bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022‒07‒03
72 papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development
  1. Therapeutic Targeting of Tumor Cells and Tumor Immune Microenvironment Vulnerabilities.
  2. Targeting Bone Tumor and Subcellular Endoplasmic Reticulum via Near Infrared II Fluorescent Polymer for Photodynamic-Immunotherapy to Break the Step-Reduction Delivery Dilemma.
  3. Metabolic plasticity of cancer cells.
  4. Remote Manipulation of ROS-Sensitive Calcium Channel Using Near-Infrared-Responsive Conjugated Oligomer Nanoparticles for Enhanced Tumor Therapy In Vivo.
  5. Folic acid conjugated PAMAM-modified mesoporous silica-coated superparamagnetic iron oxide nanoparticles for potential cancer therapy.
  6. Tumor-targeted/reduction-triggered composite multifunctional nanoparticles for breast cancer chemo-photothermal combinational therapy.
  7. PEGylated solid lipid nanoparticles functionalized by aptamer for targeted delivery of docetaxel in mice bearing C26 tumor.
  8. Phenylboronic Acid-Functionalized Copolypeptides: Facile Synthesis and Responsive Dual Anticancer Drug Release.
  9. Resveratrol and resveratrol nano-delivery systems in the treatment of inflammatory bowel disease.
  10. Allicin in Digestive System Cancer: From Biological Effects to Clinical Treatment.
  11. Exogenous iron impairs the anti-cancer effect of ascorbic acid both in vitro and in vivo.
  12. The combinational application of photodynamic therapy and nanotechnology in skin cancer treatment: A review.
  13. A mitochondria-targeting lipid-small molecule hybrid nanoparticle for imaging and therapy in an orthotopic glioma model.
  14. An Insight into Anticancer Effect of Propolis and Its Constituents: A Review of Molecular Mechanisms.
  15. pH-responsive dynamically cross-linked nanogels with effective endo-lysosomal escape for synergetic cancer therapy based on intracellular co-delivery of photosensitizers and proteins.
  16. PEGylated Prussian blue nanoparticles for modulating polyethyleneimine cytotoxicity and attenuating tumor hypoxia for dual-enhanced photodynamic therapy.
  17. Autophagy responsive intra-intercellular delivery nanoparticles for effective deep solid tumor penetration.
  18. Redox-dependent AMPK inactivation disrupts metabolic adaptation to glucose starvation in xCT-overexpressing cancer cells.
  19. Functional cRGD-Conjugated Polymer Prodrug for Targeted Drug Delivery to Liver Cancer Cells.
  20. Functional ligands for improving anticancer drug therapy: current status and applications to drug delivery systems.
  21. In vitro photodynamic therapy of methylene blue-loaded acetyl resistant starch nanoparticles.
  22. pH-responsive Mannose-modified ferrocene Metal-Organic frameworks with rare earth for Tumor-targeted synchronous Chemo/Chemodynamic therapy.
  23. Preclinical studies of the antitumor effect of curcumin-loaded polymeric nanocapsules: A systematic review and meta-analysis.
  24. Reactive Oxygen Species and Metabolism in Leukemia: A Dangerous Liaison.
  25. Advances in Hybrid Vesicular Based Drug Delivery Systems: Improved Biocompatibility, Targeting, Therapeutic Efficacy and Pharmacokinetics of Anticancer Drugs.
  26. The brilliance of nanoscience over cancer therapy: Novel promising nanotechnology-based methods for eradicating glioblastoma.
  27. Self-Emulsifying System Coloaded with Paclitaxel and Coix Seed Oil Deeply Penetrated to Enhance Efficacy of Cervical Cancer.
  28. Antimicrobial Peptide-Loaded Gelatinase-Responsive Photothermal Nanogel for the Treatment of Staphylococcus aureus-Infected Wounds.
  29. A MXene-derived redox homeostasis regulator perturbs the Nrf2 antioxidant program for reinforced sonodynamic therapy.
  30. Mechanisms of cancer cell killing by metformin: a review on different cell death pathways.
  31. Lactate: The Mediator of Metabolism and Immunosuppression.
  32. Metabolic reprogramming in hematological malignancies: advances and clinical perspectives.
  33. Multifunctional mesoporous silica nanoparticles for pH-response and photothermy enhanced osteosarcoma therapy.
  34. Flexible CuS-embedded human serum albumin hollow nanocapsules with peroxidase-like activity for synergistic sonodynamic and photothermal cancer therapy.
  35. Laccase-mediated synthesis of bioactive natural products and their analogues.
  36. Applications of nanocomposites based on zeolitic imidazolate framework-8 in photodynamic and synergistic anti-tumor therapy.
  37. Bioactive Natural Products against Systemic Arterial Hypertension: A Past 20-Year Systematic and Prospective Review.
  38. Mild Hyperthermia-Assisted ROS Scavenging Hydrogels Achieve Diabetic Wound Healing.
  39. Evaluating the effect of curcumin on the metacestode of Taenia crassiceps.
  40. Pinocembrin polymeric micellar drug delivery system: preparation, characterization and anti-hyperuricemic activity evaluation.
  41. Research Advances in Lotus Leaf as Chinese Dietary Herbal Medicine.
  42. Nonylphenol inhibited HIF-1alpha regulated aerobic glycolysis and induced ROS mediated apoptosis in rat Sertoli cells.
  43. Multifunctional amphiphilic peptide dendrimer as nonviral gene vectors for effective cancer therapy via combined gene/photodynamic therapies.
  44. Nanomaterial for Diagnosis and Treatment for Lung Cancer: A Review of Recent Patents.
  45. MicroRNA-219 loaded chitosan nanoparticles for treatment of glioblastoma.
  46. Melatonin as an adjuvant treatment modality with doxorubicin.
  47. A review of transglycosylated compounds as food additives to enhance the solubility and oral absorption of hydrophobic compounds in nutraceuticals and pharmaceuticals.
  48. A multifunctional nanoplatform for improving microwave hyperthermia by a combination therapy of vessel disruptive agent and immune modulator.
  49. Efficient delivery of PKN3 shRNA for the treatment of breast cancer via lipid nanoparticles.
  50. Development, Characterization, and In Vitro Evaluation of Cytotoxic Activity of Rutin Loaded PCL-PEG Nanoparticles Against Skov3 Ovarian Cancer Cell.
  51. Dynamic Effects of Endo-Exogenous Stimulations on Enzyme-Activatable Polymeric Nanosystems with Photo-Sono-Chemo Synergy.
  52. Macrophage membrane-biomimetic adhesive polycaprolactone nanocamptothecin for improving cancer-targeting efficiency and impairing metastasis.
  53. Agrimonia eupatoria L.: An integrative perspective on ethnomedicinal use, phenolic composition and pharmacological activity.
  54. Caffeic Acid, an Active Ingredient in Coffee, Combines with DOX for Multitarget Combination Therapy of Lung Cancer.
  55. Dendrimer-Functionalized Nanodiamonds as Safe and Efficient Drug Carriers for Cancer Therapy: Nucleus Penetrating Nanoparticles.
  56. Molecular engineering to achieve AIE-active photosensitizers with NIR emission and rapid ROS generation efficiency.
  57. Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-Resistant Lung Cancer.
  58. [How dietary interventions can change lipid metabolism to affect tumor growth].
  59. Anticancer Effect of Spices Used in Mediterranean Diet: Preventive and Therapeutic Potentials.
  60. Biodegradable and Inherently Fluorescent pH-Responsive Nanoparticles for Cancer Drug Delivery.
  61. Recent progress in therapeutic strategies and biomimetic nanomedicines for rheumatoid arthritis treatment.
  62. Inhibition of autophagy by chloroquine prevents resistance to PI3K/AKT inhibitors and potentiates their antitumor effect in combination with paclitaxel in triple negative breast cancer models.
  63. Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition.
  64. Self-boosting stimulus activation of a polyprodrug with cascade amplification for enhanced antitumor efficacy.
  65. Nanoparticles with rough surface improve the therapeutic effect of photothermal immunotherapy against melanoma.
  66. Harnessing ROS-Induced Oxidative Stress for Halting Colorectal Cancer via Thiazolidinedione-Based SOD Inhibitors.
  67. Cancer multidrug-resistance reversal by ABCB1 inhibition: A recent update.
  68. The mechanism and progress of ferroptosis in pancreatic cancer.
  69. pH-responsive Glucosamine Anchored Polydopamine Coated Mesoporous Silica Nanoparticles for delivery of Anderson-type Polyoxomolybdate in Breast Cancer.
  70. Chelerythrine Chloride Inhibits Stemness of Melanoma Cancer Stem-Like Cells (CSCs) Potentially via Inducing Reactive Oxygen Species and Causing Mitochondria Dysfunction.
  71. A new catheter-integrated drug-delivery system for controlled intravesical mitomycin C release.
  72. Biomaterials-Mediated Tumor Infarction Therapy.
  1. Front Oncol. 2022 ;12 816504
    Therapeutic Targeting of Tumor Cells and Tumor Immune Microenvironment Vulnerabilities.
    Balaraman Kalyanaraman, Gang Cheng, Micael Hardy.
      Therapeutic targeting of tumor vulnerabilities is emerging as a key area of research. This review is focused on exploiting the vulnerabilities of tumor cells and the immune cells in the tumor immune microenvironment (TIME), including tumor hypoxia, tumor acidity, the bidirectional proton-coupled monocarboxylate transporters (MCTs) of lactate, mitochondrial oxidative phosphorylation (OXPHOS), and redox enzymes in the tricarboxylic acid cycle. Cancer cells use glucose for energy even under normoxic conditions. Although cancer cells predominantly rely on glycolysis, many have fully functional mitochondria, suggesting that mitochondria are a vulnerable target organelle in cancer cells. Thus, one key distinction between cancer and normal cell metabolism is metabolic reprogramming. Mitochondria-targeted small molecule inhibitors of OXPHOS inhibit tumor proliferation and growth. Another hallmark of cancer is extracellular acidification due lactate accumulation. Emerging results show that lactate acts as a fuel for mitochondrial metabolism and supports tumor proliferation and growth. Metabolic reprogramming occurs in glycolysis-deficient tumor phenotypes and in kinase-targeted, drug-resistant cancers overexpressing OXPHOS genes. Glycolytic cancer cells located away from the vasculature overexpress MCT4 transporter to prevent overacidification by exporting lactate, and the oxidative cancer cells located near the vasculature express MCT1 transporter to provide energy through incorporation of lactate into the tricarboxylic acid cycle. MCTs are, therefore, a vulnerable target in cancer metabolism. MCT inhibitors exert synthetic lethality in combination with metformin, a weak inhibitor of OXPHOS, in cancer cells. Simultaneously targeting multiple vulnerabilities within mitochondria shows synergistic antiproliferative and antitumor effects. Developing tumor-selective, small molecule inhibitors of OXPHOS with a high therapeutic index is critical to fully exploiting the mitochondrial vulnerabilities. We and others developed small-molecule inhibitors containing triphenylphosphonium cation that potently inhibit OXPHOS in tumor cells and tissues. Factors affecting tumor cell vulnerabilities also impact immune cells in the TIME. Glycolytic tumor cells supply lactate to the tumor-suppressing regulatory T cells overexpressing MCTs. Therapeutic opportunities for targeting vulnerabilities in tumor cells and the TIME, as well as the implications on cancer health disparities and cancer treatment, are addressed.
    Keywords:  Mitochondrial drugs; metabolic reprogramming; monocarboxylate transporters; oxidative phosphorylation (OXPHOS); tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.816504
  2. Adv Sci (Weinh). 2022 Jun 26. e2201819
    Targeting Bone Tumor and Subcellular Endoplasmic Reticulum via Near Infrared II Fluorescent Polymer for Photodynamic-Immunotherapy to Break the Step-Reduction Delivery Dilemma.
    Xianghong Zhang, Jia Wan, Fuhao Mo, Dongsheng Tang, Haihua Xiao, Zhihong Li, Jinpeng Jia, Tang Liu.
      Specific localization of photosensitizers (PSs) to a certain organelle could result in targeted attack to cause greater trauma to cancer cells, eventually maximizing photodynamic therapy (PDT). However, currently, efficient and precise transportation of PSs via drug delivery to tumor cells and subcellular organelles is still challenging, due to a so-called step-reduction delivery dilemma (SRDD) which also threatens anticancer drug delivery to exert their efficacy. Herein, a cascade targeting near infrared II (NIR II) fluorescent nanoparticles (NPER/BO-PDT ) is designed that can target bone tumor first and then target the subcellular organelle of endoplasmic reticulum (ER). It is found that NPER/BO-PDT achieves the targeted accumulation of the bone tumor and then ER. NPER/BO-PDT generates reactive oxygen species (ROS) in the subcellular organelles of ER under near infrared light irradiation. The continuous ER stress by ROS promotes the release of more damage-associated molecular patterns, induces immunogenic cell death, stimulates the adaptive immune response, and further synergistically inhibits tumor growth, achieving the so-called photodynamic-immunotherapy. Overall, this study exemplifies a safe and efficient nano-drug delivery system for a bone and ER cascade targeting via delivery of PSs to break the SRDD and highlights potential clinical translation.
    Keywords:  cascade targeting; endoplasmic reticulum stress; photodynamic-immunotherapy; step-reduction delivery dilemma
    DOI:  https://doi.org/10.1002/advs.202201819
  3. Klin Onkol. 2022 ;35(3): 195-207
    Metabolic plasticity of cancer cells.
    M Raudenská, B Peltanová, K Hönigová, J Navrátil, M Masařík.
      BACKGROUND: A general characteristic of cancer metabolism is the skill to gain the essential nutrients from a relatively poor environment and use them effectively to maintain viability and create new bio-mass. The changes in intracellular and extracellular metabolites that accompany metabolic reprogramming associated with tumor growth subsequently affect gene expression, cell differentiation, and tumor microenvironment. During carcinogenesis, cancer cells face huge selection pressures that force them to constantly optimize dominant metabolic pathways and undergo major metabolic reorganizations. In general, greater flexibility of metabolic pathways increases the ability of tumor cells to satisfy their metabolic needs in a changing environment.PURPOSE: In this review, we discuss the metabolic properties of cancer cells and describe the tumor promoting effect of the transformed metabolism. We assume that changes in metabolism are significant enough to facilitate tumorigenesis and may provide interesting targets for cancer therapy.
    Keywords:  Krebs cycle; Metabolism; Warburg effect; anaplerosis; cancer; glutaminolysis; malignancy; oncogenesis; oncometabolite
    DOI:  https://doi.org/10.48095/ccko2022195
  4. Nano Lett. 2022 Jun 27.
    Remote Manipulation of ROS-Sensitive Calcium Channel Using Near-Infrared-Responsive Conjugated Oligomer Nanoparticles for Enhanced Tumor Therapy In Vivo.
    Ning Li, Yijian Gao, Boying Li, Dong Gao, Hao Geng, Shengliang Li, Chengfen Xing.
      The regulation of reactive oxygen species (ROS)-sensitive calcium (Ca2+) channels is of great significance in the treatment of tumors. Here, a simple ROS generation system is developed to activate ROS-sensitive ion channels for enhancing calcium-cascade-mediated tumor cell death under near-infrared (NIR) light irradiation. Upon irradiation with an 808 nm laser, a low-lethality amount of ROS facilitates plasmid transient potential receptor melastatin-2 (pTRPM2) gene release via cleavage of the Se-Se bonds, which contributed to enhancing the expression of TRPM2 in tumor cells. Meanwhile, ROS could potently activate TRPM2 for Ca2+ influx to inhibit early autophagy and to further induce intracellular ROS production, which ultimately led to cell death in TRPM2 expressing tumor cells. Both in vitro and in vivo data show that nanoparticles have an excellent therapeutic effect on cancer upon NIR light. This work presents a simple modality based on NIR light to remotely control the ROS-sensitive ion channel for cancer therapy.
    Keywords:  ROS-sensitive; conjugated oligomer; ion channel; near-infrared; tumor therapy
    DOI:  https://doi.org/10.1021/acs.nanolett.2c01472
  5. J Colloid Interface Sci. 2022 Jun 20. pii: S0021-9797(22)01051-7. [Epub ahead of print]625 711-721
    Folic acid conjugated PAMAM-modified mesoporous silica-coated superparamagnetic iron oxide nanoparticles for potential cancer therapy.
    T Sagir, M Huysal, M Senel, S Isık, N Burgucu, O Tabakoglu, M Zaim.
      In this study, novel folate-receptor-targeted polyamidoamine (PAMAM) dendrimer functional mesoporous silica-coated magnetic nanoparticles were prepared for drug delivery agents for photodynamic therapy applications. The surface of the magnetic nanoparticles was coated with mesoporous silica (M-MSN). The M-MSN nanoparticles were functionalized with siloxane-cored PAMAM dendrons (generation 1 to 3). The surface of the M-MSN-PAMAM nanocarriers was targeted with folic acid. Indocyanine green (ICG) a near-infrared dye was loaded in the M-MSN-PAMAM nanocarriers and the photodynamic therapy efficiency of the drug-loaded nanocarriers was evaluated on MCF-7 cells. MCF-7 cells were subjected to tissue culture E-Plate that was used to generate dynamic real-time data by measuring electrical impedance across interdigitated microelectrodes on the bottom of the plate. Light source (LEDs) was designed as a system that fit 96 well-plate and cells were irradiated at 785 nm for 20 min. Also, these results were confirmed by WST-1 assay in dark and light conditions for MCF-7 cells. The results showed that in vitro application of ICG loaded M-MSN-PAMAM-FA causes apoptosis in the MCF-7 cell line.
    Keywords:  Antitumor activity; Dendrimers; Drug delivery; Magnetic nanoparticles; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.jcis.2022.06.069
  6. Acta Pharm Sin B. 2022 Jun;12(6): 2710-2730
    Tumor-targeted/reduction-triggered composite multifunctional nanoparticles for breast cancer chemo-photothermal combinational therapy.
    Yun Yang, Danrong Hu, Yi Lu, Bingyang Chu, Xinlong He, Yu Chen, Yao Xiao, Chengli Yang, Kai Zhou, Liping Yuan, Zhiyong Qian.
      Breast cancer has become the most commonly diagnosed cancer type in the world. A combination of chemotherapy and photothermal therapy (PTT) has emerged as a promising strategy for breast cancer therapy. However, the intricacy of precise delivery and the ability to initiate drug release in specific tumor sites remains a challenging puzzle. Therefore, to ensure that the therapeutic agents are synchronously delivered to the tumor site for their synergistic effect, a multifunctional nanoparticle system (PCRHNs) is developed, which is grafted onto the prussian blue nanoparticles (PB NPs) by reduction-responsive camptothecin (CPT) prodrug copolymer, and then modified with tumor-targeting peptide cyclo(Asp-d-Phe-Lys-Arg-Gly) (cRGD) and hyaluronic acid (HA). PCRHNs exhibited nano-sized structure with good monodispersity, high load efficiency of CPT, triggered CPT release in response to reduction environment, and excellent photothermal conversion under laser irradiation. Furthermore, PCRHNs can act as a photoacoustic imaging contrast agent-guided PTT. In vivo studies indicate that PCRHNs exhibited excellent biocompatibility, prolonged blood circulation, enhanced tumor accumulation, allow tumor-specific chemo-photothermal therapy to achieve synergistic antitumor effects with reduced systemic toxicity. Moreover, hyperthermia-induced upregulation of heat shock protein 70 in the tumor cells could be inhibited by CPT. Collectively, PCRHNs may be a promising therapeutic way for breast cancer therapy.
    Keywords:  Breast cancer; Camptothecin; Chem-photothermal combinational therapy; Prussian blue nanoparticles; Reduction-responsive prodrugs
    DOI:  https://doi.org/10.1016/j.apsb.2021.08.021
  7. Drug Dev Ind Pharm. 2022 Jun 27. 1-35
    PEGylated solid lipid nanoparticles functionalized by aptamer for targeted delivery of docetaxel in mice bearing C26 tumor.
    Zahra Shakib, Asma Mahmoudi, Seyedeh Alia Moosavian, Bizhan Malaekeh-Nikouei.
      Objective: Colorectal cancer is one of the most deadly cancers in the world. Docetaxel (DTX) is a potentially important chemotherapeutic agent for the treatment of cancer. Many studies have attempted to improve its bioavailability and efficiency using different nanoparticulate drug delivery systems.Significance: In current study, PEGylated solid lipid nanoparticles (SLNs) containing DTX were prepared and modified with AS1411 anti-nucleolin aptamers to target nucleoin receptors on colorectal cancer cells.Methods: Nanoparticles were characterized and the morphology was evaluated. In vitro studies were investigated on murine colon carcinoma (C26) and Chinese hamster ovary (CHO) cell lines. Then in vivo antitumor efficacy and survival analysis were evaluated in mice bearing C26 tumor model.Results: Results showed 135-140 nm particle size and about 78% DTX entrapment efficiency for active targeted samples. PEGylated and aptamer-targeted SLNs containing DTX had the lowest IC50 (0.28 and 0.11 nM for 3 and 6 hours incubation respectively) and higher cellular uptake values in C26 cell line. Also in vivo results demonstrated that PEGylated and aptamer-targeted SLNs containing Docetaxel (Apt-PEG-SLN-DTX) improved antitumor activity and inhibited tumor growth in C26 tumor bearing mice.Conclusion: These results suggested that PEGylated and aptamer-targeted SLNs containing DTX exhibited efficient characteristics in tumor inhibitory against murine C26 carcinoma model.
    Keywords:  AS1411; Aptamer; Colon carcinoma; Docetaxel; Solid lipid nanoparticles
    DOI:  https://doi.org/10.1080/03639045.2022.2095398
  8. Biomacromolecules. 2022 Jun 27.
    Phenylboronic Acid-Functionalized Copolypeptides: Facile Synthesis and Responsive Dual Anticancer Drug Release.
    Qiang Zhang, Yuanyuan Liu, Yucheng Fei, Jiguo Xie, Xiaofei Zhao, Zhiyuan Zhong, Chao Deng.
      The incorporation of a phenylboronic acid group has appeared as an attractive strategy to build smart drug delivery systems. Here, we report novel synthesis of phenylboronic acid-functionalized copolypeptides based on an l-boronophenylalanine N-carboxyanhydride (BPA-NCA) monomer and their application for robust co-encapsulation and responsive release of dual anticancer drugs. By employing different poly(ethylene glycol) (PEG) initiators and copolymerizing with varying NCA monomers, linear and star PEG-poly(l-boronophenylalanine) copolymers (PEG-PBPA, star-PEG-PBPA), PEG-poly(l-tyrosine-co-l-boronophenylalanine) [PEG-P(Tyr-co-BPA)], PEG-poly(l-lysine-co-l-boronophenylalanine) [PEG-P(Lys-co-BPA)], and PEG-poly(β-benzyl-l-aspartate-co-l-boronophenylalanine) [PEG-P(BLA-co-BPA)] were obtained with controlled compositions. Interestingly, PEG-PBPA self-assembled into uniform micellar nanoparticles that mediated robust co-encapsulation and hydrogen peroxide (H2O2) and acid-responsive release of dual antitumor drugs, curcumin (Cur) and sorafenib tosylate (Sor). These dual drug-loaded nanoparticles (PBN-Cur/Sor) exhibited a greatly enhanced anticancer effect toward U87 MG-luciferase glioblastoma cells. The facile synthesis of phenylboronic acid-functionalized copolypeptides from BPA coupled with their robust drug loading and responsive drug release behaviors make them interesting for construction of smart cancer nanomedicines.
    DOI:  https://doi.org/10.1021/acs.biomac.2c00482
  9. J Nutr Biochem. 2022 Jun 28. pii: S0955-2863(22)00171-1. [Epub ahead of print] 109101
    Resveratrol and resveratrol nano-delivery systems in the treatment of inflammatory bowel disease.
    Vemana Gowd, Kanika, Chandrashekhar Jori, Anis Ahmad Chaudhary, Hassan Ahmed Rudayni, Rehan Khan.
      Inflammatory bowel disease (IBD) is a chronic disorder associated with the inflammation in the digestive tract. The exact cause of IBD is unknown; nevertheless, in IBD, the homeostasis of key regulatory factors involved in intestinal immunity has been documented to be disrupted. Despite the lack of a viable treatment for IBD, synthetic drugs and monoclonal antibodies are currently used to treat it. However, these treatments have side effects, and the high relapse rate limits their usage. Dietary polyphenols constitute a great variety of compounds and have shown an array of biological properties. Resveratrol is a natural polyphenol found in grapevines and berries. The therapeutic ability of resveratrol against IBD is amply demonstrated in many in vivo studies. Resveratrol can interact with several molecular targets (Nf-kB, SIRT1, mTOR, HIF-1α, miRNAs, and TNF-α) and effectively prevent/ alleviate IBD symptoms with promising results. Although resveratrol has profound anti-inflammatory properties against IBD, its therapeutic employment is limited due to its low water solubility, less chemical stability, less bioavailability, and rapid metabolism in vivo. Hence, resveratrol encapsulation using different carries and its controlled release has become a promising strategy to overcome limitations. Herein, we meticulously review, talk-over the anti-inflammatory effect and mechanisms of resveratrol in IBD. We further provide the latest information on resveratrol formulations and nano-delivery systems used in oral delivery of resveratrol for the treatment of IBD and offer our view on future research on resveratrol in IBD treatment.
    Keywords:  Colorectal cancer; Inflammation; Inflammatory bowel disease; Nano formulation; Nanoparticles; Resveratrol; Ulcerative colitis
    DOI:  https://doi.org/10.1016/j.jnutbio.2022.109101
  10. Front Pharmacol. 2022 ;13 903259
    Allicin in Digestive System Cancer: From Biological Effects to Clinical Treatment.
    Yang Zhou, Xingxuan Li, Wenyu Luo, Junfeng Zhu, Jingwen Zhao, Mengyao Wang, Lixuan Sang, Bing Chang, Bingyuan Wang.
      Allicin is the main active ingredient in freshly-crushed garlic and some other allium plants, and its anticancer effect on cancers of digestive system has been confirmed in many studies. The aim of this review is to summarize epidemiological studies and in vitro and in vivo investigations on the anticancer effects of allicin and its secondary metabolites, as well as their biological functions. In epidemiological studies of esophageal cancer, liver cancer, pancreatic cancer, and biliary tract cancer, the anticancer effect of garlic has been confirmed consistently. However, the results obtained from epidemiological studies in gastric cancer and colon cancer are inconsistent. In vitro studies demonstrated that allicin and its secondary metabolites play an antitumor role by inhibiting tumor cell proliferation, inducing apoptosis, controlling tumor invasion and metastasis, decreasing angiogenesis, suppressing Helicobacter pylori, enhancing the efficacy of chemotherapeutic drugs, and reducing the damage caused by chemotherapeutic drugs. In vivo studies further demonstrate that allicin and its secondary metabolites inhibit cancers of the digestive system. This review describes the mechanisms against cancers of digestive system and therapeutic potential of allicin and its secondary metabolites.
    Keywords:  allicin; allicin secondary metabolites; digestive system cancer; gastrointestinal cancer; therapy
    DOI:  https://doi.org/10.3389/fphar.2022.903259
  11. J Adv Res. 2022 Jun 28. pii: S2090-1232(22)00149-7. [Epub ahead of print]
    Exogenous iron impairs the anti-cancer effect of ascorbic acid both in vitro and in vivo.
    Bingling Zhong, Lin Zhao, Jie Yu, Ying Hou, Nana Ai, Jin-Jian Lu, Wei Ge, Xiuping Chen.
      INTRODUCTION: The anti-cancer effect of high concentrations of ascorbic acid (AA) has been well established while its underlying mechanisms remain unclear. The association between iron and AA has attracted great attention but was still controversial due to the complicated roles of iron in tumors.OBJECTIVES: Our study aims to explore the anti-cancer mechanisms of AA and the interaction between AA and iron in cancer.
    METHODS: The MTT and ATP assays were used to evaluate the cytotoxicity of AA. Reactive oxygen species (ROS) generation, calcium (Ca2+), and lipid peroxidation were monitored with flow cytometry. Mitochondrial dysfunction was assessed by mitochondrial membrane potential (MMP) detection with JC-1 or Tetramethylrhodamine (TMRM) staining. Mitochondrial swelling was monitored with MitoTracker Green probe. FeSO4 (Fe2+), FeCl3 (Fe3+), Ferric ammonium citrate (Fe3+), hemin chloride (Fe3+) were used as an iron donor to investigate the effects of iron on AA's anti-tumor activity. The in vivo effects of AA and iron were analyzed in xenograft zebrafish and allograft mouse models.
    RESULTS: High concentrations of AA exhibited cytotoxicity in a panel of cancer cells. AA triggered ROS-dependent non-apoptotic cell death. AA-induced cell death was essentially mediated by the accumulated intracellular Ca2+, which was partly originated from endoplasmic reticulum (ER). Surprisingly, exogenous iron could significantly reverse AA-induced ROS generation, Ca2+ overloaded, and cell death. Especially, the iron supplements significantly impaired the in vivo anti-tumor activity of AA.
    CONCLUSIONS: Our study elucidated the protective roles of iron in ROS/Ca2+ mediated necrosis triggered by AA both in vitro and in vivo, which might shed novel insight into the anti-cancer mechanisms and provide clinical application strategies for AA in cancer treatment.
    Keywords:  Ascorbic acid; Ca(2+); Iron; Necrosis; ROS
    DOI:  https://doi.org/10.1016/j.jare.2022.06.011
  12. Tissue Cell. 2022 Jun 15. pii: S0040-8166(22)00128-8. [Epub ahead of print]77 101856
    The combinational application of photodynamic therapy and nanotechnology in skin cancer treatment: A review.
    Fadya Adnane, Emad El-Zayat, Heba Mohamed Fahmy.
      Skin cancer is considered a risky worldwide disease. Traditional treatments have several weaknesses, necessitating the creation of more effective treatments. In this case, photodynamic therapy and nanotechnology were used to demonstrate their therapeutic efficacy as combinational approaches in treating different types of skin cancer. In this review, we will discuss the photoexcitation mechanism of PDT, its cell destruction capability, and give a comprehensive outlook of the different photosensitizer types. Also, light sources and their properties will be addressed. Further, we will present some of the nanoparticles used as delivery systems in the skin and show their ideal characteristics for the effective delivery of drugs for skin cancer therapy. Finally, the review aims to cover topics from the most recent reported preclinical studies and clinical trials about nanoparticles loaded with different drugs and triggered with PDT to treat different types of skin cancer. The review will demonstrate that photodynamic therapy and nanoparticles have contributed to the great evolution of skin cancer treatment by having an effective therapeutic efficiency in treating different types of skin cancer such as melanoma, squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and actinic keratosis (AK) which shows the need of using them instead of traditional technologies.
    Keywords:  Cytotoxicity; Nanoparticles; Photodynamic therapy (PDT); Phototoxicity; Skin cancer
    DOI:  https://doi.org/10.1016/j.tice.2022.101856
  13. Acta Pharm Sin B. 2022 Jun;12(6): 2672-2682
    A mitochondria-targeting lipid-small molecule hybrid nanoparticle for imaging and therapy in an orthotopic glioma model.
    Menghuan Tang, Kai Lin, Mythili Ramachandran, Longmeng Li, Hongye Zou, Huzhi Zheng, Zhao Ma, Yuanpei Li.
      Hybrid lipid‒nanoparticle complexes have shown attractive characteristics as drug carriers due to their integrated advantages from liposomes and nanoparticles. Here we developed a kind of lipid-small molecule hybrid nanoparticles (LPHNPs) for imaging and treatment in an orthotopic glioma model. LPHNPs were prepared by engineering the co-assembly of lipids and an amphiphilic pheophorbide a‒quinolinium conjugate (PQC), a mitochondria-targeting small molecule. Compared with the pure nanofiber self-assembled by PQC, LPHNPs not only preserve the comparable antiproliferative potency, but also possess a spherical nanostructure that allows the PQC molecules to be administrated through intravenous injection. Also, this co-assembly remarkably improved the drug-loading capacity and formulation stability against the physical encapsulation using conventional liposomes. By integrating the advantages from liposome and PQC molecule, LPHNPs have minimal system toxicity, enhanced potency of photodynamic therapy (PDT) and visualization capacities of drug biodistribution and tumor imaging. The hybrid nanoparticle demonstrates excellent curative effects to significantly prolong the survival of mice with the orthotopic glioma. The unique co-assembly of lipid and small molecule provides new potential for constructing new liposome-derived nanoformulations and improving cancer treatment.
    Keywords:  Cancer therapy; Drug delivery; Hybrid nanoparticle; Lipid-small molecule nanoparticle; Mitochondria targeting; Orthotopic glioma; Photodynamic therapy; Tumor imaging
    DOI:  https://doi.org/10.1016/j.apsb.2022.04.005
  14. Evid Based Complement Alternat Med. 2022 ;2022 5901191
    An Insight into Anticancer Effect of Propolis and Its Constituents: A Review of Molecular Mechanisms.
    Perumal Elumalai, Natarajan Muninathan, Sadhasivan T Megalatha, Arumugam Suresh, Kalimuthu Senthil Kumar, Nathan Jhansi, Kuppuswamy Kalaivani, Gunasekaran Krishnamoorthy.
      Propolis is a natural compound collected by honeybees from different parts of plants. Honeybees produce a sticky component besides honey by mixing the tree resin and other botanical sources with saliva called propolis or bee glue. Propolis was traditionally used as a wound healing substance, cosmetic, medicine, and many other conditions. Till now, there is no definite curable treatment for most cancers and chemotherapeutic drugs and drugs used for targeted therapies have serious side effects. According to a recent research, natural products are becoming increasingly essential in cancer prevention. Natural products are a great source of potential therapeutic agents, especially in the treatment of cancer. Previous studies have reported that the presence of caffeic acid phenethyl ester (CAPE), artepillin C, and chrysin is responsible for the anticancer potential of propolis. Most of the previous studies suggested that propolis and its active compounds inhibit cancer progression by targeting multiple signaling pathways including phosphoinositide 3-kinases (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling molecules, and induce cell cycle arrest. Induction of apoptosis by propolis is mediated through extrinsic and intrinsic apoptotic pathways. The aim of this review is to highlight and summarize the molecular targets and anticancer potential of propolis and its active compounds on cell survival, proliferation, metastasis, and apoptosis in cancer cells.
    DOI:  https://doi.org/10.1155/2022/5901191
  15. Colloids Surf B Biointerfaces. 2022 Jun 16. pii: S0927-7765(22)00321-6. [Epub ahead of print]217 112638
    pH-responsive dynamically cross-linked nanogels with effective endo-lysosomal escape for synergetic cancer therapy based on intracellular co-delivery of photosensitizers and proteins.
    Hong Yu Yang, Moon-Sun Jang, Yi Li, Jia Meng Du, Changling Liu, Jung Hee Lee, Yan Fu.
      Co-delivery of photosensitizers (PSs) and protein drugs represents great potentiality for enhancing the efficiency of synergistic cancer therapy. However, the intricate tumor-microenvironment and the lack of nanoplatforms to co-deliver both into cancer cells and activate their functions significantly hinder the clinical translation of this combined approach for cancer treatment. Herein, a chlorine e6 (Ce6)-functionalized and pH-responsive dynamically cross-linked nanogel (Ce6@NG) is fabricated by formation of benzoic imine linkages between Ce6-modified methoxy poly (ethyleneglycol)-block-poly (diethylenetriamine)-L-glutamate-Ce6 [MPEG-b-P(Deta)LG-Ce6] and terephthalaldehyde as cross-linkers for effective intracellular co-delivery of Ce6 and cytochrome c (CC), which could form a novel combination therapy system (CC/Ce6@NGs). The pH-sensitive benzoic imine bonds in the CC/Ce6@NGs endow them with excellent systemic stability under normal physiological environment while this nanosystem can be further cationized to enhance cell uptake in acidic extracellular environment. Upon cellular internalization, CC/Ce6@NGs can rapidly escape from the endo/lysosomal compartments and subsequently activate Ce6 to generate cytotoxic singlet oxygen upon laser irradiation and release of CC to induce programmed cell death by complete cleavage of benzoic imines at more acidic intracellular environments. Importantly, the catalase-like activity of CC can decompose H2O2 to produce O2 for hypoxia alleviation and improvement of the photodynamic therapy (PDT) of cancer. Moreover, this enhanced synergistic anticancer activity is confirmed both in vitro and in vivo. In view of the versatile chemical conjugation, this research offers a promising and smart nanosystem for intracellular co-delivery of PSs and therapeutic proteins.
    Keywords:  Endo-lysosomal escape; Nanogel; PH-responsive; Photodynamic therapy; Protein therapy
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112638
  16. J Mater Chem B. 2022 Jul 01.
    PEGylated Prussian blue nanoparticles for modulating polyethyleneimine cytotoxicity and attenuating tumor hypoxia for dual-enhanced photodynamic therapy.
    Huanhuan Wang, Rumeng Qu, Qi Chen, Ting Zhang, Xiaoyu Chen, Baoyan Wu, Tongsheng Chen.
      Photodynamic therapy (PDT) is a promising cancer therapy modality due to its intrinsically negligible side effects and treatment resistance. However, the development of the high-efficiency PDT still remains a challenge. Herein, a nanodrug platform PEG-Ce6-PEI@PB combined tumor acidity-induced polyethyleneimine (PEI) cytotoxicity with an oxygen self-supply property is developed for dual-enhanced PDT. The obtained PEG-Ce6-PEI@PB presents suppressed PEI cytotoxicity and chlorin e6 (Ce6) phototoxicity during the bloodstream before becoming active in tumor tissues/cells. The acidic tumor microenvironment can shed PEG coating to rebound PEI positive charges, facilitating tumor cell uptake and reverting the PEI cytotoxicity to enhance following PDT. Moreover, Prussian blue (PB) nanozymes with catalase-like activity can convert endogenous hydrogen peroxide into oxygen to relieve tumor hypoxia, which is attributed to the photosensitizer Ce6 producing more cytotoxic reactive oxygen species upon laser irradiation to further strengthen PDT. Moreover, PEG-Ce6-PEI@PB exhibits good biocompatibility and long blood circulation. More importantly, PEG-Ce6-PEI@PB-treated breast cancer cells and tumor-bearing mice present effective therapeutic efficacy upon laser irradiation, verifying the synergistic antitumor effects of PEI cytotoxicity and oxygen self-supplying PDT.
    DOI:  https://doi.org/10.1039/d2tb00571a
  17. J Nanobiotechnology. 2022 Jun 25. 20(1): 300
    Autophagy responsive intra-intercellular delivery nanoparticles for effective deep solid tumor penetration.
    Fengling Wang, Dandan Xie, Wenjing Lai, Min Zhou, Jie Wang, Rufu Xu, Jingbing Huang, Rong Zhang, Guobing Li.
      Deep tumor cells (cells in the center of solid tumors) play a crucial role in drug tolerance, metastasis, recurrence and microenvironment immune suppression. However, their deep location endows them with an untouched abdomen and makes them refractory to current treatments. Herein, we exploited the characteristic of higher autophagy in deep tumor cells than in superficial tumor cells and designed autophagy-responsive multifunctional nanoparticles (PGN) to enhance drug accumulation in deep tumor cells. PGNs were prepared by densely coating poly (lactic-co-glycolic acid) (PLGA) with cationic autophagy-responsive cell-penetrating peptide (GR9) and anionic 2,3-dimethylmaleic anhydride (DMA)-modified DSPE-PEG. The suitable nanoparticle size (122.4 nm) and charge-neutral surface (0.21 mV) of the NPs enabled long blood circulation. The hydrolysis of surface-anchored anionic DMA in the acidic microenvironment led to the exposure of the GR9 peptide and enhance tumor penetration. Once the PGN arrived in deep tumor cells with strong autophagy, GR9 was cut off by an autophagy shear enzyme, and the nanoparticles remained in the cells to undergo degradation. Furthermore, we prepared docetaxel (DTX) and chloroquine (CQ) loaded d-PGN. CQ inhibits autophagosome fusion with lysosomes, resulting in autophagosome accumulation, which further enhances the sensitivity of d-PGN to autophagy and their deep tumor retention. In vivo experiments showed that drug-loaded d-PGN achieved excellent antitumor efficacy with a peak inhibition rate of 82.1%. In conclusion, autophagy-responsive multifunctional nanoparticles provide a novel potential strategy for solid tumor treatment.
    Keywords:  Autophagy responsive; Deep penetration; Solid tumors; Transcellular transport
    DOI:  https://doi.org/10.1186/s12951-022-01514-6
  18. J Cell Sci. 2022 Jul 01. pii: jcs.259090. [Epub ahead of print]
    Redox-dependent AMPK inactivation disrupts metabolic adaptation to glucose starvation in xCT-overexpressing cancer cells.
    Younghwan Lee, Yoko Itahana, Choon Chen Ong, Koji Itahana.
      Accelerated aerobic glycolysis is a distinctive metabolic property of cancer cells that confers dependency on glucose for survival. However, the therapeutic strategies targeting this vulnerability are still inefficient and have unacceptable side effects in clinical trials. Therefore, developing biomarkers to predict therapeutic efficacy would be essential to improve the selective targeting of cancer cells. Here, we found that the cell lines sensitive to glucose deprivation have high expression of cystine/glutamate antiporter xCT. We found that cystine uptake and glutamate export through xCT contributed to rapid NADPH depletion under glucose deprivation. This collapse of the redox system oxidized and inactivated AMPK, a major regulator of metabolic adaptation, resulting in a metabolic catastrophe and cell death. While this phenomenon was prevented by pharmacological or genetic inhibition of xCT, overexpression of xCT sensitized resistant cancer cells to glucose deprivation. Taken together, these findings suggest a novel cross-talk between AMPK and xCT for the metabolism and signal transduction and reveal a metabolic vulnerability in xCT-high expressing cancer cells to glucose deprivation.
    Keywords:  AMPK; Cystine; Glucose starvation; NADPH; SLC7A11; xCT
    DOI:  https://doi.org/10.1242/jcs.259090
  19. ACS Omega. 2022 Jun 21. 7(24): 21325-21336
    Functional cRGD-Conjugated Polymer Prodrug for Targeted Drug Delivery to Liver Cancer Cells.
    Ru Zhou, Mingzu Zhang, Jinlin He, Jian Liu, Xingwei Sun, Peihong Ni.
      To overcome the limitation of conventional nanodrugs in tumor targeting efficiency, coupling targeting ligands to polymeric nanoparticles can enhance the specific binding of nanodrugs to tumors. Cyclo(Arg-Gly-Asp-d-Phe-Lys) (abbreviated as c(RGDfK)) peptide has been widely adopted due to its high affinity to the tumor marker αvβ3 integrin receptor. In this study, we develop a cRGD peptide-conjugated camptothecin (CPT) prodrug, which enables self-assembly of nanoparticles for precise targeting and enrichment in tumor tissue. We first synthesized a camptothecin derivative (CPT-ss-N3) with a reduction-sensitive bond and simultaneously modified PEG to obtain cRGD-PEG-N3. After ring-opening polymerization of the 2-(but-3-yn-1-yolxy)-2-oxo-1,3,2-dioxaphospholane (BYP), an amphiphilic polymeric prodrug, referred to as cRGD-PEG-g-(PBYP-ss-CPT), was obtained via copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The self-assembly in buffer solution of the cRGD-functional prodrug was studied through DLS and TEM. The in vitro drug release behavior of cRGD-PEG-g-(PBYP-ss-CPT) nanoparticles was investigated. The results show that the nanoparticles are reduction-responsive and the bonded CPT can be released. Endocytosis and MTT assays demonstrate that the cRGD-conjugated prodrug has better affinity for tumor cells, accumulates more intracellularly, and is therefore, more effective. The in vivo drug metabolism studies show that nanoparticles greatly prolong the retention time in circulation. By monitoring drug distribution in tumor and in various tissues, we find that free CPT can be rapidly metabolized, resulting in low accumulation in all tissues. However, cRGD-PEG-g-(PBYP-ss-CPT) nanoparticles accumulate in tumor tissues in higher amounts than PEG-g-(PBYP-ss-CPT) nanoparticles, except for the inevitable capture by the liver. This indicates that the nanomedicine with cRGD has a certain targeting property, which can improve drug delivery efficiency.
    DOI:  https://doi.org/10.1021/acsomega.2c02683
  20. Drug Deliv. 2022 Dec;29(1): 1959-1970
    Functional ligands for improving anticancer drug therapy: current status and applications to drug delivery systems.
    Rajiv Bajracharya, Jae Geun Song, Basavaraj Rudragouda Patil, Sang Hoon Lee, Hye-Mi Noh, Da-Hyun Kim, Gyu-Lin Kim, Soo-Hwa Seo, Ji-Won Park, Seong Hoon Jeong, Chang Hoon Lee, Hyo-Kyung Han.
      Conventional chemotherapy lacking target selectivity often leads to severe side effects, limiting the effectiveness of chemotherapy. Therefore, drug delivery systems ensuring both selective drug release and efficient intracellular uptake at the target sites are highly demanded in chemotherapy to improve the quality of life of patients with low toxicity. One of the effective approaches for tumor-selective drug delivery is the adoption of functional ligands that can interact with specific receptors overexpressed in malignant cancer cells. Various functional ligands including folic acid, hyaluronic acid, transferrin, peptides, and antibodies, have been extensively explored to develop tumor-selective drug delivery systems. Furthermore, cell-penetrating peptides or ligands for tight junction opening are also actively pursued to improve the intracellular trafficking of anticancer drugs. Sometimes, multiple ligands with different roles are used in combination to enhance the cellular uptake as well as target selectivity of anticancer drugs. In this review, the current status of various functional ligands applicable to improve the effectiveness of cancer chemotherapy is overviewed with a focus on their roles, characteristics, and preclinical/clinical applications.
    Keywords:  Drug delivery; anticancer; cell penetrating peptides; cell surface receptors; target selectivity; tight junction opening
    DOI:  https://doi.org/10.1080/10717544.2022.2089296
  21. Biomater Res. 2022 Jun 27. 26(1): 28
    In vitro photodynamic therapy of methylene blue-loaded acetyl resistant starch nanoparticles.
    In-Kyu Park, Do-Bin Ju, Amal Babu, Jeong-Cheol Lee, Young Jin Pyung, Chong-Su Cho, Hyun-Joong Kim.
      BACKGROUND: Combination therapies comprising multiple methods, such as photodynamic therapy have been applied to be complements chemotherapy as they increase the therapeutic efficiency by enabling the intelligent drug delivery to target sites by exposing the photosensitizer to light and activating it in the tumor tissue. This study evaluated in vitro photodynamic therapy of methylene blue (MB)-loaded acetyl resistant starch (ARS) nanoparticles (NPs).METHODS: ARS was synthesized by the reaction between resistant starch (RS) and acetic anhydride. MB-loaded ARS NPs and ARS NPs were prepared by a single emulsion method. Synthesized ARS was measured by NMR. Prepared ARS NPs and MB-loaded ARS NPs were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), X-ray diffraction, UV/Vis, and circular dichroism (CD). MB-loaded ARS NPs were treated in mouse colon cancer cells (CT-26) and they were treated under near-infrared (NIR) laser irradiation.
    RESULTS: Synthesis of ARS was confirmed by NMR and the degree of substitutions in the ARS was 7.1. The morphologies of ARS NPs observed by TEM were spherical shapes and the particle sizes of ARS NPs were 173.4 nm with a surface charge of - 17.24 mV. The d-spacing of ARS NPs was smaller than those of RS and the conformational changes of RS occurred by the formation of self-assembled polymeric NPs with induction of CD of the MB by chiral ARS NPs. The phototoxicity of CT-26 cells treated by MB-loaded ARS NPs dramatically decreased in a dose-dependent manner under NIR laser irradiation compared to free MB.
    CONCLUSION: This study demonstrated the ordered nanosized structures in the ARS NPs and conformational change from random coil structure of RS to alpha-helices one of ARS occurred and CD of the achiral MB was induced. The MB-loaded ARS NPs showed a higher generation of reactive oxygen species (ROS) in the CT-26 cells than free MB with the NIR laser irradiation and resulting in phototoxicity under irradiation.
    Keywords:  Methylene blue; Photodynamic therapy; Polymeric nanoparticles; Resistant starch
    DOI:  https://doi.org/10.1186/s40824-022-00273-7
  22. Bioorg Med Chem. 2022 Jun 14. pii: S0968-0896(22)00277-2. [Epub ahead of print]69 116885
    pH-responsive Mannose-modified ferrocene Metal-Organic frameworks with rare earth for Tumor-targeted synchronous Chemo/Chemodynamic therapy.
    Junliang Dong, Ke Ma, Jindong Ding, Yuxin Pei, Zhichao Pei.
      The combination of chemodynamic therapy (CDT) and chemotherapy is a promising strategy to achieve enhanced anticancer effects. Metal-organic frameworks (MOFs), as multifunctional drug delivery vehicles, have received extensive attention in the biomedical field. Carbohydrate has excellent biocompatibility and targeting ability, which can be used as a targeting ligand due to a specific recognition with glycoprotein receptors that overexpress on cancer cell membranes. Herein, the pH-responsive mannose-modified ferrocene MOFs with rare earth metal were synthesized via coordination-driven self-assembly of 1,1'-Ferrocenedicarboxylic acid and ytterbium chloride. Subsequently, DOX@Fc-MOFs-Mann nanoparticles (NPs) were obtained by loading doxorubicin (DOX) and modifying mannose (Mann), where DOX@Fc-MOFs-Mann NPs were able to precisely target HepG2 cells via mannose receptor and slowly decompose in the acidic environment of tumor to release ferrocene, DOX, and Yb3+. Fe2+ in ferrocene effectively activated Fenton reaction to produce high levels of reactive oxygen species (ROS) for irreversible induction of cell apoptosis or necroptosis. Combined with the chemotherapy (CT) ability of DOX, Yb3+ further induced cell death through its own toxicity to successfully achieved the rare earth metal synergistic CDT and CT combination therapy. This synergistic CDT and CT strategy not only opens up new horizons for rare earth metals in biomedical applications but also provides new inspiration into the construction of glycosyl-modified MOFs.
    Keywords:  Chemodynamic therapy; Combination therapy; Mannose; Metal-Organic Frameworks; Rare Earth Metal
    DOI:  https://doi.org/10.1016/j.bmc.2022.116885
  23. Phytother Res. 2022 Jul 01.
    Preclinical studies of the antitumor effect of curcumin-loaded polymeric nanocapsules: A systematic review and meta-analysis.
    Thayse V de Oliveira, Renan Stein, Diego F de Andrade, Ruy C R Beck.
      Curcumin, a plant-derived compound, has various well-known biological effects (anti-inflammatory, antioxidant, antitumor, among others) as well as some important limitations for formulators, such as poor water solubility and low oral bioavailability. Its nanoencapsulation is reported to overcome these drawbacks and to improve its in vivo efficacy. Here, data from preclinical in vivo studies evaluating the antitumor efficacy of curcumin-loaded polymeric nanocapsules are collected, analyzed, and discussed as a systematic review. Meta-analyses are performed to assess the contribution of this nanoencapsulation compared with nonencapsulated curcumin. Eighteen studies (116 animals) meet the inclusion criteria. The evidence that curcumin-loaded polymeric nanocapsules inhibits tumor growth (SMD: -3.03; 95% CI: -3.84, -2.21; p < 0.00001) and decreases tumor weight (SMD: -3.96; 95% CI: -6.22, -1.70; p = 0.0006) in rodents is established, regardless of the solid tumor model. To assess the quality of the studies included in the review a bias risk analysis was performed using the SYRCLE's RoB tool. Therefore, encapsulation in polymeric nanocapsules represents an important tool to improve the antitumor effects of curcumin, and this systematic review paves the way for future clinical studies and the translation of curcumin formulations into novel nanomedicines for human cancer treatment.
    Keywords:  Curcuma longa; cancer; nanomedicine; nanoparticles; polyphenols
    DOI:  https://doi.org/10.1002/ptr.7538
  24. Front Immunol. 2022 ;13 889875
    Reactive Oxygen Species and Metabolism in Leukemia: A Dangerous Liaison.
    Marta Romo-González, Carla Ijurko, Ángel Hernández-Hernández.
      Reactive oxygen species (ROS), previously considered toxic by-products of aerobic metabolism, are increasingly recognized as regulators of cellular signaling. Keeping ROS levels low is essential to safeguard the self-renewal capacity of hematopoietic stem cells (HSC). HSC reside in a hypoxic environment and have been shown to be highly dependent on the glycolytic pathway to meet their energy requirements. However, when the differentiation machinery is activated, there is an essential enhancement of ROS together with a metabolic shift toward oxidative metabolism. Initiating and sustaining leukemia depend on the activity of leukemic stem cells (LSC). LSC also show low ROS levels, but unlike HSC, LSC rely on oxygen to meet their metabolic energetic requirements through mitochondrial respiration. In contrast, leukemic blasts show high ROS levels and great metabolic plasticity, both of which seem to sustain their invasiveness. Oxidative stress and metabolism rewiring are recognized as hallmarks of cancer that are intimately intermingled. Here we present a detailed overview of these two features, sustained at different levels, that support a two-way relationship in leukemia. Modifying ROS levels and targeting metabolism are interesting therapeutic approaches. Therefore, we provide the most recent evidence on the modulation of oxidative stress and metabolism as a suitable anti-leukemic approach.
    Keywords:  NADPH oxidases (NOX); hematopoietic stem cell (HSC); leukemia; leukemic stem cell (LSC); metabolism; reactive oxygen species
    DOI:  https://doi.org/10.3389/fimmu.2022.889875
  25. Curr Drug Metab. 2022 Jun 27.
    Advances in Hybrid Vesicular Based Drug Delivery Systems: Improved Biocompatibility, Targeting, Therapeutic Efficacy and Pharmacokinetics of Anticancer Drugs.
    Aseem Setia, Ram Kumar Sahu, Supratim Ray, Retno Widyowati, Wiwied Ekasari, Swarnlata Saraf.
      Anticancer drugs and diagnostics can be transported in nanoscale vesicles that provide a flexible platform. A hybrid nanoparticle, a nano assembly made up of many types of nanostructures, has the greatest potential to perform these two activities simultaneously. Nanomedicine has shown the promise of vesicular carriers based on lipo-polymersomes, lipid peptides, and metallic hybrid nano-vesicle systems. However, there are significant limitations that hinder the clinical implementation of these systems at the commercial scale such as productivity is low, energy consumption is high, setup is expensive, process durations are long, and the current cancer therapies described in this article. Combinatorial hybrid systems can be used to reduce the above limitations. A greater therapeutic index and improved clinical results are possible with hybrid nanovesicular systems, which integrate the benefits of many carriers into a single structure. Due to their unique properties, cell-based drug delivery systems have shown tremendous benefits in the treatment of cancer. Nanoparticles (NPs) can benefit significantly from the properties of erythrocytes and platelets, which are part of the circulatory cells and circulate for a long time. Due to their unique physicochemical properties, nanomaterials play an essential role in cell-based drug delivery. Combining the advantages of different nanomaterials and cell types gives the resulting delivery systems a wide range of desirable properties. NPs are next-generation core-shell nanostructures that combine a lipid shell with a polymer core. The fabrication of lipid-polymer hybrid nanoparticles has recently undergone a fundamental shift, moving from a two-step to a one-step technique based on joint self-assembly of polymers and lipids. Oncologists are particularly interested in this method as a combinatorial drug delivery platform because of its two-in-one structure. This article addresses various preparative methods for the preparation of hybrid nano-vesicular systems. It also discusses the cellular mechanism of hybrid nano-vesicular systems and describes the thorough knowledge of various hybrid vesicular systems.
    Keywords:  Anticancer hybrid vesicular; Biocompatibility; Specific targeting; cellular mechanism; preparative method
    DOI:  https://doi.org/10.2174/1389200223666220627110049
  26. J Neurol Sci. 2022 Jun 05. pii: S0022-510X(22)00178-2. [Epub ahead of print]440 120316
    The brilliance of nanoscience over cancer therapy: Novel promising nanotechnology-based methods for eradicating glioblastoma.
    Leili Shabani, Milad Abbasi, Masoomeh Amini, Ali Mohammad Amani, Ahmad Vaez.
      Given the limited sensitivity of screening methods and the lack of effective therapeutic interventions for malignant brain tumors such as glioblastoma multiforme (also known as GBM), diagnostic and therapeutic procedures for these tumors are rarely performed on a routine basis. Nanostructures with great selectivity, including silica-based nanovehicles, metallic nanostructures, lipid nanoparticles, quantum dots, and polymeric nanoparticles, have been demonstrated to have excellent potential for passing the BBB efficiently. Based on tumor-derived cells, surface modification, encapsulation of contrast agent, bio composition, and functionalities by appropriate coating materials can all be used to take advantage of the photodynamic, magnetic, and optical capabilities of nanostructures. As a result, nanotechnology has revolutionized the detection, screening, as well as treatment of malignancies and brain tumors. In recent years, nanostructures with biomimetic activities have been designed for uptake by tumors in deep cancer regions, with the goal of monitoring and treating the disease. Also, nanostructures are exceptional nano-vehicles for delivering therapeutic agents to their targeted areas due to their special physicochemical properties, which include nanosized dimensions, larger surface area, specific geometrical characteristics, and the capabilities to encompass various substances within their inner parts or on their exterior surface. This paper describes the current developments of several nanostructures such as dendrimers, liposomes, carbon dots, carbon nanotubes, micelles, and metallic nanoparticles for efficient detection of GBM as well as drug delivery in GBM treatment. The importance of metallic nanoparticle-based radiosensitization, as well as immunotherapy, as good ways to fight metastasis and GBM growth, will also be discussed.
    Keywords:  Glioblastoma imaging; Glioblastoma multiforme; Glioblastoma treatment; Immunotherapy; Nanostructures; Radiosensitization
    DOI:  https://doi.org/10.1016/j.jns.2022.120316
  27. Curr Drug Deliv. 2022 Jun 28.
    Self-Emulsifying System Coloaded with Paclitaxel and Coix Seed Oil Deeply Penetrated to Enhance Efficacy of Cervical Cancer.
    Yunyan Chen, Shaozhen Wang, Qiyan Hu, Lingyun Zhou.
      Background：Paclitaxel (PTX), voted as the promising natural medicine molecules, is widely used in the treatment of cancers. Nevertheless, its clinical application was strictly limited by its poor water solubility. Objective：CP-MEs (Paclitaxel-coix seed oil coloaded microemulsion), a small sized self-emulsifying nanoemulsion formed of combination of PTX and coix seed oil (CSO) was developed in order to improve the solubility of paclitaxel and enhance anti-cervical cancer efficacy in vitro. CSO was selected as the oil phase to replace conventional organic solvents and achieve synergistic anti-tumor effect with paclitaxel.METHODS: Pseudoternary phase diagram was applied to the study of CP-MEs formulation. CP-MEs was prepared and characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The encapsulation efficiency and drug loading efficiency (EE and LE) was detected by HPLC. MTT was adopted to evaluate the cytotoxicity of CP-MEs against HeLa cells. The cellular uptake and apoptotic ratio of CP-MEs was evaluated by flow cytometry. Notably, HeLa 3D tumor spheroid was adopted to evaluate tumor permeability of different size microemulsion as the model.
    RESULTS: The best self-emulsifying ability was exhibited by HS 15: PEG 400 combination. The appearance of CP-MEs was clear and transparent, which exhibited a small size (30.28 ± 0.36) and slight negative surface charge (-4.40 ± 1.13) mV. The EE and LE of CP-MEs were 98.80% and 0.978%, respectively. The cumulative release rate within 48 h of the CP-MEs was 80.21%. In cellular studies, the uptake of fluorescein isothiocyanate (FITC) labeled CP-MEs (FITC/C-MEs) was 17.86-fold higher than free FITC group，leading to significant synergistic anticancer activity in terms of cytotoxicity and apoptosis induction in vitro. The apoptotic rate of CP-MEs treated was 1.70-fold higher than PTX treated. Notably, the penetration of CP-MEs in HeLa 3D tumor sphere model was enhanced, which was related to deeply penetrated microemulsion of small size mediated at the tumor site.
    CONCLUSION: With the advantage of small sized self- emulsifying system，CP-MEs holds great potential to become an efficient nano drug delivery system of cervical cancer treatment in clinic.
    Keywords:  Paclitaxel; anti-cervical cancer; coix seed oil; pseudoternary diagram; self- emulsifying; small sized
    DOI:  https://doi.org/10.2174/1567201819666220628094239
  28. ACS Biomater Sci Eng. 2022 Jun 30.
    Antimicrobial Peptide-Loaded Gelatinase-Responsive Photothermal Nanogel for the Treatment of Staphylococcus aureus-Infected Wounds.
    Mengjin Li, Xuan Wang, Cheng Wang, Lin Qiu, Yang Xuan, Xiaoling Lei, Pengju Jiang, Honglei Shi, Jianhao Wang.
      As the most common pathogen of community and nosocomial infection, the resistance of Staphylococcus aureus (S. aureus) to traditional antibiotics is still increasing with years. Although the potent antibacterial activity of antimicrobial peptides (AMPs) has been widely confirmed, the unpredictable cytotoxicity remains the biggest obstacle to their clinical application. The development of a targeted drug delivery system for S. aureus is a practical strategy to ameliorate the inherent limitations of AMPs. In this work, we constructed an AMP release nanogel (cypate-GNPs@Cy3-AMP, CGCA) of S. aureus infection microenvironment using gelatinase nanoparticles (GNPs) for toxicity control and bacterial clearance. Gelatinase present in the infected site degrades GNPs, thus releasing Cy3-AMP in situ to destroy bacterial cells. Cypate modified on the surface of GNPs supports CGCA to generate localized heat under near-infrared (NIR) laser irradiation, which together with AMPs could cause irreversible physical damage to bacteria. In addition, the encapsulation from GNPs not only effectively limited the toxicity of AMPs but also significantly promoted cell proliferation and migration in vitro. In the mouse infection model, CGCA also exhibited excellent effects of bacterial clearance and wound healing, providing a potential direction for the correct use of AMPs.
    Keywords:  antimicrobial peptides; bacteria-responsive; gelatin nanoparticles; photothermal therapy; wound infection
    DOI:  https://doi.org/10.1021/acsbiomaterials.2c00522
  29. Chem Sci. 2022 Jun 07. 13(22): 6704-6714
    A MXene-derived redox homeostasis regulator perturbs the Nrf2 antioxidant program for reinforced sonodynamic therapy.
    Huan Wang, Xinchen Liu, Xiangyu Yan, Jiawen Fan, Daowei Li, Jinsong Ren, Xiaogang Qu.
      Ultrasound (US)-mediated sonodynamic therapy (SDT) has emerged as a spatiotemporally controllable therapeutic modality in combating cancer because of its high tissue-penetration depth and minimal invasiveness. However, the elevated nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant program in cancer cells can serve as a chief reactive oxygen species (ROS) detoxification system to alleviate oxidative injury and promote tumorigenesis, and thus greatly antagonize the therapeutic efficacy of ROS-mediated anticancer therapies. Herein, we report that vanadium carbide MXene-derived carbon dots (PMQDs) can act as high-efficacy sonosensitizers to efficiently generate ROS upon US irradiation and simultaneously hinder the Nrf2 antioxidant program for enhanced sonodynamic therapy of cancer. These PMQDs show superior US-triggered ROS generating ability because of their efficient migration/separation of electron-hole pairs and narrow bandgap. Importantly, these PMQDs can serve as efficient redox homeostasis regulators to perturb the Nrf2 antioxidant mechanism and thus reduce its effects on ROS neutralization for enhanced SDT efficacy. Overall, the present study will not only provide a new paradigm to augment SDT by perturbing the Nrf2 antioxidant program, but also give valuable insights into developing high-efficacy MXene-derived nanoagents for cancer therapy.
    DOI:  https://doi.org/10.1039/d1sc07073h
  30. Mol Cell Biochem. 2022 Jun 30.
    Mechanisms of cancer cell killing by metformin: a review on different cell death pathways.
    Xiao-Yu Wu, Wen-Wen Xu, Xiang-Kun Huan, Guan-Nan Wu, Gang Li, Yu-Hong Zhou, Masoud Najafi.
      Cancer resistance to anti-tumour agents has been one of the serious challenges in different types of cancer treatment. Usually, an increase in the cell death markers can predict a higher rate of survival among patients diagnosed with cancer. By increasing the regulation of survival genes, cancer cells can display a higher resistance to therapy through the suppression of anti-tumour immunity and inhibition of cell death signalling pathways. Administration of certain adjuvants may be useful in order to increase the therapeutic efficiency of anti-cancer therapy through the stimulation of different cell death pathways. Several studies have demonstrated that metformin, an antidiabetic drug with anti-cancer properties, amplifies cell death mechanisms, especially apoptosis in a broad-spectrum of cancer cells. Stimulation of the immune system by metformin has been shown to play a key role in the induction of cell death. It seems that the induction or suppression of different cell death mechanisms has a pivotal role in either sensitization or resistance of cancer cells to therapy. This review explains the cellular and molecular mechanisms of cell death following anticancer therapy. Then, we discuss the modulatory roles of metformin on different cancer cell death pathways including apoptosis, mitotic catastrophe, senescence, autophagy, ferroptosis and pyroptosis.
    Keywords:  Apoptosis; Autophagy; Cancer; Cell death; Metformin; Senescence
    DOI:  https://doi.org/10.1007/s11010-022-04502-4
  31. Front Endocrinol (Lausanne). 2022 ;13 901495
    Lactate: The Mediator of Metabolism and Immunosuppression.
    Yuanyuan Zhang, Zhao Zhai, Jiali Duan, Xiangcai Wang, Jinghua Zhong, Longqiu Wu, An Li, Miao Cao, Yanyang Wu, Huaqiu Shi, Jianing Zhong, Zhenli Guo.
      The Warburg effect, one of the hallmarks of tumors, produces large amounts of lactate and generates an acidic tumor microenvironment via using glucose for glycolysis. As a metabolite, lactate not only serves as a substrate to provide energy for supporting cell growth and development but also acts as an important signal molecule to affect the biochemical functions of intracellular proteins and regulate the biological functions of different kinds of cells. Notably, histone lysine lactylation (Kla) is identified as a novel post-modification and carcinogenic signal, which provides the promising and potential therapeutic targets for tumors. Therefore, the metabolism and functional mechanism of lactate are becoming one of the hot fields in tumor research. Here, we review the production of lactate and its regulation on immunosuppressive cells, as well as the important role of Kla in hepatocellular carcinoma. Lactate and Kla supplement the knowledge gap in oncology and pave the way for exploring the mechanism of oncogenesis and therapeutic targets. Research is still needed in this field.
    Keywords:  histone lysine lactylation; immunosuppression; lactate; metabolic reprogramming; the Warburg effect
    DOI:  https://doi.org/10.3389/fendo.2022.901495
  32. Cancer Res. 2022 Jun 30. pii: can.22.0917. [Epub ahead of print]
    Metabolic reprogramming in hematological malignancies: advances and clinical perspectives.
    Xin Wang, Zhuoya Yu, Xiangxiang Zhou.
      Metabolic reprogramming is a hallmark of cancer progression. Metabolic activity supports tumorigenesis and tumor progression, allowing cells to uptake essential nutrients from the environment and use the nutrients to maintain viability and support proliferation. The metabolic pathways of malignant cells are altered to accommodate increased demand for energy, reducing equivalents, and biosynthetic precursors. Activated oncogenes coordinate with altered metabolism to control cell-autonomous pathways, which can lead to tumorigenesis when abnormalities accumulate. Clinical and preclinical studies have shown that targeting metabolic features of hematological malignancies is an appealing therapeutic approach. This review provides a comprehensive overview of the mechanisms of metabolic reprogramming in hematologic malignancies and potential therapeutic strategies to target cancer metabolism.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0917
  33. Colloids Surf B Biointerfaces. 2022 Jun 13. pii: S0927-7765(22)00298-3. [Epub ahead of print]217 112615
    Multifunctional mesoporous silica nanoparticles for pH-response and photothermy enhanced osteosarcoma therapy.
    Qinying Shi, Ying Lu, Guannan Zhang, Xin Yang, Rong Li, Guoliang Zhang, Xiudong Guo, Jianbo Song, Qin Ding.
      The recurrence and bone defect of malignant osteosarcoma postsurgical treatment have gained remarkable attention. Therefore, the development of multifunctional treatment platform is urgently desirable to achieve efficient tumor treatment and bone regeneration. In this paper, a multifunctional nanomaterial using mesoporous silica (MSN) as platform modified with quercetin (Qr), collagen (Col) and dopamine (PDA) was developed. Our findings demonstrated that the nanoparticles designed in this work had excellent photothermal properties and pH responsiveness. In addition, the nanoparticles had outstanding anti-tumor ability and could killed Saos-2 cells within 10 min under 808 nm laser irradiation owing to the synergistic effect of hyperthermia and Qr. Besides, the modification of PDA and Col endows the nanoparticles with excellent osteogenic activity.
    Keywords:  Light-assisted therapy; Multifunctional nanoparticles; Osseointegration; Osteosarcoma; PH response
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112615
  34. Nanoscale. 2022 Jun 29.
    Flexible CuS-embedded human serum albumin hollow nanocapsules with peroxidase-like activity for synergistic sonodynamic and photothermal cancer therapy.
    Haijiao Wang, Jun Tao, Chaoli Xu, Ying Tian, Guangming Lu, Bin Yang, Zhaogang Teng.
      Nanoparticle flexibility is an important parameter in determining cell uptake and tumor accumulation, thus modulating therapeutic efficiency in cancer treatment. Herein, we successfully prepared CuS-embedded human serum albumin hollow nanocapsules (denoted CuS/HSA) by a hard-core-assisted layer-by-layer coating approach. This approach afforded CuS/HSA hollow nanocapsules with controllable shell thickness, tunable flexibility, uniform size (272.9 nm), a large hollow cavity, peroxidase-like activity, excellent photothermal conversion ability, and a high tetra-(4-aminophenyl) porphyrin (TAPP) loading capacity (27.3 wt%). The peroxidase-like activity of the CuS nanoparticles enabled them to overcome tumor hypoxia and augment the sonodynamic therapeutic (SDT) effects and photothermal conversion ability for photothermal therapy (PTT). In vitro experiments showed that the CuS/HSA-TAPP hollow nanocapsules efficiently induced cancer cell apoptosis under US irradiation and cancer cell ablation under laser irradiation, thus facilitating synergistic SDT and PTT. Importantly, the flexibility of the CuS/HSA hollow nanocapsules resulted in significantly enhanced cellular internalization and a longer mean residence time (131.3 h) than their solid counterparts (21.0 h). In a breast tumor model, the flexible CuS/HSA hollow nanocapsules exhibited high tumor accumulation of up to 27.1%. In vivo experiments demonstrated that the flexible CuS/HSA-TAPP hollow nanocapsules effectively eliminated breast tumors via the synergistic effect of SDT and PTT.
    DOI:  https://doi.org/10.1039/d2nr00258b
  35. RSC Chem Biol. 2022 Jun 08. 3(6): 614-647
    Laccase-mediated synthesis of bioactive natural products and their analogues.
    Nunzio Cardullo, Vera Muccilli, Corrado Tringali.
      Laccases are a class of multicopper oxidases that catalyse the one-electron oxidation of four equivalents of a reducing substrate, with the concomitant four-electron reduction of dioxygen to water. Typically, they catalyse many anabolic reactions, in which mostly phenolic metabolites were subjected to oxidative coupling. Alternatively, laccases catalyse the degradation or modification of biopolymers like lignin in catabolic processes. In recent years, laccases have proved valuable and green biocatalysts for synthesising compounds with therapeutic value, including antitumor, antibiotic, antimicrobial, and antioxidant agents. Further up to date applications include oxidative depolymerisation of lignin to gain new biomaterials and bioremediation processes of industrial waste. This review summarizes selected examples from the last decade's literature about the laccase-mediated synthesis of biologically active natural products and their analogues; these will include lignans and neolignans, dimeric stilbenoids, biflavonoids, biaryls and other compounds of potential interest for the pharmaceutical industry. In addition, a short section about applications of laccases in natural polymer modification has been included.
    DOI:  https://doi.org/10.1039/d1cb00259g
  36. RSC Adv. 2022 Jun 01. 12(26): 16927-16941
    Applications of nanocomposites based on zeolitic imidazolate framework-8 in photodynamic and synergistic anti-tumor therapy.
    Wen Kang, Ying Tian, Ying Zhao, Xindao Yin, Zhaogang Teng.
      Due to the limitations resulting from hypoxia and the self-aggregation of photosensitizers, photodynamic therapy (PDT) has not been applied clinically to treat most types of solid tumors. Zeolitic imidazolate framework-8 (ZIF-8) is a common metal-organic framework that has ultra-high porosity, an adjustable structure, good biocompatibility, and pH-induced biodegradability. In this review, we summarize the applications of ZIF-8 and its derivatives in PDT. This review is divided into two parts. In the first part, we summarize progress in the application of ZIF-8 to enhance PDT and realize theranostics. We discuss the use of ZIF-8 to avoid the self-aggregation of photosensitizers, alleviate hypoxia, increase the PDT penetration depth, and combine PDT with multi-modal imaging. In the second part, we summarize how ZIF-8 can achieve synergistic PDT with other anti-tumor therapies, including chemotherapy, photothermal therapy, chemodynamic therapy, starvation therapy, protein therapy, gene therapy, and immunotherapy. Finally, we highlight the challenges that must be overcome for ZIF-8 to be widely applied in PDT. To the best of our knowledge, this is the first review of ZIF-8-based nanoplatforms for PDT.
    DOI:  https://doi.org/10.1039/d2ra01102f
  37. Evid Based Complement Alternat Med. 2022 ;2022 8499625
    Bioactive Natural Products against Systemic Arterial Hypertension: A Past 20-Year Systematic and Prospective Review.
    Maisa Gomes da Silva, Sara Léa Fortes Barbosa, Diego Santos Silva, Isadora Basílio Meneses Bezerra, Érika Alves Bezerra, Angélica Gomes Coelho, Ilmara Cecília Pinheiro da Silva Morais, Luis Mário Rezende-Júnior, Iolanda Souza do Carmo, José de Sousa Lima-Neto, Simón Gabriel Comerma-Steffensen, Antônia Maria das Graças Lopes Citó, Daniel Dias Rufino Arcanjo.
      Background: Systemic arterial hypertension is one of the most common cardiovascular risks, corresponding to 45% of deaths involving CVDs. The use of natural products, such as medicinal plants, belongs to a millennial part of human therapeutics history and has been employed as an alternative anti-hypertensive treatment.Objective: The present review aims to prospect some natural products already experimentally assayed against arterial hypertension through scientific virtual libraries and patent documents over the past 20 years. Search strategy. This is a systematic review of the adoption of the PRISMA protocol and a survey of the scientific literature that synthesizes the results from published articles between 2001 and 2020 concerning the use of medicinal plants in the management of hypertension, including which parts of the plant or organism are used, as well as the mechanisms of action underlying the anti-hypertensive effect. Furthermore, a technological prospection was also carried out in patent offices from different countries in order to check technologies based on natural products claimed for the treatment or prevention of hypertension. Inclusion criteria. Scientific articles where a natural product had been experimentally assayed for anti-hypertensive activity (part of plants, plant extracts, and products derived from other organisms) were included. Data extraction and analysis. The selected abstracts of the articles and patent documents were submitted to a rigorous reading process. Those articles and patents that were not related to anti-hypertensive effects and claimed potential applications were excluded from the search.
    Results: Eighty specimens of biological species that showed anti-hypertensive activity were recovered, with 01 representative from the kingdom Fungi and 02 from the kingdom Protista, with emphasis on the families Asteraceae and Lamiaceae, with 6 representatives each. Leaves and aerial parts were the most used parts of the plants for the extraction of anti-hypertensive products, with maceration being the most used extraction method. Regarding phytochemical analyses, the most described classes of biomolecules in the reviewed works were alkaloids, terpenes, coumarins, flavonoids, and peptides, with the reduction of oxidative stress and the release of NO among the mechanisms of action most involved in this process. Regarding the number of patent filings, China was the country that stood out as the main one, with 813 registrations.
    Conclusion: The anti-hypertensive activity of natural products is still little explored in Western countries. Besides, China and India have shown more results in this area than other countries, confirming the strong influence of traditional medicine in these countries.
    DOI:  https://doi.org/10.1155/2022/8499625
  38. ACS Macro Lett. 2022 Jun 27. 861-867
    Mild Hyperthermia-Assisted ROS Scavenging Hydrogels Achieve Diabetic Wound Healing.
    Xiaoliang Qi, Xianqin Tong, Shengye You, Ruiting Mao, Erya Cai, Wenhao Pan, Chenhao Zhang, Rongdang Hu, Jianliang Shen.
      Excessive reactive oxygen species (ROS) production induces oxidative damage to biomolecules, which can lead to the development of chronic diseases. Biocompatible hydrogel antioxidants composed of natural materials, such as polysaccharides and polyphenols, are of significant option for ROS scavenging. However, rapidly achieving hydrogel antioxidants with convenient, economical, safe, and efficient features remains challenging. Herein, facile synthesis of a physically cross-linked polyphenol/polysaccharide hydrogel by introducing tannic acid microsize particles (TAMP) into a cationic guar gum (CG) matrix is reported. Combining antioxidant/photothermal properties of TAMP and mechanical support from injectable CG, the formulated TAMP/CG is explored for treating diabetic wounds. Both in vitro and in vivo assays verify that TAMP/CG can protect the cells from ROS-induced oxidative damage, which can also be strengthened by the local photothermal heating (42 °C) triggered by near-infrared light. Overall, this study establishes the paradigm of enhanced diabetic wound healing by mild hyperthermia-assisted ROS scavenging hydrogels.
    DOI:  https://doi.org/10.1021/acsmacrolett.2c00290
  39. Exp Parasitol. 2022 Jun 28. pii: S0014-4894(22)00113-8. [Epub ahead of print] 108319
    Evaluating the effect of curcumin on the metacestode of Taenia crassiceps.
    José de Jesús Martínez-González, Sandra Lizeth Ríos-Morales, Alberto Guevara-Flores, María Del Pilar Ramos-Godinez, Alejandro López-Saavedra, Juan Luis Rendón, Irene Patricia Del Arenal Mena.
      Curcumin, a curcuminoid present in the rhizome of the plant Curcuma longa has multiple pharmacological effects including anticarcinogenic and anti-inflammatory properties. This work evaluates the anthelmintic effect of the curcumin molecule (98% pure) on Taenia crassiceps cysticerci viability in vitro. Cysticerci incubated in the presence of increasing concentrations of curcumin showed a dose-dependent mortality correlated with a significant increase in the production of reactive oxygen species and a partial inhibition of thioredoxin-glutathione reductase, the only disulfide reductase present in these parasites. At 500 μM curcumin, a 100% of cysticerci lethality was obtained after 2 h of treatment. These results suggest the curcumin-induced oxidative stress could be in the origin of the anthelminthic effect of curcumin. Mice with cysticerci were injected intraperitoneally with 20, 40, or 60 mM curcumin daily for 30 days. A decrease in the burden of cysticerci (46%) was observed with a 60 mM dose of curcumin, supporting this compound as a potential anthelmintic drug.
    Keywords:  104913); 12035); 2′,7′-dichlorodihydrofluorescein diacetate (H(2)-DCFDA) (PubChem CID; 969516); Chemical compounds; Curcumin; Curcumin (PubChem CID; Cysticercosis; N-acetyl cysteine (PubChem CID; Parasitemia; Reactive oxygen species; Taenia crassiceps; Thioredoxin-glutathione reductase
    DOI:  https://doi.org/10.1016/j.exppara.2022.108319
  40. J Microencapsul. 2022 Jun 29. 1-22
    Pinocembrin polymeric micellar drug delivery system: preparation, characterization and anti-hyperuricemic activity evaluation.
    Wanjing Rong, Xinyi Shen, Michael Adu-Frimpong, Qing He, Jian Zhang, Xiaoxiao Li, Xiaoli Xia, Feng Shi, Xia Cao, Hao Ji, Elmurat Toreniyazov, Qilong Wang, Jiangnan Yu, Ximing Xu.
      Aim Hydrophobic pinocembrin (PCB) was incorporated into a new nano-drug delivery system to enhance solubility, bioavailability and anti-hyperuricemic activity of the drug.METHODS: We fabricated PCB loaded polymeric micelles (PCB-FPM) by thin film dispersion method and appropriately determined their physical characteristics. The oral relative bioavailability and anti-hyperuricemic activity of PCB-FPM and free PCB were observed.
    RESULTS: The optimum particle size of the micelles was 19.90 ± 0.93 nm. PCB-FPM exhibited great stability within 18 days, coupled with lower cytotoxicity and higher biocompatibility. Moreover, the percent cumulative release of PCB-FPM was much higher than free PCB in the dissolution media. The oral bioavailability of PCB-FPM was increased by 2.61 times compared with free PCB. Uric acid (UA) level of rats was reduced in PCB-FPM group (200 mg/kg) by 78.82% comparable to the model control.
    CONCLUSION: PCB-FPM may become an ideal strategy to increase oral in-vivo availability and anti-hyperuricemic activity of PCB.
    Keywords:  Pinocembrin; anti-hyperuricemic activity; oral bioavailability; polymer micelles
    DOI:  https://doi.org/10.1080/02652048.2022.2096138
  41. Am J Chin Med. 2022 Jun 30. 1-23
    Research Advances in Lotus Leaf as Chinese Dietary Herbal Medicine.
    Haoxue Zheng, Lintao Han, Wenfeng Shi, Xiaoping Fang, Yi Hong, Yan Cao.
      Lotus leaf (Heye), the dry foliage of Nelumbo nucifera Gaertn, has been valuable as a dietary herbal medicine for thousands of years. Phytochemical studies indicated that alkaloids and flavonoids are the main components of Heye. Polysaccharides, terpenes, and amino acids are also active ingredients. The drug properties of Heye are mild and bitter. Meridian tropism is mainly distributed in the liver, spleen, and stomach meridian. In the Traditional Chinese medicine (TCM) theoretical system, it is in many formulas for the therapy of various symptoms, including wasting-thirst induced by summer heat, diarrhea caused by summer heat-dampness and spleen deficiency, hematochezia, flooding and spotting, among others. Nowadays, the extracts and active components of Heye demonstrate multiple bioactivities, for instance anti-obesity, anti-inflammatory, anti-oxidant, cardiovascular protective, anticancer, hepatoprotective, hypoglycemic, antiviral, antimicrobial, as well as hemostatic activities. This review will provide an overview of Heye serving as a typical plant with functions of both medicine and food, including its practical applications in terms of TCM and healthy diet, phytochemistry, pharmacological activity, together with its toxicity. Besides, the new points and prospects of Heye in the overview are also outlined straightforwardly.
    Keywords:  Heye; Lotus Leaf; Nelumbo nucifera; Pharmacological Activities; Phytochemistry; Review; Traditional Chinese Medicine
    DOI:  https://doi.org/10.1142/S0192415X22500616
  42. Ecotoxicol Environ Saf. 2022 Jun 28. pii: S0147-6513(22)00662-5. [Epub ahead of print]241 113822
    Nonylphenol inhibited HIF-1alpha regulated aerobic glycolysis and induced ROS mediated apoptosis in rat Sertoli cells.
    Qianqian Jiang, Qiannan Di, Dandan Shan, Qian Xu.
      Nonylphenol (NP) is an endocrine disruptor with reproductive toxicity, which can induce apoptosis of Sertoli cells (SCs). SCs have a high aerobic glycolytic flux to ensure sufficient lactate for germ cells as central energy metabolite, and hypoxia-inducible factors 1alpha (HIF-1α) is a major regulator of glycolysis. This study aimed to investigate whether NP can alter HIF-1α-regulated aerobic glycolysis metabolism and thus induce apoptosis in rat SCs. The results revealed that cell viability, intracellular and extracellular lactate levels, the expression of Hk2, Ldha and Mct4, and the protein levels of HIF-1α, HK2, LDHA and MCT4 were decreased significantly when rat SCs exposed to 20 and 30 μM NP for 24 h. Compared with the 30 μM NP group, the protein levels of HIF-1α, HK2 and LDHA, the expression of Hk2 and Ldha and intracellular lactate levels were increased in 30 μM NP and 125 μM cobalt chloride (CoCl2, inhibitor of HIF-1α proteasome-mediated degradation) co-treated group. Furthermore, the elevation of reactive oxygen species (ROS) and apoptosis induced by 30 μM NP were also reversed. In summary, exposure to NP inhibited the ability of SCs to produce and secrete lactate. Meanwhile, NP exposure could lead to a decrease in HIF-1α thereby inhibiting aerobic glycolysis in rat SCs, disrupting intracellular homeostasis and further inducing ROS-mediated apoptosis. This research is the first to explore the NP toxicity on SCs function with respect to nutrition support to germ cells, and provide new evidence on the inhibition of aerobic glycolysis inducing ROS-mediated apoptosis in SCs.
    Keywords:  Aerobic glycolysis; Apoptosis; HIF-1α; Lactate; Nonylphenol; Sertoli cells
    DOI:  https://doi.org/10.1016/j.ecoenv.2022.113822
  43. Colloids Surf B Biointerfaces. 2022 Jun 20. pii: S0927-7765(22)00334-4. [Epub ahead of print]217 112651
    Multifunctional amphiphilic peptide dendrimer as nonviral gene vectors for effective cancer therapy via combined gene/photodynamic therapies.
    Xu-Ying Liu, Xi Zhang, Jing-Bo Yang, Cheng-Yan Wu, Qian Wang, Zhong-Lin Lu, Quan Tang.
      Gene therapy holds great promise for treatment of gene-associated diseases. However, safe and successful clinical application urgently requires further advancement of constructing efficient delivery systems. Herein, three amphiphilic peptide dendrimers (TTC-L-KRR/KKK/KHH), containing the natural amino acid residues (lysine K, arginine R, and histidine H) and AIE-based photosensitizer (tetraphenylethenethiophene modified cyanoacrylate, TTC) modified with alkyl chain (L), have been designed and prepared for improving therapeutic potency via the combination of gene therapy (GT) and photodynamic therapy (PDT). All three compounds possessed typical aggregation-induced emission (AIE) characteristics and ultralow critical micelle concentrations (CMCs). The liposomes consisting of amphiphilic peptide dendrimers and dioleoylphosphatidylethanolamine (DOPE) can effectively bind DNA into nanoparticles with appropriate sizes, regular morphology and good biocompatibility. Among them, liposomes TTC-L-KKK/DOPE exhibited the highest transfection efficiency up to 5.7-fold as compared with Lipo2000 in HeLa cells. Meanwhile, rapid endocytosis, successful endo/lysosomal escape, gene release and rapid nuclear delivery of DNA revealed the superiority of liposomes TTC-L-KKK/DOPE during gene delivery process. More importantly, efficient reactive oxygen species (ROS) generation by TTC-L-KKK/DOPE led to effective PDT, thus improving therapeutic potency via combining with p53 mediated-gene therapy. Our work brought novel insight and direction for the construction of bio-safe and bio-imaging liposome as the multifunctional nonviral gene vectors for the effective combined gene/photodynamic therapies.
    Keywords:  Amphiphilic peptide dendrimers; Gene therapy; Natural amino acids; Nonviral gene vectors; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112651
  44. Recent Pat Anticancer Drug Discov. 2022 Jun 29.
    Nanomaterial for Diagnosis and Treatment for Lung Cancer: A Review of Recent Patents.
    Mandeep Kaur, Praveen Guleria, Vineet Kumar.
      BACKGROUND: Globally, lung cancer is one of the major killers among different kinds of cancer. Therapeutic agents can decrease the mortality rate, but their efficiency is a matter of concern and needs to be improved. Being a silent developer, the earliest detection of lung cancer is a challenging task. Nanotechnology plays a superior role to the conventional means in the detection, diagnosis and treatment of lung cancer.OBJECTIVE: Various patents on nano diagnosis and nano delivery aspect of lung cancer areanalyzed to compile the information in a nutshell. The increasing trend of patents on nano-based solutions for lung cancer opens new opportunities.
    METHODS: Google patent and Science Citation Index Expanded data sources were used to obtain relevant literature on nanodetection and nano-drug delivery for lung cancer. Various keywords were used to ensure inclusion of recent and most relevant information in each section. The gist of the patent is described with suitable subsections.
    RESULTS: Complete knowledge of recent patents on nanotechnology-based theranostics along with treatment of lung cancer is added in the paper. Nanotechnology based diagnosis and treatment of lung cancer overcome the drawbacks of traditional treatments with better stability, targeted drug delivery, controlled sustained drug release, ease of membrane transport, better therapeutic efficacy/safety ratio, optimized clinical results along with cost effective, accurate and early detection.
    CONCLUSION: Overall, the application of nanotechnology in lung cancer treatment and diagnosis is a futuristic approach. Moreover, in vitro and in vivo detection and nano drug delivery to lungs need to be rigorously pursued for a sustainable solution.
    Keywords:  Nanosensor; nano diagnosis.; nano drug delivery; nanocarrier; nanocluster; nanoparticles; slow and sustained release
    DOI:  https://doi.org/10.2174/1574892817666220629104641
  45. Artif Cells Nanomed Biotechnol. 2022 Dec;50(1): 198-207
    MicroRNA-219 loaded chitosan nanoparticles for treatment of glioblastoma.
    Rawan Alswailem, Fulwah Yahya Alqahtani, Fadilah Sfouq Aleanizy, Bahauddeen M Alrfaei, Mohammad Badran, Qamraa Hamad Alqahtani, Hosam Gharib Abdelhady, Ibrahim Alsarra.
      Recent evidence has implicated microRNA-219 (miR-219) in regulation of gene contributed in glioblastoma (GBM) pathogenesis. This study aimed to prepare miR-219 in chitosan (CS) nanoparticles (NPs), characterize and investigate their efficacy on human GBM cell line (U87 MG). NPs were prepared using ionic gelation method. The influence of process parameters on physicochemical characteristics of NPs was investigated. Apoptotic effect of miR-219 was examined on U87 MG cells. Formulated NPs showed particle size of 109 ± 2.18 nm, with poly dispersity index equal to 0.2 ± 0.05, and zeta potential of +20.5 ± 0.7 mV. Entrapment efficiency of miR-219 in loaded NP has reached 95%. The in vitro release study demonstrated sustained release pattern of miR-219 from CS-NPs. Gel retardation assay has confirmed the integrity of miR-219 after production process. The fabricated NPs reduced the survival of U87 MG cells to 78% after 24 h of post-transfection, and into 67.5% after 48 h. However, fibroblasts were not affected by the NPs, revealing their specificity for GBM cells. Given the tumour suppressing function of miR-219, and advantage of CS-NPs for gene delivery to the central nervous system, the presented NPs have a great potential for treatment of GBM.
    Keywords:  Chitosan; Glioblastoma; Nanoparticles; gene delivery; microRNA; microRNA-219
    DOI:  https://doi.org/10.1080/21691401.2022.2092123
  46. Biochimie. 2022 Jun 22. pii: S0300-9084(22)00169-9. [Epub ahead of print]
    Melatonin as an adjuvant treatment modality with doxorubicin.
    Parisa Maleki Dana, Fatemeh Sadoughi, Russel J Reiter, Sotoudeh Mohammadi, Zahra Heidar, Masoumeh Mirzamoradi, Zatollah Asemi.
      Combination chemotherapy seems to be a beneficial choice for some cancer patients particularly when the drugs target different processes of oncogenesis; patients treated with combination therapies sometimes have a better prognosis than those treated with single drug chemotherapy. However, research has shown that this is not always the case, and this approach may only increase toxicity without having a significant effect in augmenting the antitumor actions of the drugs. Doxorubicin (Dox) is one of the most common chemotherapy drugs used to treat many types of cancer, but it also has serious side effects, such as cardiotoxicity, skin necrosis, testicular toxicity, and nephrotoxicity. Many studies have examined the efficiacy of melatonin (MLT) as an anticancer agent. In fact, MLT is an anti-cancer agent that has various functions in inhibiting cancer cell proliferation, inducing apoptosis, and suppressing metastasis. Herein, we provide a comprehensive evaluation of the literature concerned with the role of MLT as an adjuvant in Dox-based chemotherapies and discuss how MLT may enhance the antitumor effects of Dox (e.g., by inducing apoptosis and suppressing metastasis) while rescuring other organs from its adverse effects, such as cardio- and nephrotoxicity.
    Keywords:  Melatonin; chemotherapy; doxorubicin; toxicity
    DOI:  https://doi.org/10.1016/j.biochi.2022.06.007
  47. Crit Rev Food Sci Nutr. 2022 Jun 27. 1-18
    A review of transglycosylated compounds as food additives to enhance the solubility and oral absorption of hydrophobic compounds in nutraceuticals and pharmaceuticals.
    Hiromasa Uchiyama, Kazunori Kadota, Yuichi Tozuka.
      Transglycosylation has been used to modify the physicochemical properties of original compounds. As a result, transglycosylated compounds can form molecular aggregates in size ranges of a few nanometers in an aqueous medium when their concentrations exceed a specific level. Incorporating these hydrophobic compounds has been observed to enhance the solubility of hydrophobic compounds into aggregate structures. Thus, this review introduces four transglycosylated compounds as food additives that can enhance the solubility and oral absorption of hydrophobic compounds. Here, transglycosylated hesperidin, transglycosylated rutin, transglycosylated naringin, and transglycosylated stevia are the focus as representative substances. Significantly, we observed that amorphous formations containing hydrophobic compounds with transglycosylated compounds improved solubility and oral absorption compared to untreated hydrophobic compounds. Moreover, combining transglycosylated compounds with hydrophilic polymers or surfactants enhanced the solubilizing effects on hydrophobic compounds. Furthermore, the enhanced solubility of hydrophobic compounds improved their oral absorption. Transglycosylated compounds also influenced nanoparticle preparation of hydrophobic compounds as a dispersant. This study demonstrated the benefits of transglycosylated compounds in developing supplements and nutraceuticals of hydrophobic compounds with poor aqueous solubility.
    Keywords:  Amorphous; flavonoids; nanoparticles; oral absorption; solubility enhancement; transglycosylation
    DOI:  https://doi.org/10.1080/10408398.2022.2092056
  48. Colloids Surf B Biointerfaces. 2022 Jun 11. pii: S0927-7765(22)00299-5. [Epub ahead of print]217 112616
    A multifunctional nanoplatform for improving microwave hyperthermia by a combination therapy of vessel disruptive agent and immune modulator.
    Zhiheng Zeng, Xiaohan Sun, Zhongbing Huang, Changhui Fu, Jun Ren, Meng Niu, Longfei Tan, Xiangling Ren, Qiong Wu, Xianwei Meng.
      Microwave (MW) hyperthermia is one of the safest and most efficient minimally invasive tumor treatment methods, it is restricted by the bottlenecks of the heat sink effect and ineffective immune activation. Herein, a multifunctional nano platform with the load of nano immune modulator bimetallic metal-organic framework (BM), tumor vessel destructive agent and prodrug for gas production is developed for improving MW hyperthermia. Specifically, the combretastatin A4 phosphate (CA4P) was a vessel destructive agent to reduce MW heat loss by destructing the tumor blood vessel. Moreover, the as designed BM can scavenge the endogenic reactive oxygen species, which is conducive to hydrogen sulfide gas (H2S) that produced by bismuth sulfide (Bi2S3) to activate immune cells. Our in vivo experimental results demonstrate the destruction of tumor blood vessels coupled with the activated immune system results in the remarkable antitumor effect. This study provides an efficient strategy to improve MW hyperthermia by a combination of vasculature-targeting therapy with systemic immunity.
    Keywords:  Bimetallic organic frameworks; H(2)S gas therapy; Heat sink effect; Immune modulator; MW hyperthermia
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112616
  49. Bioorg Med Chem. 2022 Jun 13. pii: S0968-0896(22)00276-0. [Epub ahead of print]69 116884
    Efficient delivery of PKN3 shRNA for the treatment of breast cancer via lipid nanoparticles.
    Chao Liu, Ji Wang, Yanhao Zhang, Wenhui Zha, Hao Zhang, Shuo Dong, Hanlei Xing, Xinsong Li.
      Protein kinase N3 (PKN3), an AGC-family member, is often overexpressed in breast tumor cells. RNAi therapy is a promising approach to inhibit tumor growth by reducing the expression of PKN3. In this report, lipid nanoparticles encapsulated with new shRNA PKN3 (SS-LNP/shPKN3) with redox-responsiveness were developed in order to specifically down-regulate the expression of PKN3 for breast cancer treatment. The SS-LNP/shPKN3 was prepared by microfluidic method using disulfide bonds based ionizable lipid as main component. The as-prepared SS-LNP/shPKN3 lipid nanoparticles were characterized via using dynamic light scattering (DLS) and transmission electron microscopy (TEM). The results indicated that the obtained SS-LNP/shPKN3 exhibited uniform particle size and regular spherical morphology. Moreover, glutathione (GSH) triggered release of shPKN3 confirmed the redox-responsiveness of the SS-LNP/shPKN3. Finally, the anti-tumor effect of SS-LNP/shPKN3 was evaluated against MDA-MB-231 cells and derived xenograft tumor bearing mice. It was found that the SS-LNP/shPKN3-2 had the highest PKN3 protein inhibition rate of 60.8% and tumor inhibition rate of 62.3%. Taken together, the SS-LNP/shPKN3 might be a potential therapeutic strategy for breast cancer.
    Keywords:  Breast cancer; Lipid nanoparticles; Protein kinase N3; RNAi therapy
    DOI:  https://doi.org/10.1016/j.bmc.2022.116884
  50. Asian Pac J Cancer Prev. 2022 Jun 01. pii: 90147. [Epub ahead of print]23(6): 1951-1957
    Development, Characterization, and In Vitro Evaluation of Cytotoxic Activity of Rutin Loaded PCL-PEG Nanoparticles Against Skov3 Ovarian Cancer Cell.
    Akram Firouzai-Amandi, Mahdieh Tarahomi, Hamed Rahmani Youshanlouie, Reza Mosaddeghi Heris, Davoud Jafari-Gharabaghlou, Nosratollah Zarghami, Mehdi Dadashpour.
      BACKGROUND AND PURPOSE: Rutin (RUT) is one of the phenolic compounds found in the invasive plant species, Carpobrotus edulis. Several studies have confirmed numerous pharmacological properties of RUT, including antioxidant, antidiabetic, anti-inflammatory, antimicrobial and anticancer activities. As a result, the goal of this work was to make RUT-loaded PCL-PEG and test its anti-cancer effects against the Skov3 human ovarian cancer cell line.MATERIALS AND METHODS: The NPs were made using the W1/O/W2 process, and their physicochemical properties were assessed by FE-SEM, FTIR, and DLS. MTT assay were used to investigate the anti-proliferative characteristics of drug-loaded NPs. Real-time PCR was also utilized to  examine the expression levels of apoptotic genes including caspase-8, -9, -3, and Bax, as well as anti-apoptotic genes like Bcl-2.
    RESULTS: Cytotoxicity testing revealed that RUT-loaded PCL-PEG improved cytotoxicity in a dose- and time-dependent manner. In treated MDA-MB-231 cells with RUT-loaded PCL-PEG, there was a significant up-regulation of caspase-8, -9, -3, and Bax genes compared to treated cells with free RUT.
    CONCLUSION: Finally, RUT-loaded PCL-PEG NPs are recommended as ideal delivery nanocarriers for enhancing RUT's anticancer characteristics for ovarian cancer treatment.
    Keywords:  Anticancer; Apoptosis; PCL-PEG nanoparticles; Rutin; SKOV3 cells
    DOI:  https://doi.org/10.31557/APJCP.2022.23.6.1951
  51. ACS Appl Mater Interfaces. 2022 Jun 26.
    Dynamic Effects of Endo-Exogenous Stimulations on Enzyme-Activatable Polymeric Nanosystems with Photo-Sono-Chemo Synergy.
    Pu Qiu, Mengmeng Huang, Shiwen Wu, Mei Wen, Nuo Yu, Zhigang Chen.
      Activatable polymeric nanosystems have attracted great interest, and their interactions with endo-exogenous stimulations are highly vital for therapeutic efficacy, which urgently needs systematic study. Herein we focus on systematically investigating these interactions on an enzyme-nanosystem model, the tumor-overexpressed hyaluronidase (HAase) and the doxorubicin-loaded hyaluronic-acid-porphyrin nanoassemblies (DOX@HPNAs), to augment photo-sono-chemo therapies. The HAase degrades the HPNAs in acidic solution at a higher rate than that in neutral solution, which leads to structure disassembly at the nano level, chain cleavage at the molecular level, and strong radiative recovery at the energy level. Upon excitation with light and ultrasound, the enzymatically degraded sample produces ∼2.5 times more singlet oxygen than the HPNAs because of the absence of aggregation-induced quenching and 1O2 migration limitation. The nanosystem can be activated by trimodal stimulations (acidity, ultrasound, and HAase), exerting the controllable release behavior and high release content. Moreover, the nanosystem exhibits synergistic effects among efficient photodynamic therapy, high tissue-penetrating sonodynamic therapy, and lasting chemotherapy, which induces significant necrosis and apoptosis of cancer cells. With high compatibility, tumor-targeting ability, and fluorescent-imaging-guided capability, the nanosystem achieves the highest inhibition rate of malignant tumors than the single or dual-modal therapies. Thus, the enzyme-activatable nanosystem enables the therapeutic synergy and also provides insights to develop other polymeric nanosystems.
    Keywords:  deep tissue; enzyme activation; hyaluronic acid; polymeric nanosystem; sonotherapy
    DOI:  https://doi.org/10.1021/acsami.2c05276
  52. Bioact Mater. 2023 Feb;20 449-462
    Macrophage membrane-biomimetic adhesive polycaprolactone nanocamptothecin for improving cancer-targeting efficiency and impairing metastasis.
    Kangkang Ying, Yifeng Zhu, Jianqin Wan, Chenyue Zhan, Yuchen Wang, Binbin Xie, Peirong Xu, Hongming Pan, Hangxiang Wang.
      The recent remarkable success and safety of mRNA lipid nanoparticle technology for producing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has stimulated intensive efforts to expand nanoparticle strategies to treat various diseases. Numerous synthetic nanoparticles have been developed for pharmaceutical delivery and cancer treatment. However, only a limited number of nanotherapies have enter clinical trials or are clinically approved. Systemically administered nanotherapies are likely to be sequestered by host mononuclear phagocyte system (MPS), resulting in suboptimal pharmacokinetics and insufficient drug concentrations in tumors. Bioinspired drug-delivery formulations have emerged as an alternative approach to evade the MPS and show potential to improve drug therapeutic efficacy. Here we developed a biodegradable polymer-conjugated camptothecin prodrug encapsulated in the plasma membrane of lipopolysaccharide-stimulated macrophages. Polymer conjugation revived the parent camptothecin agent (e.g., 7-ethyl-10-hydroxy-camptothecin), enabling lipid nanoparticle encapsulation. Furthermore, macrophage membrane cloaking transformed the nonadhesive lipid nanoparticles into bioadhesive nanocamptothecin, increasing the cellular uptake and tumor-tropic effects of this biomimetic therapy. When tested in a preclinical murine model of breast cancer, macrophage-camouflaged nanocamptothecin exhibited a higher level of tumor accumulation than uncoated nanoparticles. Furthermore, intravenous administration of the therapy effectively suppressed tumor growth and the metastatic burden without causing systematic toxicity. Our study describes a combinatorial strategy that uses polymeric prodrug design and cell membrane cloaking to achieve therapeutics with high efficacy and low toxicity. This approach might also be generally applicable to formulate other therapeutic candidates that are not compatible or miscible with biomimetic delivery carriers.
    Keywords:  Antimetastasis; Cancer nanomedicine; Macrophage membrane; Nanocamptothecin; Polymer prodrug
    DOI:  https://doi.org/10.1016/j.bioactmat.2022.06.013
  53. J Ethnopharmacol. 2022 Jun 22. pii: S0378-8741(22)00537-2. [Epub ahead of print]296 115498
    Agrimonia eupatoria L.: An integrative perspective on ethnomedicinal use, phenolic composition and pharmacological activity.
    Jéssica Malheiros, Daniela M Simões, Artur Figueirinha, Maria Dulce Cotrim, Diogo A Fonseca.
      ETHNOPHARMACOLOGICAL RELEVANCE: Agrimonia eupatoria L., a plant which belongs to the Rosaceae family, is widespread in temperate regions, particularly throughout the northern hemisphere. In folk medicine, this plant species has been used for its astringent, anti-inflammatory, analgesic and hypotensive properties as well as in gastrointestinal disorders. As these biological properties have been linked to its phenolic composition, this plant species could be an interesting source of bioactive compounds with therapeutic potential.AIM OF THE STUDY: The aim of the present review is to provide a comprehensive overview of the scientific literature on A. eupatoria, particularly in regard to its ethnobotanics and ethnomedicinal uses, phenolic composition and biological and pharmacological activities.
    MATERIAL AND METHODS: Literature was retrieved from several bibliographic sources, namely PubMed, ScienceDirect and Google Scholar, since the first report on A. eupatoria in 1993.
    RESULTS: Regarding the phytochemical composition, A. eupatoria is rich in phenolic acids, flavonoids and tannins. The most commonly reported compounds are astragalin, cynaroside, hyperoside, isoquercitrin, isovitexin, rutin, catechin, procyanidin B3 and agrimoniin. In terms of bioactivity, extracts or fractions obtained from this plant species have shown antioxidant, antimicrobial, antidiabetic, antinociceptive and anti-inflammatory properties, among others. So far, two clinical studies with the infusion of A. eupatoria have shown hepatoprotective properties as well as a protective role in cardiovascular disease, metabolic disorders and diabetes.
    CONCLUSIONS: In this review, an integrative perspective on ethnomedicinal use, phenolic composition and pharmacological activity of A. eupatoria has been provided. As can be seen, this plant species exhibits several potential applications, including those beyond its traditional ethnomedicinal uses, as the safety of its consumption has been shown clinically. There still is limited pharmacological evidence that corroborates the ethnomedicinal uses of this plant species as well as regarding the specific bioactive compounds.
    Keywords:  Agrimonia eupatoria L.; Bioactivity; Clinical application; Ethnomedicinal use; Pharmacological activity; Phenolic composition
    DOI:  https://doi.org/10.1016/j.jep.2022.115498
  54. J Agric Food Chem. 2022 Jun 30.
    Caffeic Acid, an Active Ingredient in Coffee, Combines with DOX for Multitarget Combination Therapy of Lung Cancer.
    Xue Bai, Shuting Li, Xinyi Liu, Hailong An, Xianjiang Kang, Shuai Guo.
      Adjuvant diet therapy is an important means of comprehensive treatment of cancer. It is recognized by patients for its high safety, painlessness, and ease to operate. However, the development of adjuvant dietary therapy is limited by unclear targets and unclear anticancer mechanisms. In this work, caffeic acid was found as an inhibitor of TMEM16A with an IC50 of 29.47 ± 3.19 μM by fluorescence quenching and whole-cell patch-clamp experiments. Caffeic acid regulated the proliferation, migration, and apoptosis of lung cancer cells targeting TMEM16A, which was detected by CCK-8, colony formation, wound healing, and Annexin V assays. In addition, molecular docking combined with site-directed mutagenesis confirmed that the binding sites of caffeic acid to TMEM16A were D439, E448, and R753. Western blot results indicated that caffeic acid regulated the growth of lung cancer through the MAPK pathway. In vitro experiments showed that the inhibitory effect of caffeic acid combined with hydroxydaunorubicin (DOX) on lung cancer cell growth was better than a double concentration of any single dose. In vivo pharmacokinetic experiments and tumor xenograft experiments indicated that the combination of 5.4 mg/kg caffeic acid and 4.1 mg/kg DOX achieved 85.6% tumor suppression rate and offset the side effects. Therefore, caffeic acid is a safe and efficient antitumor active ingredient of food that can enhance the antitumor effect of DOX.
    Keywords:  DOX; caffeic acid; lung cancer; molecular target; multitarget combined administration
    DOI:  https://doi.org/10.1021/acs.jafc.2c03009
  55. ACS Appl Bio Mater. 2022 Jun 27.
    Dendrimer-Functionalized Nanodiamonds as Safe and Efficient Drug Carriers for Cancer Therapy: Nucleus Penetrating Nanoparticles.
    Sachin Patil, Vishnu S Mishra, Nisha Yadav, Puli Chandramouli Reddy, Bimlesh Lochab.
      Nanodiamonds (NDs) are increasingly being assessed as potential candidates for drug delivery in cancer cells and they hold great promise in overcoming the side effects of traditional chemotherapeutics. In the current work, carboxylic acid functionalized nanodiamonds (ND-COOH) were covalently modified with poly(amidoamine) dendrimer (PAMAM) to form amine-terminated nanodiamonds (NP). Unlike ND-COOH, the chemically modified nanodiamond platform NP revealed a pH-independent aqueous dispersion stability, enhancing its potential as an effective carrier. Physical encapsulation of poorly water soluble cabazitaxel (CTX) drug on NP formed ND-PAMAM-CTX (NPC) nanoconjugates and substantially reduced the size of CTX from micrometer to nanometer. CTX was localized within the pores of nanoparticle aggregates and the cavities of the PAMAM dendrimer, thus facilitating the loaded drug's controlled and sustained release. NPC's cumulative CTX release efficiency was determined to be ∼95% at pH 4 after 96 h. A high cellular uptake of NPC both within the cytoplasm and nucleus of U87 cells is confirmed, accounting for a reduced IC50 value (1 nM). Both the cell cycle and Western blot analyses confirmed enhanced cell death and suppressed tubulin protein expression in NPC-treated cells. A significantly high inhibition to cell division with early apoptosis and reduced metastasis demonstrates the effective loading of CTX dosages on the nanocarrier. The present work highlights the potential of a newly designed nanocarrier NP as an efficient nanocargo for cellular delivery applications and may provide future insights to treat one of the most aggressive tumors in neuro-oncological research, glioblastoma multiforme (GBM).
    Keywords:  PAMAM functionalized; cabazitaxel; colloidal stability; drug delivery; nanocargo
    DOI:  https://doi.org/10.1021/acsabm.2c00373
  56. J Mater Chem B. 2022 Jun 29.
    Molecular engineering to achieve AIE-active photosensitizers with NIR emission and rapid ROS generation efficiency.
    Guanyu Ding, Jialin Tong, Jianye Gong, Zhiming Wang, Zhongmin Su, Lu Liu, Xu Han, Jianguo Wang, Lingyu Zhang, Xinlong Wang, Li-Li Wen, Guo-Gang Shan.
      Near-infrared (NIR) photosensitizers with rapid reactive oxygen species (ROS) production ability are in great demand owing to their promising performance toward boosting photodynamic therapy (PDT) and deep-tissue imaging, but molecular design guidelines for efficient photosensitizers are rarely elucidated. Herein, three AIEgens named DBP, TBP, and TBP-SO3 are designed and synthesized by precise donor-acceptor (D-A) molecular engineering to deeply understand the structure-property-application relationships. All the compounds exhibit AIE characteristics with strong long-wavelength emission in the aggregated state and are capable of efficiently producing ROS under white light irradiation. By controlling the ability of the D-A units, TBP-SO3 realizes NIR emission and more rapid ROS generation ability due to the promoted intersystem crossing processes compared with those of DBP and TBP. In addition, NIR-emitting TBP-SO3 is capable of specific endoplasmic reticulum targeting and excellent PDT treatment ability of cancer cells and bacteria. This successful example of molecular engineering paves a valuable way for developing advanced PSs with AIE properties, efficient ROS generation ability, and intense emission for fluorescence imaging PDT.
    DOI:  https://doi.org/10.1039/d1tb02738g
  57. Oxid Med Cell Longev. 2022 ;2022 1112987
    Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-Resistant Lung Cancer.
    Qian Xin, Qinghong Ji, Ying Zhang, Weihong Ma, Baoqing Tian, Yanli Liu, Yunsong Chen, Fei Wang, Ran Zhang, Xingwu Wang, Jupeng Yuan.
      Lung cancer has become a global health issue in recent decades. Approximately 80-85% of cases are non-small-cell lung cancer (NSCLC). Despite the high rate of resistance, cisplatin-base chemotherapy is still the main treatment for NSCLC patients. Thus, overcoming cisplatin resistance is urgently needed in NSCLC therapy. In this study, we identify NADPH metabolism and reactive oxygen species (ROS) levels as the main causes accounting for cisplatin resistance. Based on a small panel consisting of common chemotherapy drugs or compounds, APR-246 is proved to be an effective compound targeting cisplatin-resistant NSCLC cells. APR-246 specially inhibits proliferation and colony formation of cisplatin-resistant cells. In details, APR-246 can significantly cause G0/G1 accumulation and S phase arrest of cisplatin resistant cells and gives rise to severe mitochondria dysfunction as well as elevated apoptosis. Further study proves that it is the aberrant ROS levels as well as NRF2/SLC7A11/GSH axis dysfunction accounting for the specific antitumor effects of APR-246. Scavenging ROS with N-acetylcysteine (NAC) disrupts the inhibitory effect of APR-246 on cisplatin-resistant cells. Mechanistically, NRF2 is specifically degraded by the proteasome following its own ubiquitylation in APR-246-treated cisplatin-resistant cells, which in turn decreases NRF2/SLC7A11/GSH axis activity. Our study provides new insights into the biology driving cisplatin resistance of lung cancer and highlights APR-246 as a potential therapeutic reagent for overcoming cisplatin resistance.
    DOI:  https://doi.org/10.1155/2022/1112987
  58. Med Sci (Paris). 2022 Jun-Jul;38(6-7):38(6-7): 526-528
    [How dietary interventions can change lipid metabolism to affect tumor growth].
    Jean Bastin, Fatima Djouadi.
      
    DOI:  https://doi.org/10.1051/medsci/2022072
  59. Front Nutr. 2022 ;9 905658
    Anticancer Effect of Spices Used in Mediterranean Diet: Preventive and Therapeutic Potentials.
    Wamidh H Talib, Mallak J AlHur, Sumaiah Al Naimat, Rawand E Ahmad, Arkan Hadi Al-Yasari, Anfal Al-Dalaeen, Samar Thiab, Asma Ismail Mahmod.
      Cancer is one of the leading causes of death worldwide, with almost 10 million cancer-related deaths worldwide in 2020, so any investigation to prevent or cure this disease is very important. Spices have been studied widely in several countries to treat different diseases. However, studies that summarize the potential anticancer effect of spices used in Mediterranean diet are very limited. This review highlighted chemo-therapeutic and chemo-preventive effect of ginger, pepper, rosemary, turmeric, black cumin and clove. Moreover, the mechanisms of action for each one of them were figured out such as anti-angiogenesis, antioxidant, altering signaling pathways, induction of cell apoptosis, and cell cycle arrest, for several types of cancer. The most widely used spice in Mediterranean diet is black pepper (Piper nigrum L). Ginger and black cumin have the highest anticancer activity by targeting multiple cancer hallmarks. Apoptosis induction is the most common pathway activated by different spices in Mediterranean diet to inhibit cancer. Studies discussed in this review may help researchers to design and test new anticancer diets enriched with selected spices that have high activities.
    Keywords:  anti-angiogenesis; cell apoptosis; chemo-prevention; ginger; spices
    DOI:  https://doi.org/10.3389/fnut.2022.905658
  60. Pharm Res. 2022 Jun 28.
    Biodegradable and Inherently Fluorescent pH-Responsive Nanoparticles for Cancer Drug Delivery.
    Kalindu Perera, Dat X Nguyen, Dingbowen Wang, Aneetta E Kuriakose, Jian Yang, Kytai T Nguyen, Jyothi U Menon.
      PURPOSE: The development of two novel pH-only and pH- and thermo-responsive theranostic nanoparticle (NP) formulations to deliver an anticancer drug and track the accumulation and therapeutic efficacy of the formulations through inherent fluorescence.METHODS: A pH-responsive formulation was synthesized from biodegradable photoluminescent polymer (BPLP) and sodium bicarbonate (SBC) via an emulsion technique, while a thermoresponsive BPLP copolymer (TFP) and SBC were used to synthesize a dual-stimuli responsive formulation via free radical co-polymerization. Cisplatin was employed as a model drug and encapsulated during synthesis. Size, surface charge, morphology, pH-dependent fluorescence, lower critical solution temperature (LCST; TFP NPs only), cytocompatibility and in vitro uptake, drug release kinetics and anticancer efficacy were assessed.
    RESULTS: While all BPLP-SBC and TFP-SBC combinations produced spherical nanoparticles of a size between 200-300 nm, optimal polymer-SBC ratios were selected for further study. Of these, the optimal BPLP-SBC formulation was found to be cytocompatible against primary Type-1 alveolar epithelial cells (AT1) up to 100 μg/mL, and demonstrated sustained drug release over 14 days, dose-dependent uptake, and marked pH-dependent A549 cancer cell killing (72 vs. 24% cell viability, at pH 7.4 vs. 6.0). The optimal TFP-SBC formulation showed excellent cytocompatibility against AT1 cells up to 500 μg/mL, sustained release characteristics, dose-dependent uptake, pH-dependent (78% at pH 7.4 vs. 64% at pH 6.0 at 37°C) and marked temperature-dependent A549 cancer cell killing (64% at 37°C vs. 37% viability at pH 6.0, 41°C).
    CONCLUSIONS: In all, both formulations hold promise as inherently fluorescent, stimuli-responsive theranostic platforms for passively targeted anti-cancer therapy.
    Keywords:  fluorescent; nanoparticles; pH-sensitive; theranostic; thermoresponsive
    DOI:  https://doi.org/10.1007/s11095-022-03317-8
  61. Expert Opin Drug Deliv. 2022 Jun 27.
    Recent progress in therapeutic strategies and biomimetic nanomedicines for rheumatoid arthritis treatment.
    Chunhong Li, Xiu Zheng, Mei Hu, Ming Jia, Rongrong Jin, Yu Nie.
      INTRODUCTION: Rheumatoid arthritis (RA) is an autoimmune systemic disease in which inflammatory and immune cells accumulate in inflamed joints. Researchers aimed at the characteristics of RA to achieve the effect of treating RA through different therapeutic strategies, and have used various endogenous materials to design drug-loaded nanoparticles that can target RA by binding to cell adhesion molecules or chemokines. In some cases, the nanoparticles can respond to the characteristics of the microenvironment.AREAS COVERED: This article reviews the recent advances in the treatment of RA from two aspects of therapeutic strategies and delivery strategies. Therapeutic strategies mainly include neutralization of inflammatory factors, promotion of inflammatory cell apoptosis, ROS scavenger, immunosuppression, and bone tissue repair. The drug delivery strategy is mainly described from two aspects: chemically functionalized biomimetic nanoparticles and endogenous nanoparticles.
    EXPERT OPINION: Biomimetic NPs may be effective drug carriers for targeted RA treatment. NPs can reduce the clearance of mononuclear phagocytes, prolong the blood circulation time, and improve the targeting ability. With the deepening of research, more and more biomimetic NPs have entered the clinical trial stage. However, safe and scalable preparation methods are needed to improve their clinical applicability.
    Keywords:  Rheumatoid arthritis; biomimetic nanomedicines; combination therapy; inflammatory microenvironment; therapeutic strategy
    DOI:  https://doi.org/10.1080/17425247.2022.2094364
  62. J Transl Med. 2022 Jun 27. 20(1): 290
    Inhibition of autophagy by chloroquine prevents resistance to PI3K/AKT inhibitors and potentiates their antitumor effect in combination with paclitaxel in triple negative breast cancer models.
    Stefania Cocco, Alessandra Leone, Maria Serena Roca, Rita Lombardi, Michela Piezzo, Roberta Caputo, Chiara Ciardiello, Susan Costantini, Francesca Bruzzese, Maria José Sisalli, Alfredo Budillon, Michelino De Laurentiis.
      BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive disease characterized by high risk of relapse and development of resistance to different chemotherapy agents. Several targeted therapies have been investigated in TNBC with modest results in clinical trials. Among these, PI3K/AKT inhibitors have been evaluated in addition to standard therapies, yielding conflicting results and making attempts on elucidating inherent mechanisms of resistance of great interest. Increasing evidences suggest that PI3K/AKT inhibitors can induce autophagy in different cancers. Autophagy represents a supposed mechanism of drug-resistance in aggressive tumors, like TNBC. We, therefore, investigated if two PI3K/AKT inhibitors, ipatasertib and taselisib, could induce autophagy in breast cancer models, and whether chloroquine (CQ), a well known autophagy inhibitor, could potentiate ipatasertib and taselisib anti-cancer effect in combination with conventional chemotherapy.METHODS: The induction of autophagy after ipatasertib and taselisib treatment was evaluated in MDAMB231, MDAM468, MCF7, SKBR3 and MDAB361 breast cancer cell lines by assaying LC3-I conversion to LC3-II through immunoblotting and immunofluorescence. Other autophagy-markers as p62/SQSTM1 and ATG5 were evaluated by immunoblotting. Synergistic antiproliferative effect of double and triple combinations of ipatasertib/taselisib plus CQ and/or paclitaxel were evaluated by SRB assay and clonogenic assay. Anti-apoptotic effect of double combination of ipatasertib/taselisib plus CQ was evaluated by increased cleaved-PARP by immunoblot and by Annexin V- flow cytometric analysis. In vivo experiments were performed on xenograft model of MDAMB231 in NOD/SCID mice.
    RESULTS: Our results suggested that ipatasertib and taselisib induce increased autophagy signaling in different breast cancer models. This effect was particularly evident in PI3K/AKT resistant TNBC cells, where the inhibition of autophagy by CQ potentiates the therapeutic effect of PI3K/AKT inhibitors in vitro and in vivo TNBC models, synergizing with taxane-based chemotherapy.
    CONCLUSION: These data suggest that inhibition of authophagy with CQ could overcome mechanism of drug resistance to PI3K/AKT inhibitors plus paclitaxel in TNBC making the evaluation of such combinations in clinical trials warranted.
    Keywords:  Autophagy; Breast Cancer; Chloroquine; PI3K/AKT/mTOR inhibitors; TNBC
    DOI:  https://doi.org/10.1186/s12967-022-03462-z
  63. J Biol Chem. 2022 Jun 23. pii: S0021-9258(22)00628-7. [Epub ahead of print] 102186
    Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition.
    Minh V Huynh, Derek Parsonage, Tom E Forshaw, Venkat R Chirasani, G Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M Furdui, Leslie B Poole, Sharon L Campbell.
      The recent development of mutant-selective inhibitors for the oncogenic KRASG12C allele has generated considerable excitement. These inhibitors covalently engage the mutant C12 thiol located within the phosphoryl binding loop of RAS, locking the KRASG12C protein in an inactive state. While clinical trials of these inhibitors have been promising, mechanistic questions regarding the reactivity of this thiol remain. Here, we show by NMR and an independent biochemical assay that the pKa of the C12 thiol is depressed (pKa ∼7.6), consistent with susceptibility to chemical ligation. Using a validated fluorescent KRASY137W variant amenable to stopped-flow spectroscopy, we characterized the kinetics of KRASG12C fluorescence changes upon addition of ARS-853 or AMG 510, noting that at low temperatures, ARS-853 addition elicited both a rapid first phase of fluorescence change (attributed to binding, Kd = 36.0 ± 0.7 μM), and a second, slower pH-dependent phase, taken to represent covalent ligation. Consistent with the lower pKa of the C12 thiol, we found that reversible and irreversible oxidation of KRASG12C occurred readily both in vitro and in the cellular environment, preventing the covalent binding of ARS-853. Moreover, we found that oxidation of the KRASG12C Cys12 to a sulfinate altered RAS conformation and dynamics to be more similar to KRASG12D in comparison to the unmodified protein, as assessed by molecular dynamics simulations. Taken together, these findings provide insight for future KRASG12C drug discovery efforts, as well as identifying the occurrence of G12C oxidation with currently unknown biological ramifications.
    Keywords:  KRAS(G12C); RAS GTPase; covalent inhibitors; lung cancer; oxidation; thiol alkylators
    DOI:  https://doi.org/10.1016/j.jbc.2022.102186
  64. Biomater Sci. 2022 Jun 27.
    Self-boosting stimulus activation of a polyprodrug with cascade amplification for enhanced antitumor efficacy.
    Qingyu Zong, Xuan Xiao, Jisi Li, Youyong Yuan.
      The use of polyprodrugs, which bind drugs to polymer chains through responsive linkers, is a potential technique for cancer therapy; however, a lack of endogenous triggering factors limits drug activation in tumor tissue. Herein, we rationally created a reactive oxygen species (ROS)-sensitive polyprodrug (TSCA/DOX) with cascade amplification of triggering agents and drug activation by incorporating both an ROS signal amplifier (TACA) and a drug activation amplifier (SIPDOX) into a delivery system. Endogenous ROS as a triggering mechanism kicked off the initial circulation phase to increase intracellular ROS signals. Subsequently, the enhanced ROS initiated the second degradation step, allowing the polyprodrug SIPDOX to fracture spontaneously in a domino-like fashion, resulting in self-accelerated drug activation in tumor tissue. Therefore, the polyprodrug created in this study with cascade amplification of drug activation holds great promise for effective cancer treatment.
    DOI:  https://doi.org/10.1039/d2bm00647b
  65. Acta Pharm Sin B. 2022 Jun;12(6): 2934-2949
    Nanoparticles with rough surface improve the therapeutic effect of photothermal immunotherapy against melanoma.
    Jiao Xue, Yining Zhu, Shuting Bai, Chunting He, Guangsheng Du, Yuandong Zhang, Yao Zhong, Wenfei Chen, Hairui Wang, Xun Sun.
      Photothermal therapy has been intensively investigated for treating cancer in recent years. However, the long-term therapeutic outcome remains unsatisfying due to the frequently occurred metastasis and recurrence. To address this challenge, immunotherapy has been combined with photothermal therapy to activate anti-tumor immunity and relieve the immunosuppressive microenvironment within tumor sites. Here, we engineered silica-based core‒shell nanoparticles (JQ-1@PSNs-R), in which silica cores were coated with the photothermal agent polydopamine, and a bromodomain-containing protein 4 (BRD4) inhibitor JQ-1 was loaded in the polydopamine layer to combine photothermal and immune therapy for tumor elimination. Importantly, to improve the therapeutic effect, we increased the surface roughness of the nanoparticles by hydrofluoric acid (HF) etching during the fabrication process, and found that the internalization of JQ-1@PSNs-R was significantly improved, leading to a strengthened photothermal killing effect as well as the increased intracellular delivery of JQ-1. In the animal studies, the multifunctional nanoparticles with rough surfaces effectively eradicated melanoma via photothermal therapy, successfully activated tumor-specific immune responses against residual tumor cells, and further prevented tumor metastasis and recurrence. Our results indicated that JQ-1@PSNs-R could serve as an innovative and effective strategy for combined cancer therapy.
    Keywords:  Immunotherapy; JQ-1; Melanoma; Photothermal therapy; Polydopamine-coated silica nanoparticles; Rough surface
    DOI:  https://doi.org/10.1016/j.apsb.2021.11.020
  66. ACS Omega. 2022 Jun 21. 7(24): 21267-21279
    Harnessing ROS-Induced Oxidative Stress for Halting Colorectal Cancer via Thiazolidinedione-Based SOD Inhibitors.
    Mohamed Nabil Abd Al Moaty, El Sayed H El Ashry, Laila Fathy Awad, Asmaa Mostafa, Marwa M Abu-Serie, Mohamed Teleb.
      Based on the "canonical" view of reactive oxygen species' (ROS) contribution to carcinogenesis, ROS induce oxidative stress and promote various tumor progression events. However, tumor cells also need to defend themselves against oxidative damage. This "heresy" was supported by several recent studies underlining the role of cellular antioxidant capacity in promoting metastasis and resistance to chemotherapy. Accordingly, harnessing the ROS-induced oxidative stress via selective suppression of the cancer antioxidant defense machinery has been launched as an innovative anticancer strategy. Within this approach, pharmacological inhibition of superoxide dismutases (SODs), the first-line defense antioxidant enzymes for cancer cells, selectively kills tumor cells and circumvents their acquired resistance. Various SOD inhibitors have been introduced, of which some were tolerated in clinical trials. However, the hit SOD inhibitors belong to diverse chemical classes and lack comprehensive structure-activity relationships (SAR). Herein, we probe the potential of newly synthesized benzylidene thiazolidinedione derivatives to inhibit SOD in colorectal cancer with special emphasis on their effects on correlated antioxidant enzymes aldehyde dehydrogenase 1 (ALDH1) and glutathione peroxidase (GPx). This may possibly bring a new dawn for utilizing thiazolidinediones (TZDs) in cancer therapy through SOD inhibition mechanisms. The preliminary 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that all of the evaluated TZDs exhibited excellent safety profiles on normal human cells, recording an EC100 of up to 47.5-folds higher than that of doxorubicin. Compounds 3c, 6a, and 6e (IC50 = 4.4-4.7 μM) were superior to doxorubicin and other derivatives against Caco-2 colorectal cancer cells within their safe doses. The hit anticancer agents inhibited SOD (IC50 = 97.2-228.8 μM). Then, they were selected for further in-depth evaluation on the cellular level. The anticancer IC50 doses of 3c, 6a, and 6e diminished the antioxidant activities of SOD (by 29.7, 70.1, and 33.3%, respectively), ALDH1A (by 85.92, 95.84, and 86.48%, respectively), and GPX (by 50.17, 87.03, and 53.28%, respectively) in the treated Caco-2 cells, elevating the Caco-2 cellular content of ROS by 21.42, 7.863, and 8.986-folds, respectively. Docking simulations were conducted to display their possible binding modes and essential structural features. Also, their physicochemical parameters and pharmacokinetic profiles formulating drug-likeness were computed.
    DOI:  https://doi.org/10.1021/acsomega.2c02410
  67. Eur J Med Chem. 2022 Jun 17. pii: S0223-5234(22)00444-5. [Epub ahead of print]239 114542
    Cancer multidrug-resistance reversal by ABCB1 inhibition: A recent update.
    Kritika Engle, Gautam Kumar.
      Chemotherapy is one of the most common treatments for cancer that uses one or more anti-cancer drugs as a part of the standardized chemotherapy regimen. Cytotoxic chemicals delay and prevent cancer cells from multiplying, invading, and metastasizing. However, the significant drawbacks of cancer chemotherapy are the lack of selectivity of the cytotoxic drugs to tumour cells and normal cells and the development of resistance by cells for the particular drug or the combination of drugs. Multidrug resistance (MDR) is the low sensitivity of specific cells against drugs associated with cancer chemotherapy. The most common mechanisms of anticancer drug resistance are: (a) drug-dependent MDR (b) target-dependent MDR, and (c) drug target-independent MDR. In all the factors, the overexpression of multidrug efflux systems contributes significantly to the increased resistance in the cancer cells. Multidrug resistance due to efflux of anticancer drugs by membrane ABC transporters includes ABCB1, ABCC1, and ABCG2. ABCB1 inhibition can restore the sensitivity of the cancerous cells toward chemotherapeutic drugs. In this review, we discussed ABCB1 inhibitors under clinical studies with their mode of action, potency and selectivity. Also, we have highlighted the contribution of repurposing drugs, biologics and nano formulation strategies to combat multidrug resistance by modulating the ABCB1 activity.
    Keywords:  ABC efflux; ABCB1; ABCC1; ABCG2; Clinical trials; Drug repurposing; Efflux pumps; Multidrug-resistance; Nano formulation; P-gp1 efflux pump
    DOI:  https://doi.org/10.1016/j.ejmech.2022.114542
  68. Acta Histochem. 2022 Jun 27. pii: S0065-1281(22)00078-2. [Epub ahead of print]124(6): 151919
    The mechanism and progress of ferroptosis in pancreatic cancer.
    Zhi-Hang Bao, Xiang-Bin Hou, Hao-Ling Li, Yi-Feng Mao, Wen-Rui Wang.
      Pancreatic cancer is one of the deadliest cancers in the world, causing hundreds of thousands of deaths worldwide annually. Because of late diagnosis, rapid metastasis and drug resistance to chemotherapy, pancreatic cancer has a poor prognosis. Although the treatment of pancreatic cancer has made tremendous progress, the options for effective treatment are still limited, and new treatment methods are in crying needs to improve prognosis in clinic. Ferroptosis is an iron-dependent non-apoptotic cell death mode, which is mediated by lipid peroxidation and iron accumulation. Ferroptosis plays a momentous role in regulating different cancers in recent years, such as breast cancer, hepatocellular carcinoma, lung cancer and pancreatic cancer. In this present review, we elaborate on the regulatory mechanisms and signaling pathways of ferroptosis in pancreatic cancer, with the intention of delivering directions and new ideas for the treatment of pancreatic cancer.
    Keywords:  Ferroptosis; GPX4; Lipid peroxidation; Pancreatic cancer; Therapy strategy
    DOI:  https://doi.org/10.1016/j.acthis.2022.151919
  69. J Microencapsul. 2022 Jun 28. 1-43
    pH-responsive Glucosamine Anchored Polydopamine Coated Mesoporous Silica Nanoparticles for delivery of Anderson-type Polyoxomolybdate in Breast Cancer.
    Maryam Ramezani-Aliakbari, Jaleh Varshosaz, Mina Mirian, Ghadamali Khodarahmi, Mahboubeh Rostami.
      AIM: This study aimed to develop novel pH-sensitive Glucosamine (Glu) targeted Polydopamine (PDA) coated mesoporous silica (SBA-15) nanoparticles (NPs) for selective delivery of anticancer Anderson-type manganese polyoxomolybdate (POMo) to breast cancer.METHODS: The POMo@SBA-PDA-Glu NPs were prepared via direct hydrothermal synthesis of SBA, POMo loading, in situ PDA post functionalization, and Glu anchoring; the chemical structures were fully studied by different characterization methods. The anticancer activity was studied by MTT method and Annexin V-FITC apoptosis detection kit.
    RESULTS: The optimized NPs had a hydrodynamic size (HS) of 195 nm, a zeta potential (ZP) of -18.9 mV, a loading content percent (LC%) of 45%, and a pH-responsive release profile. The targeted NPs showed increased anticancer activity against breast cancer cell lines compared to the free POMo with the highest cellular uptake and apoptosis level in the MDA-MB-231 cells.
    CONCLUSIONS: POMo@SBA-PDA-Glu NPs could be a promising anticancer candidate for further studies.
    Keywords:  Anderson-type Manganese Polyoxomolybdate (POMo); Anticancer activity; Barbara Amorphous-15 mesoporous Silica (SBA-15); Nanoparticles (NPs); Polydopamine (PDA); Targeted drug delivery
    DOI:  https://doi.org/10.1080/02652048.2022.2096139
  70. Comput Math Methods Med. 2022 ;2022 4000733
    Chelerythrine Chloride Inhibits Stemness of Melanoma Cancer Stem-Like Cells (CSCs) Potentially via Inducing Reactive Oxygen Species and Causing Mitochondria Dysfunction.
    Hong Li, Mei He, Pengyu Zhao, Ping Liu, Wei Chen, Xuewen Xu.
      Growing evidence has demonstrated that high heterogeneity contributes to poor prognosis and malignancies. The existence of melanoma cancer stem-like cells (CSCs), which are a small subpopulation of melanoma cells, is responsible for tumour resistance to therapies. Recently, plant secondary metabolites have attracted attention because they are considered promising compounds that are isolated from herbs that could help to target different subpopulations of tumours. In the present study, we aimed to identify the antitumourigenic activities of the medicinal compound chelerythrine chloride (CHE) on melanoma CSCs. CHE (30-40 μmol/L) induced apoptosis in A375 and A2058 CSCs. A relatively low dose of CHE (1-5 μmol/L) inhibited the stemness of melanoma CSCs without inducing apoptosis. Coculture of CHE with A375 and A2058 cells also inhibited sphere formation and decreased stemness factors, including Nanog, Oct4, and Sox2. In functional characterizations, we observed that CHE treatment increased both cellular reactive oxygen species (ROS) and mitochondrial ROS, which resulted in a decrease in mitochondrial energy production and sphere formation. Abolishing CHE-induced ROS by N-acetyl-L-cysteine (NAC), a ROS scavenger, reversed the inhibitory effects of CHE on sphere formation, suggesting that CHE-induced ROS are the potential cause of the inhibition of sphere formation. In conclusion, CHE may exert its antitumour effect as an antistem cell natural compound, suggesting that selection of the antistem cell effects of natural compounds might be a promising strategy to overcome the poor prognosis of melanoma due to the presence of CSCs.
    DOI:  https://doi.org/10.1155/2022/4000733
  71. Urol Oncol. 2022 Jun 23. pii: S1078-1439(22)00193-4. [Epub ahead of print]
    A new catheter-integrated drug-delivery system for controlled intravesical mitomycin C release.
    Kristian Stærk, Janni Søvsø Hjelmager, Martin Alm, Peter Thomsen, Thomas Emil Andersen.
      BACKGROUND: Intravesical treatment of bladder cancer is preferred over systemic administration. However, the efficacy of intravesical instillations is challenged by the periodic voiding that flushes out the instilled drug and ultimately reduces drug exposure to the bladder epithelium. Here, we demonstrate a new catheter-integrated drug-delivery concept that utilizes a silicone-based interpenetrating polymer network (IPN) as material for the catheter balloon, to facilitate continuous release of the bladder cancer adjuvant, Mitomycin C, from a balloon-reservoir to the urinary bladder.METHODS: Long-term release properties and anti-carcinoma cell efficacy of released drug was investigated in vitro. Short-term release experiments were performed in live pigs to evaluate the IPN prototype catheter in a physiological relevant environment in vivo.
    RESULTS: Sustained zero-order release of Mitomycin C was achieved for 12 days in vitro without refilling the balloon. Mitomycin C was released from the IPN-balloons into the urinary bladder of live pigs in concentrations adequate to inhibit carcinoma cell growth.
    CONCLUSION: The IPN catheter represents a new drug-delivery concept for prolonged Mitomycin C delivery to the urinary bladder.
    Keywords:  Bladder cancer; Chemotherapy, Intravesical drug-delivery, Pig model; Drug delivery; Interpenetrating polymer network; Mitomycin C
    DOI:  https://doi.org/10.1016/j.urolonc.2022.05.022
  72. Front Bioeng Biotechnol. 2022 ;10 916926
    Biomaterials-Mediated Tumor Infarction Therapy.
    Shizheng Tong, Wei Zhao, Duoyi Zhao, Weilin Zhang, Zhiyu Zhang.
      Agents for tumor vascular infarction are recently developed therapeutic agents for the vascular destruction of tumors. They can suppress the progression of the tumor by preventing the flow of nutrition and oxygen to its tissues. Agents of tumor vascular infarction can be divided into three categories according to the differences in their pathways of action: those that use the thrombin-activating pathway, fibrin-activating pathway, and platelet-activating pathway. However, poor targeting ability, low permeation, and potential side-effects restrict the development of the corresponding drugs. Biomaterials can subtly avoid these drawbacks to suppress the tumor. In this article, the authors summarize currently used biomaterials for tumor infarction therapy with the goal of identifying its mechanism, and discuss outstanding deficiencies in methods of this kind.
    Keywords:  biomaterial; cancer therapy; infarction; peptide; tumor vessels
    DOI:  https://doi.org/10.3389/fbioe.2022.916926
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