism, and cellular proliferation. Although TBK1 mutations have not been reported in human cancers, aberrant TBK1 activation has been implicated in the oncogenesis of several types of cancer, including leukemia and solid tumors with KRAS-activating mutations. As such, TBK1 has been proposed to be a feasible target for pharmacological treatment of these types of cancer. Studies suggest that TBK1 inhibition suppresses cancer development not only by directly suppressing the proliferation and survival of cancer cells but also by activating antitumor T-cell immunity. Several small molecule inhibitors of TBK1 have been identified and interrogated. However, to this point, only momelotinib (MMB)/CYT387 has been evaluated as a cancer therapy in clinical trials, while amlexanox (AMX) has been evaluated clinically for treatment of type II diabetes, nonalcoholic fatty liver disease, and obesity. In this review, we summarize advances in research into TBK1 signaling pathways and regulation, as well as recent studies on TBK1 in cancer pathogenesis. We also discuss the potential molecular mechanisms of targeting TBK1 for cancer treatment. We hope that our effort can help to stimulate the development of novel strategies for targeting TBK1 signaling in future approaches to cancer therapy.
    Keywords:  Autophagy; Cancer pathogenesis; Immunity; Inflammation; Mitophagy; Oncogenesis; Proliferation; Survival; TBK1; TBK1 inhibitor
    DOI:  https://doi.org/10.1186/s13046-022-02352-y
  80. Nanomedicine (Lond). 2022 Apr 08.
    Graphene oxide induces autophagy and apoptosis via ROS-dependent AMPK/mTOR/ULK-1 pathway in colorectal cancer cells.
    Jiamen Shen, Jiatian Dong, Feng Shao, Jiaying Zhao, Lifeng Gong, Huipeng Wang, Wenjie Chen, Yafei Zhang, Yuankun Cai.
      Aim: To investigate the anticancer effects and action mechanism of graphene oxide (GO) in colorectal cancer (CRC). Materials & methods: Anticancer effects and mechanisms of GO in CRC were investigated both in vivo and in vitro. Results: GO significantly inhibited tumor growth both in vitro and in vivo. GO was able to enter HCT116 cells through endocytosis. GO treatment resulted in cytotoxicity, reactive oxygen species (ROS) production, apoptosis, autophagy and activation of the AMPK/mTOR/ULK1 signal pathway. However, ROS scavenger N-acetylcysteine (NAC) attenuated the above effects and restored the effects of GO on protein expressions related to apoptosis, autophagy and AMPK/mTOR/ULK1 signal pathways. Conclusion: GO exerts anticancer effects against CRC via ROS-dependent AMPK/mTOR/ULK-1 pathway-related autophagy and apoptosis.
    Keywords:  apoptosis; autophagy; colorectal cancer; graphene oxide; reactive oxygen species
    DOI:  https://doi.org/10.2217/nnm-2022-0030
  81. Nanomedicine. 2022 Apr 04. pii: S1549-9634(22)00043-0. [Epub ahead of print] 102557
    A nanotherapy responsive to the inflammatory microenvironment for the dual-targeted treatment of atherosclerosis.
    Ge Li, Fei Xu, Bo Yang, Xinyue Lu, Xiangyu Li, Yanfei Qi, Lesheng Teng, Youxin Li, Fengying Sun, Wenhua Liu.
      Atherosclerosis remains the main cause of death and disability, as well as a leading cause of coronary arterial disease. Inflammation is one of the pathogenic factors of arteriosclerosis; however, the current treatments based on lowering the level of inflammation in the plaque tissue of patients with atherosclerosis are not clinically used. Herein, we hypothesize that αvβ3 receptor affinity and low pH sensitivity may be regarded as a valid therapeutic strategy for targeting sites of atherosclerosis according to the microenvironments of inflammation. To prove this tentative hypothesis, an acid-labile material polyketal named PK3 was synthesized, and the cRGDfc peptide was used to modify nanoparticles composed of poly(lactide-co-glycolide) (PLGA), lecithin, and PK3, loaded with the anti-atherosclerotic drug rapamycin (RAP). The nanoparticles were prepared using an O/W method and then characterized, which showed an appropriate particle size and fulfilling responsive behaviors. In vitro release studies and stability tests showed that these nanoparticles can be effectively internalized by human umbilical vein endothelial cells (HUVECs), and also show a good in vitro anti-inflammatory effect. After intravenous (i.v.) injection, RGD targeted by pH-responsive nanotherapy (RAP-Nps-RGD) may be accumulated at the plaque site in ApoE-/- mice with atherosclerosis and can effectively attenuate plaque progression compared to other formulations. Moreover, its good safety profile and biocompatibility have been revealed in both in vitro and in vivo estimations. Accordingly, the prospect of nanoparticles responsive to the inflammatory microenvironment for preventing atherosclerotic through inflammation modulation provides great feasibility for the administration of alternate drug molecules to inflamed sites to slow down the process of arteriosclerosis.
    Keywords:  Atherosclerosis; Drug delivery; Inflammation; Responsive nanoparticle; Targeted therapy
    DOI:  https://doi.org/10.1016/j.nano.2022.102557
  82. Bioact Mater. 2022 Oct;16 47-56
    Formulation of pH-responsive PEGylated nanoparticles with high drug loading capacity and programmable drug release for enhanced antibacterial activity.
    Dawei Li, Guoke Tang, Hui Yao, Yuqi Zhu, Changgui Shi, Qiang Fu, Fei Yang, Xing Wang.
      In the current global crisis of antibiotic resistance, delivery systems are emerging to combat resistant bacteria in a more efficient manner. Despite the significant advances of antibiotic nanocarriers, many challenges like poor biocompatibility, premature drug release, suboptimal targeting to infection sites and short blood circulation time are still challenging. To achieve targeted drug delivery and enhance antibacterial activity, here we reported a kind of pH-responsive nanoparticles by simply self-assembly of an amphiphilic poly(ethylene glycol)-Schiff-vancomycin (PEG-Schiff-Van) prodrug and free Van in one drug delivery system. The acid-liable Schiff base furnished the PEG-Schiff-Van@Van with good storage stability in the neutral environment and susceptible disassembly in response to faintly acidic condition. Notably, on account of the combination of physical encapsulation and chemical conjugation of vancomycin, these nanocarriers with favorable biocompatibility and high drug loading capacity displayed a programmed drug release behavior, which was capable of rapidly reaching high drug concentration to effectively kill the bacteria at an early period and continuously exerting an bacteria-sensitive effect whenever needed over a long period. In addition, more Schiff-base moieties within the PEG-Schiff-Van@Van nanocarriers may also make great contributions on promoting the antimicrobial activity. Using this strategy, this system was designed to have programmable structural destabilization and sequential drug release due to changes in pH that were synonymous with bacterial infection sites, thereby presenting prominent antibacterial therapy both in vitro and in vivo. This work represents a synergistic strategy on offering important guidance to rational design of multifunctional antimicrobial vehicles, which would be a promising class of antimicrobial materials for potential clinical translation.
    Keywords:  Antibacterial activity; PEGylated; Programmable drug release; Schiff base; pH-responsive prodrug
    DOI:  https://doi.org/10.1016/j.bioactmat.2022.02.018
  83. Pharmacol Res. 2022 Apr 01. pii: S1043-6618(22)00147-5. [Epub ahead of print] 106202
    An Overview of the Pharmacological Activities of Scopoletin against Different Chronic Diseases.
    Dey Parama, Sosmitha Girisa, Elina Khatoon, Aviral Kumar, Mohammed S Alqahtani, Mohamed Abbas, Gautam Sethi, Ajaikumar B Kunnumakkara.
      Chronic diseases are considered a major public health concern worldwide, and most of these diseases like cancer, cardiovascular, metabolic, and neurological disorders occur due to atypical regulation of multiple signaling pathways. It has also been observed that most of the currently approved therapies for these diseases fail to show prolonged efficacy due to their mono-targeted nature and are also associated with the development of chemoresistance, thus restricting their utility. The plant-derived compounds, on the other hand, show multi-targeted nature, and thus these phytochemicals have gained wide attention as they offer negligible side effects. The present review aims to recapitulate the potential effects of one such phytochemical, Scopoletin, which was found to have a diverse range of pharmacological activities such as anti-cancer, anti-diabetic, anti-inflammatory, cardioprotective, hepatoprotective, etc. Scopoletin modulated multiple molecular signatures in cancer, including AMPK, EGFR, MAPK/ ERK, NF-κB, PI3K/Akt/ mTOR, and STAT3 and regulated the levels of critical markers of metabolic diseases such as ALT, AST, TG, and TC; inflammatory diseases such as ILs and TNFs; neurological diseases such as AChE, etc. thus relieving the symptoms and severity associated with these diseases. Further, this compound has a non-toxic nature and possesses an excellent pharmacokinetic property, which warrants further investigation in clinical settings for developing it as a potential drug.
    Keywords:  CVDs; Scopoletin; cancer; neurological diseases, metabolic diseases, inflammatory diseases
    DOI:  https://doi.org/10.1016/j.phrs.2022.106202
  84. AAPS PharmSciTech. 2022 Apr 05. 23(4): 106
    Design, Characterization, and Evaluation of Diosmetin-Loaded Solid Self-microemulsifying Drug Delivery System Prepared by Electrospray for Improved Bioavailability.
    Zhengqing Gu, Yuanyuan Xue, Shuang Li, Michael Adu-Frimpong, Ying Xu, Jiangnan Yu, Ximing Xu, Yuan Zhu.
      Diosmetin (DIOS) is a functional compound with poor water solubility, bad permeability, and crystal form. Self-microemulsifying drug delivery system (SMEDDS) was an effective formulation to overcome these shortcomings. In this study, liquid SMEDDS was prepared using Capmul® MCM C8 EP/NF, Cremophor EL, and PEG 400 (2:5.6:2.4, w/w/w) as excipients. Then, the novel technology of electrospray solidified liquid SMEDDS and prepared solid SMEDDS for inhibiting crystallization. Polyvinyl pyrrolidone (PVP) was used as carrier to construct DIOS-loaded solid SMEDDS, with polyethylene oxide (PEO) contributing to the formation of regular sphere in the process of spinning. The particle size of solid SMEDDS (194 ± 5 nm) was much bigger than of liquid SMEDDS (25 ± 1 nm), while DIOS-loaded solid SMEDDS showed greater dissolution rates in pH 1.2 and pH 6.8 media through in vitro drug release study. The solid nanoparticles were smooth and uniform from the graph of a scanning electron microscope (SEM). The graph of a transmission electron microscope (TEM) showed that small droplets were loaded in the matrix. Furthermore, DIOS was encapsulated by matrix in amorphous state via differential scanning calorimetry (DSC) and attenuated total reflection Fourier transform infrared (ATR-FTIR). The crystalline of DIOS was not formed in solid SMEDDS due to the characteristic peaks of DIOS disappeared in X-ray diffraction (XRD) pattern. Therefore, the oral bioavailability of DIOS improved significantly compared with liquid SMEDDS (4.27-fold). Hence, solid SMEDDS could improve the solubility and bioavailability of DIOS, through transfer of the state of crystalline to amorphous by electrospray technology.
    Keywords:  diosmetin; electrospray; oral bioavailability; self-microemulsifying drug delivery system (SMEDDS); solidification
    DOI:  https://doi.org/10.1208/s12249-022-02263-3
  85. Curr Drug Deliv. 2022 Apr 01.
    Exploring nose to brain nano delivery for effective management of migraine.
    Vidhi Tanna, Sujata P Sawarkar, Padmini Ravikumar.
      Migraine is a disabling disease, characterized by severe throbbing headache. Patients demand quick relief from this pain. The presence of blood brain barrier does not permit the drug to penetrate the brain effectively. Administration of conventional anti-migraine medications via oral route leads to erratic absorption of drugs. Delayed gastric emptying is also responsible for ineffective absorption of drug. Migraine induced nausea and vomiting, further limits patient compliance to oral medication. Other limitations associated with oral route include extensive first pass metabolism, slow onset of action, inability to cross blood brain barrier and requirement of large amount of dose/dosage and frequent administration. The anti-migraine drugs used in migraine like triptans are therapeutically effective but have low bioavaialability on oral administration. Also, these drugs are associated with several cardiovascular complications. The oral dose of most antimigraine drugs oral tritpans, Ergot amine, NSAIDs and CGRP antagonist is quite high because of their poor bioavailability. As a result of these drugs are associated with several side effects. This aspects necessitates the need of developing a dosage form that can deliver drug directly brain thereby reducing the dose. Use of invasive techniques to deliver these therapeutics to the brain do exist, however, they are painful, require expert assistance and are not cost-effective approach for migraine treatment. These limitations demand development of a novel non-invasive approach that is safe, efficacious and has high patient compliance. As, reported it is possible to target the brain tissue by administering the drug intranasally using olfactory and the trigeminal pathway. This route is non-invasive, avoids first-pass metabolism, eliminates nausea and vomiting, helps reduce dose, and thus helps achieve increase patient compliance. Some factors like solubility, lipophilicity of the drug, mucociliary clearance, enzymatic degradation hinder the bioavailability of the drug by nasal route. Therefore, there is a grave need to develop novel nasal formulations with prolonged nasal residence time, which can modulate pharmacokinetics for adequate therapeutic response, and render efficient yet robust brain targeting. It is necessary to consider these challenges in developing efficient intranasal dosage form. This review gives a brief overview of all the novel carriers reported for improving the treatment of migraine. Nanocarrier based delivery systems like in-situ gels, micro emulsion, nanoemulsion, nanoparticles, vesicular systems, micelles, and microspheres used in nose to brain delivery of migraine therapeutics are also discussed in the article.
    Keywords:  Migraine; brain targeting; intranasal; nanocarriers; nose-to-brain drug delivery; olfactory pathway; trigeminal pathway
    DOI:  https://doi.org/10.2174/1567201819666220401091632
  86. Adv Sci (Weinh). 2022 Apr 07. e2200731
    Wirelessly Activated Nanotherapeutics for In Vivo Programmable Photodynamic-Chemotherapy of Orthotopic Bladder Cancer.
    Bowen Sun, Juwita Norasmara Bte Rahmat, Han Joon Kim, Ratha Mahendran, Kesavan Esuvaranathan, Edmund Chiong, John S Ho, Koon Gee Neoh, Yong Zhang.
      Photochemical internalization (PCI) is a promising intervention using photodynamic therapy (PDT) to enhance the activity of chemotherapeutic drugs. However, current bladder cancer treatments involve high-dose chemotherapy and high-irradiance PDT which cause debilitating side effects. Moreover, low penetration of light and drugs in target tissues and cumbersome light delivery procedures hinder the clinical utility of PDT and chemotherapy combination for PCI. To circumvent these challenges, a photodynamic-chemotherapy approach is developed comprising tumor-targeting glycosylated nanocarriers, coloaded with chlorin e6 (Ce6) and gemcitabine elaidate (GemE), and a miniaturized implantable wirelessly powered light-emitting diode (LED) as a light source. The device successfully delivers four weekly light doses to the bladder while the nanocarrier promoted the specific accumulation of drugs in tumors. This approach facilitates the combination of low-irradiance PDT (1 mW cm-2 ) and low-dose chemotherapy (≈1500× lower than clinical dose) which significantly cures and controls orthotopic disease burden (90% treated vs control, 35%) in mice, demonstrating a potential new bladder cancer treatment option.
    Keywords:  bladder cancer; photodynamic therapy; targeted drug delivery; wireless photonics
    DOI:  https://doi.org/10.1002/advs.202200731
  87. Front Chem. 2022 ;10 881812
    Bioresponsive Nanomaterials: Recent Advances in Cancer Multimodal Imaging and Imaging-Guided Therapy.
    Zeng Zeng, Huali Gao, CongXian Chen, Lianbo Xiao, Kun Zhang.
      Cancer is a serious health problem which increasingly causes morbidity and mortality worldwide. It causes abnormal and uncontrolled cell division. Traditional cancer treatments include surgery, chemotherapy, radiotherapy and so on. These traditional therapies suffer from high toxicity and arouse safety concern in normal area and have difficulty in accurately targeting tumour. Recently, a variety of nanomaterials could be used for cancer diagnosis and therapy. Nanomaterials have several advantages, e.g., high concentration in tumour via targeting design, reduced toxicity in normal area and controlled drug release after various rational designs. They can combine with many types of biomaterials in order to improve biocompatibility. In this review, we outlined the latest research on the use of bioresponsive nanomaterials for various cancer imaging modalities (magnetic resonance imaging, positron emission tomography and phototacoustic imaging) and imaging-guided therapy means (chemotherapy, radiotherapy, photothermal therapy and photodynamic therapy), followed by discussing the challenges and future perspectives of this bioresponsive nanomaterials in biomedicine.
    Keywords:  cancer; imaging; nanomaterials; photodynamic therapy; photothemal
    DOI:  https://doi.org/10.3389/fchem.2022.881812
  88. Cardiovasc Res. 2022 Apr 07. pii: cvac058. [Epub ahead of print]
    Metaboloepigenetics in cancer, immunity and cardiovascular disease.
    Samuel T Keating, Assam El-Osta.
      The influence of cellular metabolism on epigenetic pathways are well documented but misunderstood. Scientists have long known of the metabolic impact on epigenetic determinants. More often than not, that title role for DNA methylation was portrayed by the metabolite SAM or S-adenosylmethionine. Technically speaking there are many other metabolites that drive epigenetic processes that instruct seemingly distant - yet highly connect pathways - and none more so than our understanding of the cancer epigenome. Recent studies have shown that available energy link the extracellular environment to influence cellular responses. This focused review examines the recent interest in epigenomics and casts cancer, metabolism and immunity in unfamiliar roles - cooperating. There are not only language lessons from cancer research, we have come round to appreciate that reaching into areas previously thought of as too distinct are also object lessons in understanding health and disease. The Warburg effect is one such signature of how glycolysis influences metabolic shift during oncogenesis. That shift in metabolism - now recognised as central to proliferation in cancer biology - influence core enzymes that not only control gene expression but are also central to replication, condensation and the repair of nucleic acid. These nuclear processes rely on metabolism and with glucose at center stage the role of respiration and oxidative metabolism are now synonymous with the mitochondria as the powerhouses of metaboloepigenetics. The emerging evidence for metaboloepigenetics in trained innate immunity has revealed recognisable signalling pathways with antecedent extracellular stimulation. With due consideration to immunometabolism we discuss the striking signalling similarities influencing these core pathways. The immunometabolic-epigenetic axis in cardiovascular disease has deeply etched connections with inflammation and we examine the chromatin template as a carrier of epigenetic indices that determine the expression of genes influencing atherosclerosis and vascular complications of diabetes.
    Keywords:  Metabolism; cardiovascular disease; diabetes; epigenetics; glycolysis; metaboloepigenetics; trained immunity
    DOI:  https://doi.org/10.1093/cvr/cvac058
  89. Nanomedicine. 2022 Apr 04. pii: S1549-9634(22)00041-7. [Epub ahead of print] 102555
    Fabrication of tumor targeting rare-earth nanocrystals for real-time NIR-IIb fluorescence imaging-guided breast Cancer precise surgery.
    Kang-Liang Lou, Pei-Yuan Wang, Rui-Qin Yang, Yi-Yang Gao, Hai-Na Tian, Yong-Ying Dang, Yang Li, Wen-He Huang, Min-Chen, Xiao-Long Liu, Guo-Jun Zhang.
      The near-infrared fluorescence imaging has been integrated into the operating room to guide tumor resection, potentially reducing the positive margin rates in breast-conserving surgery (BCS). Relative to the wildly used first near-infrared fluorescence imaging, imaging in the second near-infrared (NIR-II) region possesses higher contrast and deeper tissue penetration, particularly in the NIR-IIb window, offering many new opportunities for imaging-guided BCS. Here, we fabricate the c(RGDfC) functionalized erbium-based rare-earth nanoparticles (ErNPs@cRGD) with superior optical property in NIR-IIb region. Owing to deeper tissue penetration and efficient tumor targeting, ErNPs@cRGD-based NIR-IIb fluorescence imaging achieved enhanced signal-to-background ratios in tumor visualization, which was able to guide more complete tumor resection, identify multiple microtumors and distinguish malignant lesions from normal tissues in various mice models. Based on these, this NIR-IIb imaging strategy for surgical navigation can significantly reduce positive margin rates and improve prognosis, laying a foundation for the clinical resection of breast cancer.
    Keywords:  Breast cancer; Imaging-guided tumor surgery; NIR-IIb fluorescence imaging; Rare-earth nanoparticles; Surgical navigation
    DOI:  https://doi.org/10.1016/j.nano.2022.102555
  90. Front Genet. 2022 ;13 841639
    Cholesterol-Lowering Phytochemicals: Targeting the Mevalonate Pathway for Anticancer Interventions.
    Kagiso Laka, Lilian Makgoo, Zukile Mbita.
      There are a plethora of cancer causes and the road to fully understanding the carcinogenesis process remains a dream that keeps changing. However, a list of role players that are implicated in the carcinogens process is getting lengthier. Cholesterol is known as bad sterol that is heavily linked with cardiovascular diseases; however, it is also comprehensively associated with carcinogenesis. There is an extensive list of strategies that have been used to lower cholesterol; nevertheless, the need to find better and effective strategies remains vastly important. The role played by cholesterol in the induction of the carcinogenesis process has attracted huge interest in recent years. Phytochemicals can be dubbed as magic tramp cards that humans could exploit for lowering cancer-causing cholesterol. Additionally, the mechanisms that are regulated by phytochemicals can be targeted for anticancer drug development. One of the key role players in cancer development and suppression, Tumour Protein 53 (TP53), is crucial in regulating the biogenesis of cholesterol and is targeted by several phytochemicals. This minireview covers the role of p53 in the mevalonate pathway and how bioactive phytochemicals target the mevalonate pathway and promote p53-dependent anticancer activities.
    Keywords:  cancer; cholesterol; mevalonate pathway; p53; phytochemicals
    DOI:  https://doi.org/10.3389/fgene.2022.841639
  91. Cancer Biol Ther. 2022 Dec 31. 23(1): 254-264
    Epigenetic drugs induce the potency of classic chemotherapy, suppress post-treatment re-growth of breast cancer, but preserve the wound healing ability of stem cells.
    Andrew Zheng, Michelle Bilbao, Janhvi Sookram, Kimberly M Linden, Andrew B Morgan, Olga Ostrovsky.
      Epigenetic therapy augments neoadjuvant chemotherapy (NACT) in breast cancer and may aid post-surgical wound healing affected by NACT. Our study investigates: (1) The cytotoxicity of classic paclitaxel chemotherapy on triple negative breast cancer (TNBC) independently and in combination with epigenetic drugs. (2) The sustainable inhibition of breast cancer regrowth following paclitaxel and epigenetic therapies. (3) The effects of paclitaxel with and without epigenetic therapy on the post-treatment viability and wound healing potential of adipose stem cells (ASCs). Cytotoxicity assays were performed on TNBC and ASCs. Cells were treated and recovered in drug-free medium. Cell viability was measured via cell counts and MTT assays. W -ound healing was tested with scratch assays. The combination of epigenetic drugs shows increased toxicity against TNBC cells compared to standard chemotherapy alone. Moreover, the combination of paclitaxel with epigenetic treatments causes cancer toxicity that is sustainable to TNBC cells after the drugs' removal with minimal effect on ASCs wound healing ability. The use of epigenetic drugs in addition to standard chemotherapy is cytotoxic to TNBC cells and prevents post-treatment recovery of TNBC while maintaining ASC wound healing ability. This strategy may be useful in maximizing post-surgical wound healing following NACT in TNBC.
    Keywords:  Triple negative breast cancer; adipose-derived stem cells; breast conserving therapy; epigenetic drugs; neoadjuvant chemotherapy; wound healing
    DOI:  https://doi.org/10.1080/15384047.2022.2052540
  92. Appl Biochem Biotechnol. 2022 Apr 07.
    Flavored Food Additives on the Leaves of Piper betle L.: A Human Health Perspective.
    Biswajit Patra, Saroj Kumar Deep, Rosina Rosalin, Surya Narayan Pradhan.
      Natural products and traditional ethnomedicines are of great effect in therapeutics. Such types of medicine have been practiced in certain areas of the world to treat different health conditions. This pilot investigation aims to review the cumulative health effect of addendums used in betel quid such as areca nut, lime, and tobacco-associated betel quid chewing and without tobacco-associated chewing. This review shows that betel leaf extract and its essential oil could inhibit growth of microbes and damage different gram-positive and gram-negative bacteria as well as various fungus species. Some studies concluded that the combination of Piper leaves essential oil with antibiotics have potential effect on oral microorganisms. Long-term consumption of betel quid with tobacco is known to cause cancer, chromosomal aberrations, and pharynx tumors. However, consumption of betel leaf without tobacco has health benefits because of ethnomedicinal properties. Its essential is oil utilized as raw material for perfumes and mouth fresheners manufacturing. Scientific researches on this plant revealed that it possesses many beneficial activities to be used for developing novel drugs. However, compounds of betel leaves have beneficial natural antioxidant. Chewing and intake of leaves have effect on moving parts of salivary gland which is the main step of digestion. Its components also act as heartbeat regulators in relaxing the blood vessels to reduce hypertension. So this review discussed the natural compounds of betel leaves which is used as traditional medicine to further develop drug discovery.
    Keywords:  Betel quid; Drug discovery; Essential oil; Therapeutics; Tobacco conjugate
    DOI:  https://doi.org/10.1007/s12010-022-03912-w
  93. Drug Deliv. 2022 Dec;29(1): 1112-1121
    In vitro and in vivo characterization of Entacapone-loaded nanostructured lipid carriers developed by quality-by-design approach.
    Yogeeta Agrawal, Kiran Patil, Hitendra Mahajan, Mrugendra Potdar, Pratiksha Joshi, Kartik Nakhate, Charu Sharma, Sameer N Goyal, Shreesh Ojha.
      Entacapone, a reversible catechol-o-methyl transferase inhibitor, is used to enhance the action of dopamine agonists by reducing their metabolism and the 'Wearing-off' effects associated with long-term use in the treatment of Parkinson's disease. It is used as an adjunct to levodopa/Carbidopa therapy. Due to limited dissolution and first-pass clearance, it suffers low and variable bioavailability issues. To overcome this problem, the present study aims to explore the potential of nanostructured lipid carriers (NLCs) for the delivery of Entacapone. The Quality by Design (QbD) approach was used for the systematic development of NLCs. The 23 full factorial designs were investigated using Design-Expert®11 software. The three independent variables namely content of total lipid (X1), surfactant (X2), and sonication time (X3) were optimized against two responses namely particle size and entrapment efficiency. The optimized NLCs were characterized for their size, surface morphology, entrapment efficiency, drug release, thermal and crystallographic studies. In-vivo pharmacokinetic studies in Entacapone-loaded NLCs showed an increase in t1/2, AUC0-∞, MRT compared to free drug. The reduction in elimination (Kel) depicts the prolonged action of Entacapone by loading in NLCs. The results displayed Entacapone-loaded NLCs have promising potential for oral delivery and enhanced therapeutic effect which otherwise was a major issue.
    Keywords:  Entacapone; Parkinson's disease; nanostructured lipid carriers; quality by design
    DOI:  https://doi.org/10.1080/10717544.2022.2058651
  94. Bioact Mater. 2022 Nov;17 125-146
    Gallium containing bioactive materials: A review of anticancer, antibacterial, and osteogenic properties.
    Fatih Kurtuldu, Nurshen Mutlu, Aldo R Boccaccini, Dušan Galusek.
      The incorporation of gallium into bioactive materials has been reported to enhance osteogenesis, to influence blood clotting, and to induce anti-cancer and anti-bacterial activity. Gallium-doped biomaterials prepared by various techniques include melt-derived and sol-gel-derived bioactive glasses, calcium phosphate bioceramics, metals and coatings. In this review, we summarize the recently reported developments in antibacterial, anticancer, osteogenesis, and hemostasis properties of Ga-doped biomaterials and briefly outline the mechanisms leading to Ga biological effects. The key finding is that gallium addition to biomaterials has great potential for treating bone-related diseases since it can be efficiently transferred to the desired region at a controllable rate. Besides, it can be used as a potential substitute for antibiotics for the inhibition of infections during the initial and advanced phases of the wound healing process. Ga is also used as an anticancer agent due to the increased concentration of gallium around excessive cell proliferation (tumor) sites. Moreover, we highlight the possibility to design different therapeutic approaches aimed at increasing the efficiency of the use of gallium containing bioactive materials for multifunctional applications.
    Keywords:  Antibacterial; Bioactive materials; Cancer treatment; Hemostasis; Osteogenesis
    DOI:  https://doi.org/10.1016/j.bioactmat.2021.12.034
  95. Crit Rev Ther Drug Carrier Syst. 2022 ;39(3): 1-44
    Getting into the Brain: Are We in Yet or Just Knocking at the Door?
    Kalpana Nagpal, Dhirender Singh, Amit Bhatia, Pradeep Kumar.
      Nanomedicine, a promising addition to the spectrum of biomedicine, has viewed countless breakthroughs in the implementations of "site-specific" drug delivery. The promises of nanomedicines revolve around their unique physicochemical properties that permit the transport of therapeutics to the desired site of action, improve the pharmacokinetic endpoint, maximize the pharmacological influence of treatment, and overcome the limitation of remedies that otherwise would impede the therapeutic effectiveness. One of most insurmountable challenge possessed by conventional drug-delivery in getting therapeutics across the central-nervous-system is to conquer the harsh passage of the blood-brain barrier (BBB). Many published studies revealed BBB to be a complex, dynamic interface that acclimatizes to the needs of the central nervous system (CNS). These physical and biochemical barriers pose a significant challenge to the effective management of brain-related disorders such as neurodegenerative diseases. This challenge is widely accepted and defeated with the advent of a new class of brain-targeted nanomedicines. This review is an effort to overview the key research trends in nanotechnology over the past decade concerning the BBB as a regulatory interface and factors affecting CNS drug delivery. The review further summarized the specific diversity of various nanomedicinal approaches, the critical and elementary structural component of their design, the surface engineering of vehicles carrying drug at the nanoscale, selected current clinical successes, and future prospects along with hidden perils.
    DOI:  https://doi.org/10.1615/CritRevTherDrugCarrierSyst.2021038918
  96. Int J Immunopathol Pharmacol. 2022 Jan-Dec;36:36 3946320221086079
    Evodiamine suppresses the progression of non-small cell lung carcinoma via endoplasmic reticulum stress-mediated apoptosis pathway in vivo and in vitro.
    Yuting Li, Yuming Wang, Xiaoqun Wang, Lulu Jin, Lu Yang, Jinli Zhu, Hongwu Wang, Fang Zheng, Huantian Cui, Xiaojiang Li, Yingjie Jia.
       BACKGROUND: Evodiamine (EVO) is one of the major components isolated from Evodia rutaecarpa (Juss.). Recent studies have shown that EVO has an anti-cancer effect. However, the pharmacological mechanism by which EVO impacts cancer is still poorly understood.
    OBJECTIVES: This study focused on asking the anti-cancer effect of EVO in human non-small cell lung carcinoma (NSCLC), and in particular to investigate whether EVO acts via modulating the endoplasmic reticulum stress (ERS)-mediated apoptosis pathway.
    MATERIALS AND METHODS: A Lewis lung carcinoma (LLC) tumor-bearing mouse model was treated with low-dose EVO (5 mg/kg) and high-dose EVO (10 mg/kg) intraperitoneally for 14 d. The effects of EVO on tumor growth, apoptosis, and ERS were assessed. In addition, NSCLC A549 and LLC cells were treated with EVO in vitro. The effects of EVO on cell proliferation, apoptosis, and ERS were investigated. Finally, 4-phenylbutyric acid (4-PBA), an ERS inhibitor, was used to validate whether EVO induced apoptosis of NSCLC cells by modulating ERS.
    RESULTS: EVO treatment significantly inhibited tumor growth in LLC tumor-bearing mice. H&E staining indicated that EVO treatment reduced the number of tumor cells and the nucleo-plasmic ratio. Immunostaining showed that EVO treatment significantly decreased the expression of Ki-67. TUNEL staining revealed that EVO induced apoptosis in the tumor. Likewise, EVO treatment up-regulated the expression of apoptosis-related genes and proteins and increased activation of the ERS pathway in the tumor. Additionally, EVO inhibited cell proliferation and increased cell apoptotic rates in A549 and LLC cells. EVO also increased the expression levels of genes and proteins associated with ERS-mediated apoptosis pathway in vitro. The effects of EVO on apoptosis were abolished by 4-PBA treatment.
    CONCLUSIONS: Our study demonstrated that EVO suppresses the progression of NSCLC by modulating the ERS-mediated apoptosis pathway.
    Keywords:  A549 cells; Evodiamine; apoptosis; endoplasmic reticulum stress; lewis lung carcinoma cells; non-small cell lung carcinoma
    DOI:  https://doi.org/10.1177/03946320221086079
  97. Compr Rev Food Sci Food Saf. 2022 Apr 05.
    Vitamin A fortification: Recent advances in encapsulation technologies.
    Vaibhav Kumar Maurya, Amita Shakya, Khalid Bashir, Satish Chand Kushwaha, David Julian McClements.
      Vitamin A is an essential micronutrient whose deficiency is still a major health concern in many regions of the world. It plays an essential role in human growth and development, immunity, and vision, but may also help prevent several other chronic diseases. The total amount of vitamin A in the human diet often falls below the recommended dietary allowance of approximately 900-1000 μ$ \umu $ g/day for a healthy adult. Moreover, a significant proportion of vitamin A may be degraded during food processing, storage, and distribution, thereby reducing its bioactivity. Finally, the vitamin A in some foods has a relatively low bioavailability, which further reduces its efficacy. The World Health Organization has recommended fortification of foods and beverages as a safe and cost-effective means of addressing vitamin A deficiency. However, there are several factors that must be overcome before effective fortified foods can be developed, including the low solubility, chemical stability, and bioavailability of this oil-soluble vitamin. Consequently, strategies are required to evenly disperse the vitamin throughout food matrices, to inhibit its chemical degradation, to avoid any adverse interactions with any other food components, to ensure the food is palatable, and to increase its bioavailability. In this review article, we discuss the chemical, physical, and nutritional attributes of vitamin A, its main dietary sources, the factors contributing to its current deficiency, and various strategies to address these deficiencies, including diet diversification, biofortification, and food fortification.
    Keywords:  bioavailability; delivery systems; encapsulation; fortification; vitamin A; vitamin A deficiency
    DOI:  https://doi.org/10.1111/1541-4337.12941
  98. Bioact Mater. 2022 Oct;16 418-432
    Biomimetic nanoparticles directly remodel immunosuppressive microenvironment for boosting glioblastoma immunotherapy.
    Tingting Wang, Hao Zhang, Weibao Qiu, Yaobao Han, Hanghang Liu, Zhen Li.
      Glioblastoma (GBM), as a very aggressive cancer of central nervous system, is very challenging to completely cure by the conventional combination of surgical resection with radiotherapy and chemotherapy. The success of emerging immunotherapy in hot tumors has attracted considerable interest for the treatment of GBM, but the unique tumor immunosuppressive microenvironment (TIME) of GBM leads to the failure of immunotherapy. Here, we show the significant improvement of the immunotherapy efficacy of GBM by modulating the TIME through novel all-in-one biomimetic nanoparticles (i.e. CS-I/J@CM NPs). The nanoparticles consist of utrasmall Cu2-x Se nanoparticles (NPs) with outstanding intrinsic properties (e.g., photo-responsive Fenton-like catalytic property for inducing immunogenic cell death (ICD) and alleviating the hypoxia of tumor), indoximod (IND, an inhibitor of indoleamine-2,3-dioxygenease in tumor), JQ1 (an inhibitor for reducing the expression of PD-L1 by tumor cells), and tumor cell membrane for improving the targeting capability and accumulation of nanoparticles in tumor. We reveal that these smart CS-I/J@CM NPs could drastically activate the immune responses through remodeling TIME of GBM by multiple functions. They could (1) increase M1-phenotype macrophages at tumor site by promoting the polarization of tumor-associated macrophages through the reactive oxygen species (ROS) and oxygen generated from the Fenton-like reaction between nanoparticles and H2O2 within tumor under NIR II irradiation; (2) decrease the infiltration of Tregs cells at tumor site through the release of IND; (3) decrease the expression of PD-L1 on tumor cells through JQ1. The notable increments of anti-tumor CD8+T cells in the tumor and memory T cells (TEM) in the spleen show excellent therapy efficacy and effectively prevent the recurrence of GBM after modulation of the TIME. This work demonstrates the modulation of TIME could be a significant strategy to improve the immunotherapy of GBM and other cold tumors.
    Keywords:  Glioblastoma; Immune checkpoint blockade therapy; Immunotherapy; Tumor immune microenvironment; Ultrasmall copper selenide nanoparticles
    DOI:  https://doi.org/10.1016/j.bioactmat.2021.12.029
  99. Chem Pharm Bull (Tokyo). 2022 ;70(4): 304-308
    Isolation of Natural Prodrug-Like Metabolite by Simulating Human Prodrug Activation in Filamentous Fungus.
    Takumi Okamoto, Shinji Kishimoto, Kenji Watanabe.
      Prodrugs have seen increased clinical applications as therapeutic agents, as they reduce undesirable side effects and improve the therapeutic potential of drugs. While microorganisms produce numerous secondary metabolites with useful medicinal properties, there are only a handful of naturally occurring prodrugs discovered to date. The techniques of isolating secondary metabolites with therapeutic potential from natural product producers have been developed extensively over the years. However, the methods of identifying prodrugs from microbes have not been examined in depth, partly because prodrug-type compounds inherently lack the biological activities that are often used to screen for therapeutically useful secondary metabolites. Therefore, we hypothesized that the difficulty in searching for natural prodrug-type compounds may be addressed by simulating human prodrug activation within natural product-producing microbes. We chose to introduce human CYP (hCYP) into natural product-producing filamentous fungi, because hCYPs are the key enzymes that activate prodrugs in human body, and filamentous fungi are known to be prolific producers of a wide variety of natural products. Here, we successfully identified a cytotoxic, antibiotic and potential anti-diabetic natural product leporin B from Aspergillus flavus that was previously not known to produce this compound. Through bioinformatic and metabolite analyses, we identified the prodrug-equivalent compound leporin C that is converted into leporin B by the action of the hCYP isoenzyme 3A4. By employing various prodrug-activating enzymes and microbes that biosynthesize diverse arrays of natural products, we should be able to probe wider biosynthetic space for identification of interesting prodrug-type natural products.
    Keywords:  CYP; natural product biosynthesis; prodrug strategy
    DOI:  https://doi.org/10.1248/cpb.c21-01099
  100. J Healthc Eng. 2022 ;2022 1620802
    Antitumor Effects of 10058-F4 and Curcumin in Combination Therapy for Pancreatic Cancer In Vitro and In Vivo.
    Zhang Jie, Zhang Jinna, Zhang Jingjun, Li Pengcheng, Yang Fang, Chen Qinyang, Chen Taiyu, Jiang Hequn, Ren Tao.
       Background: Pancreatic cancer (PC) stands out as one of the most lethal cancers. Due to late diagnosis, only a fraction of patients can be resected. Although it still has significant adverse effects and poor results, the treatment is connected with better overall survival than the prior treatment. Thus, new alternative therapy for advanced PC is needed. Materials/Methods. The impact of 10058-F4 and curcumin combination therapy on apoptosis and cell growth in SW1990 pancreatic cancer cells were determined in vitro using the CCK-8 assay and flow cytometry of Annexin V-FITC/PI, and the in vivo antitumor effect was determined utilizing SW1990-bearing pancreatic tumor mouse models induced by subcutaneous implantation.
    Results: At concentrations of (10 mol/L+2 mol/L), 10058-F4+curcumin obtained the highest rate of SW1990 cell death, and they had a beneficial effect on SW1990 pancreatic tumor-bearing animals. Furthermore, c-Myc, Akt phosphorylation, and the expression of apoptosis-related molecular were reduced, and the combination therapy modified the expression of apoptosis-related molecular.
    Conclusions: In vitro and in vivo, the combination of 10058-F4 plus curcumin has antipancreatic cancer actions that are substantially effective.
    DOI:  https://doi.org/10.1155/2022/1620802
  101. Bioorg Med Chem. 2022 Apr 01. pii: S0968-0896(22)00131-6. [Epub ahead of print] 116739
    Synthesis of novel dual target inhibitors of PARP and EGFR and their antitumor activities in triple negative breast cancers.
    Shanshan Lin, Xiao Zhang, Zelei Yu, Xiuwang Huang, Jianhua Xu, Yang Liu, Lixian Wu.
      The therapeutic strategy of poly (ADP-ribose) polymerase (PARP) inhibition of BRCA1/2 mutant cancers has been overwhelmingly successful, however, the highly aggressive triple negative breast cancers (TNBC) that receptor protein tyrosine kinase (RTKs) is known to be overexpressed are not sensitive to PARP inhibitors. Our research focused on exploring PARP inhibitors incorporating a bicyclic tetrahydropyridine pyrimidine. All synthesized compounds were more potent than Olaparib (ola) in killing tumor cells, especially in TNBC. Furthermore, compound 7 exhibited strong inhibitory effects on PARP enzymatic activity, moreover, the expression of EGFR and phosphorylated EGFR was inhibited by compound 7. Therefore, compound 7 can effectively inhibit TNBC cells with high expression of EGFR. In addition, significant synergistic effect of anti-tumor effect of new PARP inhibitors and adriamycin was also observed.
    Keywords:  Antitumor; EGFR; PARP inhibitor; TNBC; Tetrahydropyrido[4,3d] pyrimidines
    DOI:  https://doi.org/10.1016/j.bmc.2022.116739
  102. Drug Deliv. 2022 Dec;29(1): 1142-1149
    Application of chitosan/alginate nanoparticle in oral drug delivery systems: prospects and challenges.
    Shangyong Li, Hui Zhang, Kaiwei Chen, Mengfei Jin, Son Hai Vu, Samil Jung, Ningning He, Zhou Zheng, Myeong-Sok Lee.
      Oral drug delivery systems (ODDSs) have various advantages of simple operation and few side effects. ODDSs are highly desirable for colon-targeted therapy (e.g. ulcerative colitis and colorectal cancer), as they improve therapeutic efficiency and reduce systemic toxicity. Chitosan/alginate nanoparticles (CANPs) show strong electrostatic interaction between the carboxyl group of alginates and the amino group of chitosan which leads to shrinkage and gel formation at low pH, thereby protecting the drugs from the gastrointestinal tract (GIT) and aggressive gastric environment. Meanwhile, CANPs as biocompatible polymer, show intestinal mucosal adhesion, which could extend the retention time of drugs on inflammatory sites. Recently, CANPs have attracted increasing interest as colon-targeted oral drug delivery system for intestinal diseases. The purpose of this review is to summarize the application and treatment of CANPs in intestinal diseases and insulin delivery. And then provide a future perspective of the potential and development direction of CANPs as colon-targeted ODDSs.
    Keywords:  Oral drug delivery; chitosan/alginate nanoparticle; colon cancer; insulin; ulcerative colitis
    DOI:  https://doi.org/10.1080/10717544.2022.2058646
  103. Cell Commun Signal. 2022 Apr 07. 20(1): 49
    Cancer combination therapies by angiogenesis inhibitors; a comprehensive review.
    Mohammad Javed Ansari, Dmitry Bokov, Alexander Markov, Abduladheem Turki Jalil, Mohammed Nader Shalaby, Wanich Suksatan, Supat Chupradit, Hasan S Al-Ghamdi, Navid Shomali, Amir Zamani, Ali Mohammadi, Mehdi Dadashpour.
      Abnormal vasculature is one of the most conspicuous traits of tumor tissue, largely contributing to tumor immune evasion. The deregulation mainly arises from the potentiated pro-angiogenic factors secretion and can also target immune cells' biological events, such as migration and activation. Owing to this fact, angiogenesis blockade therapy was established to fight cancer by eliminating the nutrient and oxygen supply to the malignant cells by impairing the vascular network. Given the dominant role of vascular-endothelium growth factor (VEGF) in the angiogenesis process, the well-known anti-angiogenic agents mainly depend on the targeting of its actions. However, cancer cells mainly show resistance to anti-angiogenic agents by several mechanisms, and also potentiated local invasiveness and also distant metastasis have been observed following their administration. Herein, we will focus on clinical developments of angiogenesis blockade therapy, more particular, in combination with other conventional treatments, such as immunotherapy, chemoradiotherapy, targeted therapy, and also cancer vaccines. Video abstract.
    Keywords:  Angiogenesis; Anti-angiogenic agents; Combination therapy; Resistance; Tumor
    DOI:  https://doi.org/10.1186/s12964-022-00838-y
  104. AAPS PharmSciTech. 2022 Apr 05. 23(4): 104
    Rethinking Breast Cancer Chemoprevention: Technological Advantages and Enhanced Performance of a Nanoethosomal-Based Hydrogel for Topical Administration of Fenretinide.
    Alexsandra Conceição Apolinário, Giovanna Cassone Salata, Marcelo Medina de Souza, Marlus Chorilli, Luciana Biagini Lopes.
      Herein, we developed an ethosomal hydrogel based on three types of ethosomes: simple, mixed (surfactant-based micelles and lipid vesicles) or binary (comprising two type of alcohols). Ethanol injection was employed for vesicles preparation, and sodium alginate, as gelling agent. We purposed the local-transdermal administration of the off-the-shelf retinoid fenretinide (FENR) for chemoprevention of breast cancer. Rheograms and flow index values for alginate dispersion (without ethosomes) and hydrogels containing simple, mixed or binary ethosomes suggested pseudoplastic behavior. An increase in the apparent viscosity was observed upon ethosome incorporation. The ethosomal hydrogel displayed increased bioadhesion compared to the alginate dispersion, suggesting that the lipid vesicles contribute to the gelling and bioadhesion processes. In the Hen's Egg Test-Chorioallantoic Membrane model, few spots of lysis and hemorrhage were observed for formulations containing simple (score of 2) and mixed vesicles (score 4), but not for the hydrogel based on the binary system, indicating its lower irritation potential. The binary ethosomal hydrogel provided a slower FENR in vitro release and delivered 2.6-fold less drug into viable skin layers compared to the ethosome dispersion, supporting the ability of the gel matrix to slow down drug release. The ethosomal hydrogel decreased by ~ five-fold the IC50 values of FENR in MCF-7 cells. In conclusion, binary ethosomal gels presented technological advantages, provided sustained drug release and skin penetration, and did not preclude drug cytotoxic effects, supporting their potential applicability as topical chemopreventive systems.
    Keywords:  Bioadhesion; Nanomedicine; Retinoid; Transdermal hydrogel
    DOI:  https://doi.org/10.1208/s12249-022-02257-1
  105. Bioact Mater. 2022 Nov;17 394-405
    Black Mn-containing layered double hydroxide coated magnesium alloy for osteosarcoma therapy, bacteria killing, and bone regeneration.
    Dongdong Zhang, Shi Cheng, Ji Tan, Juning Xie, Yu Zhang, Shuhan Chen, Huihui Du, Shi Qian, Yuqing Qiao, Feng Peng, Xuanyong Liu.
      Osteosarcoma (OS) tissue resection with distinctive bactericidal activity, followed by regeneration of bone defects, is a highly demanded clinical treatment. Biodegradable Mg-based implants with desirable osteopromotive and superior mechanical properties to polymers and ceramics are promising new platforms for treating bone-related diseases. Integration of biodegradation control, osteosarcoma destruction, anti-bacteria, and bone defect regeneration abilities on Mg-based implants by applying biosafe and facile strategy is a promising and challenging topic. Here, a black Mn-containing layered double hydroxide (LDH) nanosheet-modified Mg-based implants was developed. Benefiting from the distinctive capabilities of the constructed black LDH film, including near-infrared optical absorption and reactive oxygen species (ROS) generation in a tumor-specific microenvironment, the tumor cells and tissue could be effectively eliminated. Concomitant bacteria could be killed by localized hyperthermia. Furthermore, the enhanced corrosion resistance and synergistic biofunctions of Mn and Mg ions of the constructed black LDH-modified Mg implants significantly facilitated cell adhesion, spreading and proliferation and osteogenic differentiation in vitro, and accelerated bone regeneration in vivo. This work offers a new platform and feasible strategy for OS therapeutics and bone defect regeneration, which broadens the biomedical application of Mg-based alloys.
    Keywords:  Anti-bacterial; Anti-tumor; Biodegradable magnesium; Bone regeneration; Layered double hydroxides
    DOI:  https://doi.org/10.1016/j.bioactmat.2022.01.032
  106. Int J Pharm. 2022 Mar 31. pii: S0378-5173(22)00267-8. [Epub ahead of print] 121712
    Pectin coated Nanostructured Lipid Carriers for Targeted Piperine Delivery to Hepatocellular Carcinoma.
    Eman Mm Shehata, Mennatallah A Gowayed, Samar O El-Ganainy, Eman Sheta, Yosra Sr Elnaggar, Ossama Y Abdallah.
      Piperine (PIP) is a herbal drug with well-known anticancer activity against different types of cancer including hepatocellular carcinoma. However, low aqueous solubility and extensive first-pass metabolism limit its clinical use. In this study, positively charged PIP-loaded nanostructured lipid carriers (PIP-NLCs) were prepared via melt-emulsification and ultra-sonication method followed by pectin coating to get novel pectin-coated NLCs (PIP-P-NLCs) targeting hepatocellular carcinoma. Complete in vitro characterization was performed. In addition, cytotoxicity and cellular uptake of nanosystems in HepG2 cells were evaluated. Finally, in vivo anticancer activity was tested in the diethylnitrosamine-induced hepatocellular carcinoma mice model. Successful pectin coating was confirmed by an increased particle size of PIP-NLCs from 150.28±2.51 nm to 205.24±5.13 nm and revered Zeta potential from 33.34±3.52 mV to -27.63±2.05 mV. Nanosystems had high entrapment efficiency, good stability, spherical shape, and sustained drug release over 24 hours. Targeted P-NLCs enhanced the cytotoxicity and cellular uptake compared to untargeted NLCs. Furthermore, PIP-P-NLCs improved in vivo anticancer effect of PIP as proved by histological examination of liver tissues, suppression of liver enzymes and oxidative stress environment in the liver, and alteration of cell cycle regulators. To conclude, PIP-P-NLCs can act as a promising approach for targeted delivery of PIP to hepatocellular carcinoma.
    Keywords:  ASGPRs-targeting; hepatocellular carcinoma; nanostructured lipid carriers; pectin; piperine
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121712
  107. Appl Bionics Biomech. 2022 ;2022 6405400
    Preliminary Study on the Therapeutic Effect of Doxorubicin-Loaded Targeting Nanoparticles on Glioma.
    Weitu Lan, Hongguang Zhang, Bo Yang.
      Doxorubicin (DOX) is an anthracycline anticancer drug, which is often associated with drug resistance and cytotoxicity. More unfortunately, the biological barrier in the human environment can weaken the efficacy of DOX, such as the blood-brain barrier (BBB). This work attempts to make efforts to solve this problem. We used polyethylene glycol distearoylphosphatidylethanolamine (PEG-DSPE) as a nanocarrier and DOX as a model drug to construct a composite nanodrug (TF-PEG-DSPE/DOX NPs) by coupling transferrin (TF). The results of glioma experiments show that the nanodrug can effectively penetrate BBB to achieve an antitumor effect.
    DOI:  https://doi.org/10.1155/2022/6405400
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