bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–12–04
sixty-six papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Natural compounds targeting glycolysis as promising therapeutics for gastric cancer: A review.
  2. Ferroptosis: From regulation of lipid peroxidation to the treatment of diseases.
  3. Self-immolative nanosensitizer for glutathione depletion- assisted sonodynamic therapy.
  4. Radiotherapy modulates tumor cell fate decisions: a review.
  5. Nano-inspired smart medicines targeting brain cancer: diagnosis and treatment.
  6. Ketogenic diets and Ketone suplementation: A strategy for therapeutic intervention.
  7. Quercetin as a cancer chemopreventive or chemotherapeutic agent: Where we stand.
  8. Multifunctional plant virus nanoparticles: An emerging strategy for therapy of cancer.
  9. Identification of natural products and FDA-approved drugs for targeting cancer stem cell (CSC) propagation.
  10. Depletion of gut microbiota improves the therapeutic efficacy of cancer nanomedicine.
  11. How to manage KRAS G12C-mutated advanced non-small-cell lung cancer.
  12. Stimuli-responsive nanoparticle-nanofiber hybrids for drug delivery and photodynamic therapy.
  13. Synergistic effect of metformin and doxorubicin on the metastatic potential of T24 cells.
  14. Current Research on Spray-Dried Chitosan Nanocomposite Microparticles for Pulmonary Drug Delivery.
  15. "Bottom up design of nanoparticles for anti-cancer diapeutics: put the drug in the cancer's food".
  16. An Oxygen-Sufficient Nanoplatform for Enhanced Imaging-Guided Microwave Dynamic Therapy Against Hypoxic Tumors.
  17. Molecular mechanisms behind ROS regulation in cancer: A balancing act between augmented tumorigenesis and cell apoptosis.
  18. Remodeling tumor microenvironment with natural products to overcome drug resistance.
  19. Bibliometric and visual analysis in the field of ketogenic diet on cancer from 2012 to 2021.
  20. Hypoxia Enhances Glioma Resistance to Sulfasalazine-Induced Ferroptosis by Upregulating SLC7A11 via PI3K/AKT/HIF-1α Axis.
  21. Lysosomal-mediated drug release and activation for cancer therapy and immunotherapy.
  22. Brain targeted intra nasal acyclovir lipid nanoparticles; in-vitro characterization and in-vivo biodistribution studies.
  23. Biomimetic nanoparticles for tumor immunotherapy.
  24. Cold stimuli, hot topic: An updated review on the biological activity of menthol in relation to inflammation.
  25. Nanoparticles and phototherapy combination as therapeutic alternative in prostate cancer: A scoping review.
  26. Colon cancer exosome-derived biomimetic nanoplatform for curcumin-mediated sonodynamic therapy and calcium overload.
  27. Polysaccharide-based hydrogels for drug delivery and wound management: A review.
  28. Formulation and characterization of liposomes containing drug absorption enhancers for optimized anti-HIV and antimalarial drug delivery.
  29. Mutant Kras and mTOR crosstalk drives hepatocellular carcinoma development via PEG3/STAT3/BEX2 signaling.
  30. A self-cascaded unimolecular prodrug for pH-responsive chemotherapy and tumor-detained photodynamic-immunotherapy of triple-negative breast cancer.
  31. In Response to Precision Medicine: Current Subcellular Targeting Strategies for Cancer Therapy.
  32. Overexpression of miR-181a regulates the Warburg effect in triple-negative breast cancer.
  33. Dual-modified starch nanoparticles containing aromatic systems with highly efficient encapsulation of curcumin and their antibacterial applications.
  34. Novel Mucoadhesive Chitosomes as a Platform for Enhanced Oral Bioavailability of Cinnarizine.
  35. Lactylation of PKM2 Suppresses Inflammatory Metabolic Adaptation in Pro-inflammatory Macrophages.
  36. Local anti-inflammatory effect and immunomodulatory activity of chitosan-based dressing in skin wound healing: A systematic review.
  37. Acetic acid enhances the effect of photodynamic therapy in gastric cancer cells via the production of reactive oxygen species.
  38. Polyphenols for the Prevention and Treatment of Cognitive Impairment.
  39. Advances in the Biological Functions of Extracellular Vesicles and their Potential Use in Treating Oral Cancer.
  40. Development of nanoparticle loaded microneedles for drug delivery to a brain tumour resection site.
  41. Regulatory Components of Oxidative Stress and Inflammation and Their Complex Interplay in Carcinogenesis.
  42. Ketogenic Diet and Beta-Hydroxybutyrate in Colorectal Cancer.
  43. Cell and tissue specific metabolism of nucleoside and nucleotide drugs: case studies and implications for precision medicine.
  44. Requirement of hepatic pyruvate carboxylase during fasting, high fat, and ketogenic diet.
  45. Light and immunostimulant mediated in situ re-education of tumor-associated macrophages using photosensitizer conjugated mannan nanoparticles for boosting immuno-photodynamic anti-metastasis therapy.
  46. Targeting proteasome enhances anticancer activity of oncolytic HSV-1 in colorectal cancer.
  47. Alterations in the omics profiles in mevalonate pathway-inhibited cancer cells.
  48. Editorial: Metabolic reprogramming in breast cancer.
  49. Repurposing immunosuppressants for antileukemia therapy.
  50. Exosomes: special nano-therapeutic carrier for cancers, overview on anticancer drugs.
  51. A thermo-responsive hydrogel loaded with an ionic liquid microemulsion for transdermal delivery of methotrexate.
  52. Polymeric Nanofibers for Drug Delivery Applications: A Recent Review.
  53. Atorvastatin induces downregulation of matrix metalloproteinase-2/9 in MDA-MB-231 triple negative breast cancer cells.
  54. Lipid Microparticles Show Similar Efficacy With Lipid Nanoparticles in Delivering mRNA and Preventing Cancer.
  55. Knowledge-driven design and optimization of potent symmetric anticancer molecules: A case study on PKM2 activators.
  56. Injectable chitosan-based self-healing supramolecular hydrogels with temperature and pH dual-responsivenesses.
  57. The application of exosomes in the treatment of triple-negative breast cancer.
  58. Vitamin B5 rewires Th17 cell metabolism via impeding PKM2 nuclear translocation.
  59. Opportunities for accelerating drug discovery and development by using engineered drug-metabolizing enzymes.
  60. Epigallocatechin-3-gallate Delivered in Nanoparticles Increases Cytotoxicity in Three Breast Carcinoma Cell Lines.
  61. Emerging Sonodynamic Therapy-Based Nanomedicines for Cancer Immunotherapy.
  62. High-Density Branched PEGylation for Nanoparticle Drug Delivery.
  63. Retinoids in cancer chemoprevention and therapy: Meta-analysis of randomized controlled trials.
  64. Resveratrol induces the production of reactive oxygen species, interferes with the cell cycle, and inhibits the cell migration of bladder tumour cells with different TP53 status.
  65. Metabolic determinants of tumour initiation.
  66. Co-delivery of ibrutinib and hydroxychloroquine by albumin nanoparticles for enhanced chemotherapy of glioma.
  1. Front Pharmacol. 2022 ;13 1004383
    Natural compounds targeting glycolysis as promising therapeutics for gastric cancer: A review.
    Maoyuan Zhao, Feng Wei, Guangwei Sun, Yueqiang Wen, Juyi Xiang, Fangting Su, Lu Zhan, Qing Nian, Yu Chen, Jinhao Zeng.
      Gastric cancer, a common malignant disease, seriously endangers human health and life. The high mortality rate due to gastric cancer can be attributed to a lack of effective therapeutic drugs. Cancer cells utilize the glycolytic pathway to produce energy even under aerobic conditions, commonly referred to as the Warburg effect, which is a characteristic of gastric cancer. The identification of new targets based on the glycolytic pathway for the treatment of gastric cancer is a viable option, and accumulating evidence has shown that phytochemicals have extensive anti-glycolytic properties. We reviewed the effects and mechanisms of action of phytochemicals on aerobic glycolysis in gastric cancer cells. Phytochemicals can effectively inhibit aerobic glycolysis in gastric cancer cells, suppress cell proliferation and migration, and promote apoptosis, via the PI3K/Akt, c-Myc, p53, and other signaling pathways. These pathways affect the expressions of HIF-1α, HK2, LDH, and other glycolysis-related proteins. This review further assesses the potential of using plant-derived compounds for the treatment of gastric cancer and sheds insight into the development of new drugs.
    Keywords:  Warburg effect; biological products; gastric neoplasm; glycolysis; phytochemicals
    DOI:  https://doi.org/10.3389/fphar.2022.1004383
  2. Cell Biol Toxicol. 2022 Dec 02.
    Ferroptosis: From regulation of lipid peroxidation to the treatment of diseases.
    Yonghui Lv, Meiying Wu, Zhe Wang, Junqing Wang.
      Ferroptosis is a regulated cell death mainly manifested by iron-dependent lipid peroxide accumulation. The leading cause of ferroptosis is the imbalance of intracellular oxidative systems (e.g., LOXs, POR, ROS) and antioxidant systems (e.g., GSH/GPx4, CoQ10/FSP1, BH4/GCH1), which is regulated by a complex network. In the past decade, this metabolic network has been continuously refined, and the links with various pathophysiological processes have been gradually established. Apoptosis has been regarded as the only form of regulated cell death for a long time, and the application of chemotherapeutic drugs to induce apoptosis of cancer cells is the mainstream method. However, studies have reported that cancer cells' key features are resistance to apoptosis and chemotherapeutics. For high proliferation, cancer cells often have very active lipid metabolism and iron metabolism, which pave the way for ferroptosis. Interestingly, researchers found that drug-resistant or highly aggressive cancer cells are more prone to ferroptosis. Therefore, ferroptosis may be a potential strategy to eliminate cancer cells. In addition, links between ferroptosis and other diseases, such as neurological disorders and ischemia-reperfusion injury, have also been found. Understanding these diseases from the perspective of ferroptosis may provide new insights into clinical treatment. Herein, the metabolic processes in ferroptosis are reviewed, and the potential mechanisms and targets of ferroptosis in different diseases are summarized.
    Keywords:  Diseases; Ferroptosis; Iron metabolism; Lipid metabolism; Redox regulation
    DOI:  https://doi.org/10.1007/s10565-022-09778-2
  3. Theranostics. 2022 ;12(17): 7465-7475
    Self-immolative nanosensitizer for glutathione depletion- assisted sonodynamic therapy.
    Chan Ho Kim, Dong Gil You, Pramod Kumar E K, Kyung Hee Han, Wooram Um, Jeongjin Lee, Jae Ah Lee, Jae Min Jung, Heegun Kang, Jae Hyung Park.
      Background: Despite remarkable advances in sonodynamic therapy (SDT) of cancer, the low reactive oxygen species (ROS) quantum yield of the sonosensitizer remains a critical concern in glutathione (GSH)-overexpressing cancer cells. Methods: For enhanced SDT, we report hydrophilized self-immolative polymer (SIP)-decorated TiO2 nanoparticles (HSIPT-NPs) to achieve on-demand GSH depletion and ROS generation. Results: Upon intracellular delivery of HSIPT-NPs into hydrogen peroxide-rich cancer cells, SIP is degraded through electron transfer to produce GSH-depleting quinone methide, reprogramming GSH high cancer cells into GSH low phenotype. In the presence of ultrasound, compared to conventional TiO2 NPs, HSIPT-NPs induce significantly higher oxidative stress to cancer cells by incapacitating their antioxidant effects. SDT with HSIPT-NPs effectively inhibit tumor growth in mice via the synergistic effects of GSH depletion and ROS generation. Conclusion: On the basis of their ability to reprogram cancer cells, HSIPT-NPs offer considerable potential as a nanosensitizer for enhanced SDT.
    Keywords:  TiO2 nanoparticles; glutathione; reactive oxygen species; self-immolative polymer; sonodynamic therapy
    DOI:  https://doi.org/10.7150/thno.75007
  4. Radiat Oncol. 2022 Dec 01. 17(1): 196
    Radiotherapy modulates tumor cell fate decisions: a review.
    Haoran Chen, Zhongyu Han, Qian Luo, Yi Wang, Qiju Li, Lisui Zhou, Houdong Zuo.
      Cancer has always been a worldwide problem, and the application of radiotherapy has greatly improved the survival rate of cancer patients. Radiotherapy can modulate multiple cell fate decisions to kill tumor cells and achieve its therapeutic effect. With the development of radiotherapy technology, how to increase the killing effect of tumor cells and reduce the side effects on normal cells has become a new problem. In this review, we summarize the mechanisms by which radiotherapy induces tumor cell apoptosis, necrosis, necroptosis, pyroptosis, ferroptosis, autophagy, senescence, mitotic catastrophe, and cuproptosis. An in-depth understanding of these radiotherapy-related cell fate decisions can greatly improve the efficiency of radiotherapy for cancer.
    Keywords:  Apoptosis; Autophagy; Cuproptosis; Ferroptosis; Mitotic catastrophe; Necroptosis; Necrosis; Pyroptosis; Radiotherapy; Senescence
    DOI:  https://doi.org/10.1186/s13014-022-02171-7
  5. J Biol Inorg Chem. 2022 Nov 30.
    Nano-inspired smart medicines targeting brain cancer: diagnosis and treatment.
    Raksha Anand, Lakhan Kumar, Lalit Mohan, Navneeta Bharadvaja.
      Cancer, despite being the bull's eye for the research community, accounts for a large number of morbidity and mortality. Cancer of the brain is considered the most intractable, with the least diagnosis rates, hence treatment and survival. Despite the extensive development of therapeutic molecules, their targeting to the diseased site is a challenge. Specially tailored nanoparticles can efficiently deliver drugs and genes to the brain to treat tumours and diseases. These nanotechnology-based strategies target the blood-brain barrier, the local space, or a specific cell type. These nanoparticles are preferred over other forms of targeted drug delivery due to the chances for controlled delivery of therapeutic cargo to the intended receptor. Targeted cancer therapy involves using specific receptor-blocking compounds that block the spreading or growth of cancerous cells. This review presents an account of the recent applications of nano-based cancer theragnostic, which deal in conjunct functionalities of nanoparticles for effective diagnosis and treatment of cancer. It commences with an introduction to tumours of the brain and their grades, followed by hurdles in its conventional diagnosis and treatment. The characteristic mechanism of nanoparticles for efficiently tracing brain tumour grade and delivery of therapeutic genes or drugs has been summarised. Nanocarriers like liposomes have been widely used and commercialized for human brain cancer treatment. However, nano-inspired structures await their translational recognition. The green synthesis of nanomaterials and their advantages have been discussed. The article highlights the challenges in the nano-modulation of brain cancer and its future outlook.
    Keywords:  Brain cancer; Cancer theranostics; Green nanomaterials; Nano-modulation; Nanomedicine
    DOI:  https://doi.org/10.1007/s00775-022-01981-0
  6. Front Nutr. 2022 ;9 947567
    Ketogenic diets and Ketone suplementation: A strategy for therapeutic intervention.
    Christiaan G J Saris, Silvie Timmers.
      Ketogenic diets and orally administered exogenous ketone supplements are strategies to increase serum ketone bodies serving as an alternative energy fuel for high energy demanding tissues, such as the brain, muscles, and the heart. The ketogenic diet is a low-carbohydrate and fat-rich diet, whereas ketone supplements are usually supplied as esters or salts. Nutritional ketosis, defined as serum ketone concentrations of ≥ 0.5 mmol/L, has a fasting-like effect and results in all sorts of metabolic shifts and thereby enhancing the health status. In this review, we thus discuss the different interventions to reach nutritional ketosis, and summarize the effects on heart diseases, epilepsy, mitochondrial diseases, and neurodegenerative disorders. Interest in the proposed therapeutic benefits of nutritional ketosis has been growing the past recent years. The implication of this nutritional intervention is becoming more evident and has shown interesting potential. Mechanistic insights explaining the overall health effects of the ketogenic state, will lead to precision nutrition for the latter diseases.
    Keywords:  ketogenic diet; ketone bodies; ketone supplementation; nutritional ketosis; precision nutrition
    DOI:  https://doi.org/10.3389/fnut.2022.947567
  7. Phytother Res. 2022 Nov 28.
    Quercetin as a cancer chemopreventive or chemotherapeutic agent: Where we stand.
    Alberto Boretti.
      Quercetin has a wide range of potential health benefits, working as a direct or indirect agent or an adjuvant following different principles. It may be used as a generally useful or exclusive supplement, but also specifically used to treat an acute or chronic condition. Quercetin may work as a cancer chemopreventive and chemotherapeutic agent, because this versatile substance, which owns antioxidant and anti-inflammatory properties, may also kill cancer cells and also holds senolytic properties. While both the specific chemo-preventive or chemotherapeutic uses as a drug need clinical trials, it may be used without any contraindication as a general chemo-preventive supplement.
    Keywords:  cancer; chemopreventive agents; chemotherapeutic agents; quercetin; quercetin supplementation
    DOI:  https://doi.org/10.1002/ptr.7699
  8. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2022 Nov 30. e1872
    Multifunctional plant virus nanoparticles: An emerging strategy for therapy of cancer.
    Mehdi Azizi, Mehdi Shahgolzari, Sonia Fathi-Karkan, Maryam Ghasemi, Hadi Samadian.
      Cancer therapy requires sophisticated treatment strategies to obtain the highest success. Nanotechnology is enabling, revolutionizing, and multidisciplinary concepts to improve conventional cancer treatment modalities. Nanomaterials have a central role in this scenario, explaining why various nanomaterials are currently being developed for cancer therapy. Viral nanoparticles (VNPs) have shown promising performance in cancer therapy due to their unique features. VNPs possess morphological homogeneity, ease of functionalization, biocompatibility, biodegradability, water solubility, and high absorption efficiency that are beneficial for cancer therapy applications. In the current review paper, we highlight state-of-the-art properties and potentials of plant viruses, strategies for multifunctional plant VNPs formulations, potential applications and challenges in VNPs-based cancer therapy, and finally practical solutions to bring potential cancer therapy one step closer to real applications. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Biology-Inspired Nanomaterials > Protein and Virus-Based Structures.
    Keywords:  cancer; nanotechnology; targeted drug delivery; viral nanoparticles
    DOI:  https://doi.org/10.1002/wnan.1872
  9. Aging (Albany NY). 2022 Dec 01. 14
    Identification of natural products and FDA-approved drugs for targeting cancer stem cell (CSC) propagation.
    Gloria Bonuccelli, Federica Sotgia, Michael P Lisanti.
      Here, we report the identification of key compounds that effectively inhibit the anchorage-independent growth and propagation of cancer stem cells (CSCs), as determined via screening using MCF7 cells, a human breast adenocarcinoma cell line. More specifically, we employed the mammosphere assay as an experimental format, which involves the generation of 3D spheroid cultures, using low-attachment plates. These positive hit compounds can be divided into 5 categories: 1) dietary supplements (quercetin and glucosamine); 2) FDA-approved drugs (carvedilol and ciprofloxacin); 3) natural products (aloe emodin, aloin, tannic acid, chlorophyllin copper salt, azelaic acid and adipic acid); 4) flavours (citral and limonene); and 5) vitamins (nicotinamide and nicotinic acid). In addition, for the compounds quercetin, glucosamine and carvedilol, we further assessed their metabolic action, using the Seahorse to conduct metabolic flux analysis. Our results indicate that these treatments can affect glycolytic flux and suppress oxidative mitochondrial metabolism (OXPHOS). Therefore, quercetin, glucosamine and carvedilol can reprogram the metabolic phenotype of breast cancer cells. Despite having diverse chemical structures, these compounds all interfere with mitochondrial metabolism. As these compounds halt CSCs propagation, ultimately, they may have therapeutic potential.
    Keywords:  FDA approved drugs; cancer stem cells; drug screening; mammospheres; natural compounds
    DOI:  https://doi.org/10.18632/aging.204412
  10. Theranostics. 2022 ;12(17): 7390-7403
    Depletion of gut microbiota improves the therapeutic efficacy of cancer nanomedicine.
    Ray Putra Prajnamitra, Yuan-Yuan Cheng, Chaw Yee Beh, Chien-Yi Lu, Jen-Hao Lin, Shu-Chian Ruan, Sheng-Lun Chen, Hung-Chih Chen, Ruey-Bing Yang, Patrick Ching-Ho Hsieh.
      Rationale: Gut microbiota plays a crucial role in cancer development and treatment. Studies show that although the gut microbiota is able to promote tumor growth, its presence also improves the efficacy of cancer treatment such as immunotherapy. To date, understanding of the potential impact of the gut microbiota on other treatment modalities such as cancer nanomedicine is still limited. In this study, we aimed to establish the relationship between gut microbiota and cancer nanomedicine, which can potentially open a new path in cancer treatment that combines gut microbiota modulation along with nanotherapeutics. Methods: Mice bearing 4T1 triple-negative breast cancer cells were subjected to gut microbiota modulation by antibiotics (ABX) treatment in the drinking water. Mice given normal water was used for control. The effects of ABX treatment towards gut bacteria was studied by RT-qPCR and 16S next generation sequencing of fecal samples. The mice were then subjected to liposomal doxorubicin (LipoDox) treatment and the amount of nanotherapeutics that accumulated in the tumors was quantified. For therapeutic efficacy, the mice were subjected to ABX treatment and given three injections of LipoDox or saline, while the tumor growth was monitored throughout. Results: Analysis of fecal bacterial content showed that ABX treatment resulted in depletion of gut microbiota. Quantification of LipoDox content revealed significantly increased accumulation in ABX tumor compared to control. Compared to LipoDox treatment alone, we found that combined gut microbiota depletion and LipoDox treatment resulted in augmented long-term anti-tumor efficacy and significantly improved median survival compared to LipoDox only (control vs ABX = 58.5 vs 74 days, p = 0.0002, n = 10 for both groups), with two mice surviving until the end of the experimental end point without experiencing relapse. We also identified the increase in vascular permeability of ABX-treated tumors correlated to for improved therapeutic efficacy and outcome. Conclusion: We showed that gut microbiota depletion led to enhanced tumor vascular permeability, which allowed a larger amount of LipoDox nanoparticles to accumulate in the tumor, leading to better long-term effects. Our results suggest that gut microbiota modulation may be exploited in combination with available nanomedicine-based therapeutics to improve cancer diagnosis, therapeutic efficacy and outcome.
    Keywords:  Gut microbiota; LipoDox; nanomedicine; triple-negative breast cancer; vascular permeability
    DOI:  https://doi.org/10.7150/thno.73873
  11. Drugs Context. 2022 ;pii: 2022-7-4. [Epub ahead of print]11
    How to manage KRAS G12C-mutated advanced non-small-cell lung cancer.
    Biagio Ricciuti, Alessia Mira, Elisa Andrini, Pietro Scaparone, Sandra Vietti Michelina, Federica Pecci, Luca Cantini, Andrea De Giglio, Giuseppe Lamberti, Chiara Ambrogio, Giulio Metro.
      Constitutive KRAS signalling drives tumorigenesis across several cancer types. In non-small-cell lung cancer (NSCLC) activating KRAS mutations occur in ~30% of cases, and the glycine to cysteine substitution at codon 12 (G12C) is the most common KRAS alteration. Although KRAS mutations have been considered undruggable for over 40 years, the recent discovery of allelic-specific KRAS inhibitors has paved the way to personalized cancer medicine for patients with tumours harbouring these mutations. Here, we review the current treatment landscape for patients with advanced NSCLCs harbouring a KRAS G12C mutation, including PD-(L) 1-based therapies and direct KRAS inhibitors as well as sequential treatment options. We also explore the possible mechanisms of resistance to KRAS inhibition and strategies to overcome resistance in patients with KRAS G12C-mutant NSCLC.
    Keywords:  G12C; KRAS; NSCLC; immunotherapy; sotorasib
    DOI:  https://doi.org/10.7573/dic.2022-7-4
  12. Int J Pharm. 2022 Nov 26. pii: S0378-5173(22)00997-8. [Epub ahead of print]630 122442
    Stimuli-responsive nanoparticle-nanofiber hybrids for drug delivery and photodynamic therapy.
    Gözde Kabay, Ahmet Ersin Meydan, Taesik Eom, Bong Sup Shim, Mehmet Mutlu, Gizem Kaleli-Can.
      Hybrid nanomaterials possess integrated multi-components to syncretize various properties and functions within a single entity. Owing to this synergistic effect, they promise efficient anti-cancer therapy. In line with this target, we produced stimuli-responsive nanoparticle-nanofiber hybrids (NNHs) via embedding photoresponsive natural melanin nanoparticles (MNPs) within a biocompatible polycaprolactone (PCL) nanofiber matrix. Electrospinning was performed to produce monolithic and core-shell structured NNHs using a single and a coaxial nozzle. The NNHs were upgraded to drug delivery systems by model hydrophilic drug-ampicillin (amp)-loading. The drug release results showed that monolithic PCL meshes displayed a burst release, whereas nanohybrid formation with MNPs improved the release profile toward Fickian diffusion. Core-shell NNH presented a more sustained drug release profile than its MNP-free replica and monolithic NNH because its encapsulating shell layer hindered the diffusion of the drug. The photodynamic therapy accompanied by UV-A-irradiation on monolithic and core-shell NNHs yielded up to 34 % and 37 % malignant melanoma cell death. Moreover, this study proved the potency of MNPs-enhanced NNHs in drug delivery and photodynamic therapy applications. Even so, more efforts should be concerted to unlock unknown features of the NNHs, which have the power to advance emerging areas, including but not limited to material science, biosensing, and theranostics.
    Keywords:  Electrospinning; Eumelanin; Melanoma; Photodynamic therapy; Zero-order kinetics
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122442
  13. Acta Histochem. 2022 Nov 28. pii: S0065-1281(22)00134-9. [Epub ahead of print]125(1): 151975
    Synergistic effect of metformin and doxorubicin on the metastatic potential of T24 cells.
    Agnieszka Mlicka, Paweł Mlicki, Paweł Niewiadomski, Wioletta Zielińska, Marta Hałas-Wiśniewska, Magdalena Izdebska.
       BACKGROUND: The motor ability of cancer cells to cross the basement membrane contributes to their implantation in a new location. Metastasis is a significant factor that worsens the prognosis of cancer patients. Thus, reducing cell invasiveness is an important aspect of anticancer therapy, also in bladder cancer treatment.
    MATERIAL: The study material was the T24 cell line of human urinary bladder cancer. The migratory potential of the cells and the effect of the treatment with individually doses and synergistic combination of doxorubicin and metformin in the 500:1 ratio for 24 h were analyzed.
    RESULTS: The results obtained show a compound-initiated decrease in the motor abilities of bladder cancer cells compared to controls. A decrease in the rate of colony formation was observed, as well as inhibition of migration through inserts. The visualized reorganization of the vimentin and actin networks confirms the drug-initiated limitation of the metastatic potential of T24 cells.
    CONCLUSION: According to our knowledge, we are the first to show, that combination of doxorubicin and metformin also worth considering in the treatment of bladder cancer. We showed that simultaneous administration of these cytostatic enhances the antiproliferative effect of drugs, but also limits cells' migratory potential.
    Keywords:  Bladder cancer; Doxorubicin; Metastasis; Metformin
    DOI:  https://doi.org/10.1016/j.acthis.2022.151975
  14. Pharm Nanotechnol. 2022 Nov 28.
    Current Research on Spray-Dried Chitosan Nanocomposite Microparticles for Pulmonary Drug Delivery.
    Saba Albetawi.
      Using the pulmonary route for systemic and local drug delivery is an attractive method of drug administration because it has a high alveolar surface area, abundant blood flow, a thin air-blood barrier, and low metabolic activity. In recent years, the evolution of inhalable chitosan nanocomposite microparticles formulations enabled researchers to develop new pulmonary drug delivery platforms that combine the advantages of microparticles and nanoparticles using a biocompatible, biodegradable polymer with polycationic nature and inherent immunogenicity that enhances cell targeting. Therefore, this review aims to offer an overview of the recent advances in inhalable chitosan nanocomposites microparticles formulated in the previous five years in terms of primary nanoparticles manufacturing methods; namely, ionic crosslinking of chitosan using tripolyphosphate, electrospinning/electrospraying, layer-by-layer deposition, and nanospray drying; final microparticles manufacturing techniques using spray drying, nano spray drying, and supercritical assisted spray drying; in addition to the process optimization of the previously mentioned manufacturing methods. Furthermore, this review highlights using chitosan and its derivatives in primary nanoparticles preparation and as a polysaccharide to distribute the prepared nanoparticles in microparticles. Finally, this review discusses the factors affecting yield, encapsulation efficiency, in vitro aerosolization properties, size, morphological characters, in vitro release, and in vivo evaluation of inhalable chitosan nanocomposite microparticles.
    Keywords:  Chitosan; Lung Deposition; Nanocomposite; Nanocomposite Microparticles; Pulmonary; Spray Drying
    DOI:  https://doi.org/10.2174/2211738511666221128093822
  15. J Drug Target. 2022 Nov 30. 1
    "Bottom up design of nanoparticles for anti-cancer diapeutics: put the drug in the cancer's food".
      
    DOI:  https://doi.org/10.1080/1061186X.2022.2154460
  16. Int J Nanomedicine. 2022 ;17 5525-5545
    An Oxygen-Sufficient Nanoplatform for Enhanced Imaging-Guided Microwave Dynamic Therapy Against Hypoxic Tumors.
    Rui Yang, Jiayan Huang, Min Liao, Jianbo Huang, Binyang Gao, Huan Zhang, Jie Zhou, Jinshun Xu, Qiang Lu.
       Background: Microwave dynamic therapy (MDT) as a novel reactive oxygen species (ROS)-based therapeutic modality has been explored as a promising modality for cancer treatment. However, the intrinsic hypoxic tumor microenvironment (TME) restricted the effectiveness of the MDT. The aim of this study is to develop an oxygen-sufficient nanoplatform with multi-modal imaging capability for enhanced MDT against hypoxic tumors.
    Methods and Materials: The liquid perfluorocarbon-based nanoplatform PFP@IR780@O2 was constructed by the phospholipid hydration and sonication method. Then, the characteristics, intracellular uptake process, and subcellular localization of PFP@IR780@O2 were verified. Additionally, the abilities of ROS generation, the anti-hypoxia capability, multi-mode imaging capabilities, and MDT efficacy of the nanoplatform were evaluated via in vitro and in vivo experiments. Finally, the in vivo biocompatibility and toxicity were also evaluated.
    Results: The prepared nanoparticles PFP@IR780@O2 exhibited suitable size, improved stability, elevated dissolved oxygen level, enhanced cellular uptake, and mitochondria targeting capacity. Additionally, PFP@IR780@O2 demonstrated in vitro and in vivo multimodal imaging capabilities involving ultrasound, fluorescence, and photoacoustic imaging. In vivo studies also indicated that nanoparticles were safe and capable of accumulating in the tumor site after intravenous injection. Furthermore, the PFP@IR780@O2 nanoplatform mediated MDT could effectively alleviate the hypoxic TME, and elevate ROS concentration, thereby resulting in significant tumor growth inhibition.
    Conclusion: Overall, the oxygen-sufficient nanoplatform with multi-bimodal imaging capability demonstrated improved MDT efficiency, indicating a promising strategy for treating hypoxic tumors.
    Keywords:  nanomedicine; perfluorocarbon; reactive oxygen species; tumor hypoxia relief
    DOI:  https://doi.org/10.2147/IJN.S387223
  17. Arch Toxicol. 2022 Nov 28.
    Molecular mechanisms behind ROS regulation in cancer: A balancing act between augmented tumorigenesis and cell apoptosis.
    Hardeep Singh Tuli, Jagjit Kaur, Kanupriya Vashishth, Katrin Sak, Ujjawal Sharma, Renuka Choudhary, Tapan Behl, Tejveer Singh, Sheetu Sharma, Adesh K Saini, Kuldeep Dhama, Mehmet Varol, Gautam Sethi.
      ROS include hydroxyl radicals (HO.), superoxide (O2..), and hydrogen peroxide (H2O2). ROS are typically produced under physiological conditions and play crucial roles in living organisms. It is known that ROS, which are created spontaneously by cells through aerobic metabolism in mitochondria, can have either a beneficial or detrimental influence on biological systems. Moderate levels of ROS can cause oxidative damage to proteins, DNA and lipids, which can aid in the pathogenesis of many disorders, including cancer. However, excessive concentrations of ROS can initiate programmed cell death in cancer. Presently, a variety of chemotherapeutic drugs and herbal agents are being investigated to induce ROS-mediated cell death in cancer. Therefore, preserving ROS homeostasis is essential for ensuring normal cell development and survival. On account of a significant association of ROS levels at various concentrations with carcinogenesis in a number of malignancies, further studies are needed to determine the underlying molecular mechanisms and develop the possibilities for intervening in these processes.
    Keywords:  Angiogenesis; Apoptosis; Cancer; Inflammation; Metastasis; ROS; miRNA
    DOI:  https://doi.org/10.1007/s00204-022-03421-z
  18. Front Immunol. 2022 ;13 1051998
    Remodeling tumor microenvironment with natural products to overcome drug resistance.
    Wanlu Zhang, Shubo Li, Chunting Li, Tianye Li, Yongye Huang.
      With cancer incidence rates continuing to increase and occurrence of resistance in drug treatment, there is a pressing demand to find safer and more effective anticancer strategy for cancer patients. Natural products, have the advantage of low toxicity and multiple action targets, are always used in the treatment of cancer prevention in early stage and cancer supplement in late stage. Tumor microenvironment is necessary for cancer cells to survive and progression, and immune activation is a vital means for the tumor microenvironment to eliminate cancer cells. A number of studies have found that various natural products could target and regulate immune cells such as T cells, macrophages, mast cells as well as inflammatory cytokines in the tumor microenvironment. Natural products tuning the tumor microenvironment via various mechanisms to activate the immune response have immeasurable potential for cancer immunotherapy. In this review, it highlights the research findings related to natural products regulating immune responses against cancer, especially reveals the possibility of utilizing natural products to remodel the tumor microenvironment to overcome drug resistance.
    Keywords:  cancer stem cells; drug resistance; natural products; p53; traditional Chinese medicine; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2022.1051998
  19. Front Nutr. 2022 ;9 1060436
    Bibliometric and visual analysis in the field of ketogenic diet on cancer from 2012 to 2021.
    Rongrong Li, Qingcheng Huang, Chenxiao Ye, Changhong Wu, Ning Luo, Yi Lu, Jianqiao Fang, Yun Wang.
      Increasing evidence demonstrated that the ketogenic diet (KD) played a positive effect on cancer treatment. However, no systematic review and bibliometric analysis were conducted in this field. This study aimed to explore the current status, and reveal the potential trends and hotspots to provide a reference for future research. Publications were extracted from the Web of Science Core Collection. CiteSpace (5.6.R3) software and the website of bibliometrics were used for visual analysis. A total of 500 publications with 334 articles and 166 reviews were included, with the timespan of 2012 to 2021. The United States was the most productive country. Majority of the top 10 institutions were from the United States, and Harvard University was the top-contributing institution. The most prolific author and the co-cited author was Thomas N Seyfried from Boston College. The highest cited reference was published in PLoS ONE, authored by Abdelwahab Mohammed G, with 161 citations. Glioma and breast cancer were the most common types of cancer in this field, while hepatocellular carcinoma and pancreatic cancer were the new hotspots. The anti-tumor mechanism of KD mainly focused on regulating metabolism, decanoic acid, oxidative stress, fatty acid oxidation, and cell apoptosis. Additionally, the presence of "chemotherapy" and "radiotherapy" in the keywords indicated that KD combined with anti-tumor research was a topic, while "immunotherapy" has became a recent frontiers. Notably, as a metabolic therapy, KD was deserved more attention in the treatment of hepatocellular carcinoma and pancreatic cancer, and KD combined with immunotherapy was the new hotspot and frontier. Additionally, more molecular studies and high-quality uniformly, randomized, controlled clinical trials are urgently warranted to evaluate the effect of KD in multiple cancers.
    Keywords:  bibliometric analysis; cancer; clinical trials; immunotherapy; ketogenic diet; mechanism
    DOI:  https://doi.org/10.3389/fnut.2022.1060436
  20. Oxid Med Cell Longev. 2022 ;2022 7862430
    Hypoxia Enhances Glioma Resistance to Sulfasalazine-Induced Ferroptosis by Upregulating SLC7A11 via PI3K/AKT/HIF-1α Axis.
    Shicheng Sun, Changfa Guo, Taihong Gao, Dengzhen Ma, Xiangsheng Su, Qi Pang, Rui Zhang.
      Glioma is the most common primary brain tumor, with a high rate of recurrence and treatment resistance. Glioblastoma is highly invasive, infiltrating surrounding brain parenchyma, and is known to cause intracranial metastasis resulting in a dismal prognosis. Hypoxia contributes significantly to chemo- and radiotherapy resistance in cancer. Ferroptosis is a nonapoptotic oxidative cell death that has been identified as a potential anticancer mechanism. Sulfasalazine (SAS) activates ferroptosis and plays a potential role in tumor treatment. However, the relationship between hypoxia and SAS resistance has not been elucidated. This study is aimed at investigating the role of hypoxia in SAS-induced ferroptosis and the underlying mechanisms. Here, we found that hypoxia significantly suppressed SAS-induced ferroptosis by upregulating SLC7A11 expression in the U87 and U251 glioma cell lines. Hypoxia promotes SLC7A11 expression by enhancing the PI3K/AKT/HIF-1α pathway. The AKT inhibitor MK-2206 and HIF-1α inhibitor PX-478 significantly reversed this effect. In addition, under normoxia, PX-478 induced a higher lipid peroxidation level by decreasing SLC7A11 expression in the U87 and U251 cells but could not induce cell death directly; it could significantly enhance the tumor cell killing effect of SAS. In vivo, the combination of PX-478 and SAS had a coordinated synergistic effect on anticancer activity, as revealed by subcutaneous and orthotopic xenograft mouse models. In conclusion, hypoxia enhanced glioma resistance to SAS-induced ferroptosis by upregulating SLC7A11 via activating the PI3K/AKT/HIF-1α axis. Combination therapy with PX-478 and SAS may be a potential strategy against glioma.
    DOI:  https://doi.org/10.1155/2022/7862430
  21. Adv Drug Deliv Rev. 2022 Nov 24. pii: S0169-409X(22)00514-2. [Epub ahead of print]192 114624
    Lysosomal-mediated drug release and activation for cancer therapy and immunotherapy.
    Yinping Sun, Yongjie Sha, Guanhong Cui, Fenghua Meng, Zhiyuan Zhong.
      The development of carrier systems that are able to transport and release therapeutics to target cells is an emergent strategy to treat cancer; however, they following endocytosis are usually trapped in the endo/lysosomal compartments. The efficacy of drug conjugates and nanotherapeutics relies critically on their intracellular drug release ability, for which advanced systems responding to the unique lysosomal environment such as acidic pH and abundant enzymes (e.g. cathepsin B, sulfatase and β-glucuronidase) or equipped with photochemical internalization property have been energetically pursued. In this review, we highlight the recent designs of smart systems that promote efficient lysosomal release and/or escape of anticancer agents including chemotherapeutics (e.g. doxorubicin, platinum, chloroquine and hydrochloroquine) and biotherapeutics (e.g. proteins, siRNA, miRNA, mRNA and pDNA) to cancer cells or immunotherapeutic agents (e.g. antigens, mRNA and immunoadjuvants) to antigen-presenting cells (APCs), thereby boosting cancer therapy and immunotherapy. Lysosomal-mediated drug release presents an appealing approach to develop innovative cancer therapeutics and immunotherapeutics.
    Keywords:  Cancer therapy; Enzyme-sensitive; Intracellular drug release; Targeted delivery; pH-sensitive
    DOI:  https://doi.org/10.1016/j.addr.2022.114624
  22. Pak J Pharm Sci. 2022 Sep;35(5): 1363-1369
    Brain targeted intra nasal acyclovir lipid nanoparticles; in-vitro characterization and in-vivo biodistribution studies.
    Kousalya Selvaraj, Gowthamarajan Kuppusamy, Vyshnavi Tallapaneni, Veera Venkata Satyanarayana Reddy Karri.
      Acyclovir (ACY) is an antiviral class of drugs used to treat herpes simplex virus infections such as herpes simplex encephalitis (HSE). ACY is widely distributed; Systemic exposure of ACY leads to serious adverse effects. Because of its high pH, intravenous ACY may cause phlebitis and local inflammation if extravasation occurs. This study aims to enhance acyclovir delivery to the brain via the intranasal route by formulating ACY nano lipid carriers (ACY-NLCs) to circumvent the side-effects, as mentioned earlier. ACY-NLCs were prepared by emulsification, followed by ultrasonication. A Box-Behnken statistical design with three factors, three levels and 17 runs was selected for the optimization study using Design- Expert Software. Nanoparticles were characterized for particle size, entrapment efficiency and in-vitro drug release. ACY- NLC showed biphasic release pattern i.e. an initial faster release followed by sustained release. Biodistribution study by imaging, Nanoparticles were slowly cleared and biodistributed to the other organs was observed in 2nd and 3rd hr post-administration. From the toxicity studies, NLC formulation is safe and non-toxic for the nasal administration. Rhodamine loaeded NLCs were quickly adsorbed by the olfactory tract and distributed mainly to the lungs through respiratory tract and were also detected in the trachea and olfactory bulb. Biodistribution study of dye loaded NLCs reach brain compared to the Rhodamine-solution.
  23. Front Bioeng Biotechnol. 2022 ;10 989881
    Biomimetic nanoparticles for tumor immunotherapy.
    Hanqing Yu, Meng Wu, Siyu Chen, Mingming Song, Yulin Yue.
      Currently, tumor treatment research still focuses on the cancer cells themselves, but the fact that the immune system plays an important role in inhibiting tumor development cannot be ignored. The activation of the immune system depends on the difference between self and non-self. Unfortunately, cancer is characterized by genetic changes in the host cells that lead to uncontrolled cell proliferation and evade immune surveillance. Cancer immunotherapy aims to coordinate a patient's immune system to target, fight, and destroy cancer cells without destroying the normal cells. Nevertheless, antitumor immunity driven by the autoimmune system alone may be inadequate for treatment. The development of drug delivery systems (DDS) based on nanoparticles can not only promote immunotherapy but also improve the immunosuppressive tumor microenvironment (ITM), which provides promising strategies for cancer treatment. However, conventional nano drug delivery systems (NDDS) are subject to several limitations in clinical transformation, such as immunogenicity and the potential toxicity risks of the carrier materials, premature drug leakage at off-target sites during circulation and drug load content. In order to address these limitations, this paper reviews the trends and progress of biomimetic NDDS and discusses the applications of each biomimetic system in tumor immunotherapy. Furthermore, we review the various combination immunotherapies based on biomimetic NDDS and key considerations for clinical transformation.
    Keywords:  biomimetic nanoparticles; cell membrane; immunotherapy; nano drug delivery systems; tumor microenvironment
    DOI:  https://doi.org/10.3389/fbioe.2022.989881
  24. Front Immunol. 2022 ;13 1023746
    Cold stimuli, hot topic: An updated review on the biological activity of menthol in relation to inflammation.
    Haojin Cheng, Xuemei An.
       Background: Rising incidence of inflammation-related diseases is an increasing concern nowadays. However, while menthol is a wildly-used and efficacious complementary medicine, its pharmacological mechanism still remains uncertain. Superimposed upon that, the aim of this review is to summarize the contemporary evidence of menthol's anti-inflammatory activity.
    Methods: Using the pharmacopeias and electronic databases, including Web of Science, PubMed, and CNKI, this study analyzed the relevant research articles and review articles from 2002 to 2022 and concluded those results and conjectures to finish this article.
    Results: The decrease in pro-inflammatory cytokines and related inflammatory markers, as well as associated pathway activation, was found to play the greatest role in the protective effects of menthol against inflammatory damage or association with protection against chronic inflammation.
    Conclusion: This review mainly concludes the progress in menthol's anti-inflammatory activity. Further studies are needed to establish relationships between the mechanisms of action and to clarify the clinical relevance of any anti-inflammatory effects.
    Keywords:  TRPM-8; inflammation; menthol; natural products; review
    DOI:  https://doi.org/10.3389/fimmu.2022.1023746
  25. Eur J Pharmacol. 2022 Nov 23. pii: S0014-2999(22)00682-3. [Epub ahead of print] 175421
    Nanoparticles and phototherapy combination as therapeutic alternative in prostate cancer: A scoping review.
    Liah Aira Dias Ferreira, Camila Rambo, Mariah Joanna Koch Gomes, Karen Dyminski Parente Ribeiro, Gustavo Araujo de Nishimoto, Leonardo Gomes Rosa da Tisatto, Lucas Diego Fritzen, Yasmin Biscola da Cruz, Aline Lika Kambara, Maria Julia Victor Barbosa Rodrigues, Gabriel Alcantarilla Nogueira, Heloisa Draghetti Salvador, Camila Freitas de Oliveira-Toré, Iara José Messias de Reason, José Ederaldo Queiroz Telles, Fernanda Tomiotto-Pellissier.
      Prostate cancer (CaP) is one of the most common types of cancers worldwide. Despite the existing surgical techniques, prostatectomy patients may experience tumor recurrence. In addition, castration-resistant cancers pose a challenge, especially given their lack of response to standard care. Thus, the development of more efficient therapies has become a field of great interest, and photothermal therapy (PTT) and photodynamic therapy (PDT) are promising alternatives, given their high capacity to cause cell injury and consequent tumor ablation. Phototherapy, along with chemotherapy, has also been shown to be more effective than pharmacotherapy alone. Free molecules used as photosensitizers are rapidly cleared from the body, do not accumulate in the tumor, and are primarily hydrophobic and require toxic solvents. Thus, the use of nanoparticles can be an effective strategy, given their ability to carry or bind to different molecules, protecting them from degradation and allowing their association with other surface ligands, which favors permeation and retention at the tumor site. Despite this, there is still a gap in the literature regarding the use of phototherapy in association with nanotechnology for the treatment of CaP. In this scoping review, it was found that most of the particles studied could act synergistically through PDT and PTT. In addition, fluorescent quenchers can act as diagnostic and therapeutic tools. However, future clinical studies should be performed to confirm the benefits and safety of the combination of nanoparticles and phototherapy for CaP.
    Keywords:  Antineoplastic; Antitumor; Evidence-based medicine; Nanoparticles; Photoradiation; Prostate tumor; Prostatic neoplasm
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175421
  26. Front Bioeng Biotechnol. 2022 ;10 1069676
    Colon cancer exosome-derived biomimetic nanoplatform for curcumin-mediated sonodynamic therapy and calcium overload.
    Yang Li, Chunyu Huang, Youhua Xu.
      Sonodynamic therapy (SDT) possesses unique properties such as being minimally invasive, exhibiting low toxicity, as well as ability to impart the treatment in the deep tissues, and hence has been extensively used. However, inherent defects such as low water-soluble sonosensitizers can limit the clinical application of SDT, and tumor microenvironment (TME) can further compromise the effect of a single SDT. To overcome these challenges, we have designed a bionic nano-system (ECaC) by coating mesoporous calcium carbonate nanoparticles (CaCO3 NPs) and sonosensitizer curcumin (Cur) into tumor-derived exosomes for developing enhanced SDT. Exosome membrane could endow CaCO3 NPs with homologous targeting abilities. In addition, compared with the bare CaCO3 NPs, ECaC showed significant accumulation in the tumor cell species. Subsequently, CaCO3 NPs upon reaching the tumor site can be degraded into Ca2+ in response to the acidic microenvironment of the tumor to destroy the cellular mitochondria. Hence, the cellular respiration could be destroyed to be a vulnerable state, causing oxidative stress, enhancing Cur-mediated chemotherapy/SDT. This synergistically dynamic therapy has demonstrated significant anti-tumor effects under in vitro and in vivo settings without exhibiting any toxic side effects. Our prepared biomimetic nano-system can effectively deliver the hydrophobic Cur to the tumor sites, which holds great promise in field of drug delivery and can broaden the application of exosomes, as this method has a certain enlightenment effect on the subsequent development of exosomes.
    Keywords:  calcium carbonate; curcumin; drug delivery; exosome; sonodynamic therapy
    DOI:  https://doi.org/10.3389/fbioe.2022.1069676
  27. Expert Opin Drug Deliv. 2022 Nov 28.
    Polysaccharide-based hydrogels for drug delivery and wound management: A review.
    Dhruv Sanjanwala, Vaishali Londhe, Rashmi Trivedi, Smita Bonde, Sujata Sawarkar, Vinita Kale, Vandana Patravale.
       INTRODUCTION: Hydrogels are three-dimensional crosslinked networks of hydrophilic polymers, capable of absorbing large quantities of water or aqueous fluids. Polysaccharide-based hydrogels (PBHs) offer several advantages over their synthetic counterparts. Their natural origin contributes to their non-toxicity, high biocompatibility, and in vivo biodegradability. Their properties can be tuned finely to obtain hydrogels with desired mechanical, structural, and chemical properties.
    AREAS COVERED: Such versatile characteristics have potentiated the use of PBHs for the delivery of drugs, vaccines, protein & peptide therapeutics, genes, cells, probiotics, bacteriophages, and other therapeutic agents. Recent advances in hydrogel-based formulations such as nanogels, microgels, microneedles, hydrogel beads, nanocarrier-loaded hydrogels, and complexation hydrogels have enabled the precise delivery of a wide range of therapeutics. This review aims to give a holistic overview of hydrogels in the delivery of a variety of therapeutics through different routes, which is seldom covered in other reviews.
    EXPERT OPINION: PBHs have been used to enable the oral delivery of vaccines and other biologicals, thereby allowing self-administration of life-saving vaccines, saving countless lives, especially during public health emergencies. There is a lack of commercialized wound dressings for the treatment of chronic wounds. PBH-based wound dressings, especially those based on chitosan and loaded with actives and growth factors have the potential to help in the long-term treatment of such wounds. Recent developments in the 3D printing of hydrogels can enable the quick and large-scale production of drug-loaded hydrogels.
    Keywords:  carbohydrate hydrogels; cell therapy; chitosan; drug delivery; gene delivery; vaccine delivery; wound healing
    DOI:  https://doi.org/10.1080/17425247.2022.2152791
  28. Drug Deliv Transl Res. 2022 Nov 28.
    Formulation and characterization of liposomes containing drug absorption enhancers for optimized anti-HIV and antimalarial drug delivery.
    Poloko Stephen Kheoane, Gillian Mary-Anne Enslin, Clemence Tarirai.
      Most of the current clinically used anti-HIV and antimalarial drugs have low bioavailability, either due to poor solubility and permeability, rapid clearance from anatomical reservoirs and poor retention at their site of action (e.g. due to the p-glycoprotein efflux system), and extreme first-pass metabolism (e.g. by the cytochrome P450 enzymes). Hence, new approaches such as the incorporation of drug absorption enhancers (DAEs) (also referred to as bioenhancers) into dosage forms, and exploration of nanocarriers such as liposomes as novel dosage forms, are needed and may provide a viable means that could improve the bioavailability of both anti-HIV and antimalarial drugs. Liposomes loaded with efavirenz or mefloquine in combination with drug absorption enhancers, as well as placebo dosage forms, were prepared using a thin-lipid film hydration technique and characterized for their particle size and zeta potentials, entrapment efficiency, in vitro drug release, and in vitro drug permeability. Liposomes were further investigated for their biocompatibility (safety) using H-4-II-E liver cells in vitro. Drug-loaded liposomes prepared using l-α-phospatidylcholine, dioleoyl (DOPC) and cholesterol (CHOL) (1:1 mol/mol) as well as liposomes made of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), CHOL, and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) (4:6:26 mol/mol/mol) exhibited the best results in terms of their entrapment efficiency, particle size, zeta potential, in vitro drug release, and permeability. DSPC:CHOL:DPPC liposomes released EFV-based formulations better than DPPC:CHOL liposomes for immediate release behaviour. DOPC:CHOL liposomes produced a controlled release and more drug was released in the presence of DAEs for both EFV (0.4-fold higher) and MQ-based (sevenfold higher) formulations in the first 2 h. However, these liposomes were less biocompatible (< 50% cell viability) with liver cells. DOPC:CHOL and DSPC:CHOL:DPPC liposomes could provide a useful nano-formulation platform, which could ensure drug loading, followed by sustained release of both anti-HIV and antimalaria drugs.
    Keywords:  Anti-HIV drugs; Anti-malarial drugs; Bioavailability; Cytotoxicity; Drug absorption enhancers; Liposomes
    DOI:  https://doi.org/10.1007/s13346-022-01264-w
  29. Theranostics. 2022 ;12(18): 7903-7919
    Mutant Kras and mTOR crosstalk drives hepatocellular carcinoma development via PEG3/STAT3/BEX2 signaling.
    Yuan-Deng Luo, Xiao-Yu Liu, Lei Fang, Hong-Qiang Yu, Yu-Jun Zhang, Min Chen, Lei-Da Zhang, Chuan-Ming Xie.
      Background & Aims: Abnormal activation of mTOR through loss of tuberous sclerosis complex (Tsc) frequently occurs in hepatocellular carcinoma (HCC). Mutant Kras could induce aggressive HCCs. Here, we aim to identify the predictive or prognostic biomarkers for HCC patients with Kras mutant and mTOR hyperactivation, and to provide potential therapeutic approaches for this subtype of HCCs. Methods: We generated transgenic mice in which hepatocytic mTOR was hyperactivated through Tsc1 insufficiency with or without oncogenic KrasG12D. Bioinformatics and gain- or loss-of-function studies were used to illustrate the mechanisms underlying oncogenic pathway alterations. Transcriptional profiling was used to identify biomarker for the subtype of HCC. The therapeutic efficacy of targeting mTOR was tested in a liver orthotropic homogeneous murine model. Results: Oncogenic KrasG12D facilitated mTOR activation via the Mek/Erk/ROS axis, leading to HCC tumorigenesis and metastasis. Inhibition of Mek/Erk enhanced the anticancer effect of mTOR inhibitor via reduction of mTOR activity. Paternally expressed 3 (PEG3) was responsible for Kras/Erk- and mTOR-driven HCC. Elevated PEG3 protein interacted with STAT3 and promoted its transcriptional activity, resulting in the upregulation of proliferation- and metastasis-related proteins. Targeting mTOR significantly inhibited these actions in vitro and in vivo. Moreover, in clinical samples, PEG3 was identified as a new poor prognostic marker for HCC patients with Kras/Erk and mTOR hyperactivation. Conclusion: These findings reveal the underlying mechanism of hepatocytic Kras/Erk-driven mTOR activation and its downstream targets (PEG3 and STAT3) in HCC, identify PEG3 as a new prognostic biomarker for HCC with Kras/Erk and mTOR hyperactivation, and provide a potential therapeutic strategy for this subset of HCC patients.
    Keywords:  Cancer therapy; Kras/Mek/Erk; PEG3; STAT3; hepatocellular carcinoma
    DOI:  https://doi.org/10.7150/thno.76873
  30. Biomaterials. 2022 Nov 21. pii: S0142-9612(22)00560-9. [Epub ahead of print]292 121920
    A self-cascaded unimolecular prodrug for pH-responsive chemotherapy and tumor-detained photodynamic-immunotherapy of triple-negative breast cancer.
    Defan Yao, Yanshu Wang, Kexin Bian, Bingbo Zhang, Dengbin Wang.
      Despite the success of immune checkpoint blockade (ICB) therapy in cancer management, ICB-based immunotherapy of triple-negative breast cancer (TNBC) still suffers from immunosuppressive tumor microenvironment (ITM). To break through the bottleneck of TNBC immunotherapy, a self-cascaded unimolecular prodrug consisting of an acidic pH-activatable doxorubicin and an aggregation-induced emission luminogen (AIEgen) photosensitizer coupled to a caspase-3-responsive peptide was engineered. The generated prodrug, could not only release doxorubicin initiatively in acidic tumor microenvironment, but also activate apoptosis-related caspase-3. The activated caspase-3 could in turn trigger release and in situ aggregation of photosensitizers. Importantly, the unimolecular prodrug exhibits a renal clearance pathway similar to small molecules in vivo, while the aggregated AIEgens prolong tumor retention for long-term fluorescence imaging and repeatable photodynamic therapy (PDT) by only one single-dose injection. Furthermore, the tumor-detained PDT boosts both immunogenic cell death of TNBC cells and maturation of dendritic cells. Finally, the combination of repeatable PDT with ICB therapy further promotes the proliferation and intratumoral infiltration of cytotoxic T lymphocytes, and effectively suppresses tumor growth and pulmonary metastasis. This prodrug is a proof-of-concept that confirms the first self-cascaded chemo-PDT strategy to reverse the ITM and boost the ICB-mediated TNBC immunotherapy.
    Keywords:  Cancer immunotherapy; Photodynamic therapy; Prodrug; Triple-negative breast cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121920
  31. Adv Mater. 2022 Nov 29. e2209529
    In Response to Precision Medicine: Current Subcellular Targeting Strategies for Cancer Therapy.
    Zheng Li, Jianhua Zou, Xiaoyuan Chen.
      Emerging as a potent anti-cancer treatment, subcellular targeted cancer therapy has drawn increasing attention, bringing great opportunities for clinical application. In this review, we summarize two targeting strategies for four main subcellular organelles (mitochondria, lysosome, endoplasmic reticulum, and nucleus), including molecule and nanomaterial (inorganic nanoparticles, micelles, organic polymers, and others)-based targeted delivery or therapeutic strategies. Phototherapy, chemotherapy, radiotherapy, immunotherapy, and "all-in-one" combination therapy are among the strategies covered in detail. Such materials have been constructed based on the specific properties and relevant mechanisms of organelles, enabling the elimination of tumors by inducing dysfunction in the corresponding organelles or destroying specific structures. The challenges faced by organelle-targeting cancer therapies are also summarized. Looking forward, we envision a paradigm for organelle-targeting therapy with enhanced therapeutic efficacy compared to current clinical approaches. This article is protected by copyright. All rights reserved.
    Keywords:  cancer therapy; molecules; nanomaterials; precision medicine; subcellular organelle targeting
    DOI:  https://doi.org/10.1002/adma.202209529
  32. Climacteric. 2022 Dec 02. 1-8
    Overexpression of miR-181a regulates the Warburg effect in triple-negative breast cancer.
    Y Wang, H Tahiri, C Yang, M Gu, X Ruan, P Hardy.
       OBJECTIVE: Triple-negative breast cancer (TNBC) is highly aggressive and leads to a poor prognosis. microRNA-181a (miR-181a) exhibits strong antineoplastic effects in many types of cancer. In this study, we examine the responses of human miR-181a-transfected TNBC cells and explore the mechanisms underlying the observed effects.
    METHODS: A series of cellular assays were conducted using cells from the MDA-MB-231 TNBC line to assess the impact of miR-181a overexpression. The extracellular acidification rate, lactate production and glucose uptake were evaluated as a measure of aerobic glycolysis (i.e. the Warburg effect). The expressions of glycolysis-related gene were analyzed.
    RESULTS: Viability, migration and survival of miR-181a-transfected MDA-MB-231 cells were all significantly reduced. miR-181a inhibited glycolysis in TNBC cells by reducing the rates of glucose uptake and lactate production and a substantial downregulation of factors known to contribute to the Warburg effect, including the serine/threonine kinase, AKT3, hypoxia-inducible factor-1α (HIF-1α) and progesterone receptor membrane component 1 (PGRMC1).
    CONCLUSION: Our results demonstrate that miR-181a may regulate glycolysis in MDA-MB-231 TNBC cells, potentially via interference with components of the AKT3-HIF-1α and PGRMC1 pathways. These results suggest that miR-181a might be developed as a therapeutic agent for use in antineoplastic regimens directed at TNBC and PGRMC1-overexpressing breast cancers.
    Keywords:  AKT3; PGRMC1; Triple-negative breast cancer; Warburg effect; glycolysis; miR-181a
    DOI:  https://doi.org/10.1080/13697137.2022.2147821
  33. Food Res Int. 2022 Dec;pii: S0963-9969(22)00984-X. [Epub ahead of print]162(Pt A): 111926
    Dual-modified starch nanoparticles containing aromatic systems with highly efficient encapsulation of curcumin and their antibacterial applications.
    Ruixia Wang, Xuyang Qin, Yanjin Du, Zhongguo Shan, Chao Shi, Kerang Huang, Jiacheng Wang, Kangkang Zhi.
      A series of cinnamic acid (CA)-esterified debranched starch (CDS) containing aromatic systems were prepared and successfully fabricated as nanoparticles to encapsulate curcumin by taking advantage of the additional π-π interactions provided from CA. The CDS nanoparticles (CDS NPs) have good dispersion (polydispersity index of 0.124-0.314) and sizes range of 130-330 nm. The excellent biosafety of CDS NPs was demonstrated by hemolysis, cytotoxicity and mutagenicity assays. Efficient encapsulation (LC = 26.86 %) and sustained release of curcumin were achieved, and the curcumin-encapsulated CDS NPs (CDS-Cur NPs) increased 266-fold water solubility and 2.3-6.5-fold photothermal stability for curcumin, compared to free curcumin. Functional studies showed that CDS-Cur NPs exhibited superior biofilm scavenging ability, with a 2-4.3-fold improvement compared to free curcumin. In addition, CDS-Cur NPs also exhibited far superior antibacterial effects than free curcumin in a bacteriostatic food model of chicken breast. This study not only provides a new scheme for the efficient loading of curcumin, but also provides new ideas for the usage of starch-based materials in antibacterial applications.
    Keywords:  Antibacterial activity; Cinnamic acid; Curcumin; Debranched Starch; Esterification
    DOI:  https://doi.org/10.1016/j.foodres.2022.111926
  34. Int J Nanomedicine. 2022 ;17 5641-5660
    Novel Mucoadhesive Chitosomes as a Platform for Enhanced Oral Bioavailability of Cinnarizine.
    Hagar Ahmed Oransa, Mariza Fouad Boughdady, Hassan Mohamed El-Sabbagh.
       Purpose: Cinnarizine (CIN) is a class II BSC drug, suffering from erratic bioavailability due to its pH-dependent solubility. It has preferential absorption in the stomach. In this study, new chitosan (CS) coated niosomes of CIN (CIN-loaded chitosomes) have been developed to extend the gastric retention and ameliorate CIN oral bioavailability.
    Methods: Various CIN-loaded niosomes were fabricated by thin-film hydration technique and fully characterized. Based on the predetermined criteria of low particle size (PS) and high entrapment efficiency percent (EE%), niosomal formulation F1 was selected and further coated with different CS concentrations. The optimized chitosomal formulation (C2) was evaluated through solid state characterization and mucoadhesive efficiency testing. It was also subjected to cytotoxicity study on Caco-2 cells; besides, in vitro drug release, stability and pharmacokinetic studies were assessed.
    Results: The optimized chitosomal formulation (C2) exhibited an EE% of 58.30±2.75%, PS of 440 ±13.03 nm, PDI of 0.335±0.21 and ZP of +28.1±0.10 mv. Solid state characterization results revealed the compatibility between the vesicle components and the entrapment of CIN within niosomal vesicles. C2 formulation demonstrated favorable mucoadhesive efficiency. The cytotoxicity study on Caco-2 cells manifested the safety of the optimized chitosomal formulation (C2) over the free drug. Additionally, it displayed a remarkable sustaining of CIN in vitro release up to 8 h and exhibited a good stability at the refrigerated temperature up to 3 months. In vivo pharmacokinetic assessment revealed that the CIN bioavailability from the optimized chitosomal formulation C2 was enhanced by 2.79 and 1.92 folds compared to the free drug and uncoated niosomal formulation F1, respectively. The priority of the chitosomal formulation (C2) over the niosomal one (F1) was also conferred.
    Conclusion: Novel formulation of chitosan coated niosomes (chitosomes) could be presented as a promising platform to improve the oral bioavailability of drugs with narrow absorption window.
    Keywords:  chitosan; cinnarizine; mucoadhesion; niosome
    DOI:  https://doi.org/10.2147/IJN.S384494
  35. Int J Biol Sci. 2022 ;18(16): 6210-6225
    Lactylation of PKM2 Suppresses Inflammatory Metabolic Adaptation in Pro-inflammatory Macrophages.
    Jizhuang Wang, Peilang Yang, Tianyi Yu, Min Gao, Dan Liu, Jie Zhang, Chenghao Lu, Xuelian Chen, Xiong Zhang, Yan Liu.
      Emerging evidence suggests that metabolic adaptation is a vital hallmark and prerequisite for macrophage phenotype transition. Pyruvate kinase M2 (PKM2) is an essential molecular determinant of metabolic adaptions in pro-inflammatory macrophages. Post-translational modifications play a central role in the regulation of PKM2. However, doubt remains on whether lactylation in PKM2 exists and how lactylation modulates the function of PKM2. For the first time, our study reports that lactate inhibits the Warburg effect by activating PKM2, promoting the transition of pro-inflammatory macrophages towards a reparative phenotype. We identify PKM2 as a lactylation substrate and confirm that lactylation occurs mainly at the K62 site. We find that lactate increases the lactylation level of PKM2, which inhibits its tetramer-to-dimer transition, promoting its pyruvate kinase activity and reducing nuclear distribution. In short, our study reports a novel post-translational modification type in PKM2 and clarifies its potential role in regulating inflammatory metabolic adaptation in pro-inflammatory macrophages.
    Keywords:  Glycolysis; Lactylation; Macrophage; PKM2
    DOI:  https://doi.org/10.7150/ijbs.75434
  36. J Clin Transl Res. 2022 Dec 29. 8(6): 488-498
    Local anti-inflammatory effect and immunomodulatory activity of chitosan-based dressing in skin wound healing: A systematic review.
    Karla C Maita, Francisco R Avila, Ricardo A Torres-Guzman, John P Garcia, Abdullah S Eldaly, Luiza Palmieri, Omar S Emam, Olivia Ho, Antonio J Forte.
       Background and Aim: Wound healing is a complex process comprised of several distinct phases. An imbalance in any of the stages creates a chronic wound with the potential to cause life-threatening complications for patients. Chitosan (CS) is a biopolymer that has shown to positively impact the different healing phases. This systematic review aimed to evaluate the anti-inflammatory and immunomodulatory properties of CS-based wound therapy for the skin healing process after an injury.
    Methods: A systematic review was conducted in November 2021 following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The PubMed, Embase, Google Scholar, and Cochrane online databases were queried to capture all publications in the past 10 years that investigated the CS effects on inflammation and immune reaction.
    Results: A total of 234 studies were screened after removing duplicates and 14 articles fulfilled our inclusion and exclusion criteria. In the studies, CS was combined with a wide range of products. One clinical trial was found that treated patients with diabetic foot ulcers. All animal models in the studies used a full-thickness skin wound to test the effectiveness of CS in the healing process. Decreased pro-inflammatory cytokine levels, a shortened inflammatory phase and accelerated wound closure was observed in all of the studies.
    Conclusions: CS proved to be a feasible, versatile, and multifaceted biomaterial that enhances the biological response to a skin injury. When combined with other products, its potential to boost the healing process through regulation of the inflammatory and cellular activity is increased.
    Relevance for Patients: Although few clinical trials have been completed, CS has become an excellent alternative to modulate the local inflammatory response promoting wound healing. Especially in patients with associated comorbidities that affect the typical resolution of skin healing, such as diabetes and vascular insufficiency. Therefore, using bioactive wound dressings based on CS combined with nanoparticles, growth factors, lived cells, or medications released in a controlled manner positively impacts patient life by shorting the wound healing process.
    Keywords:  biocompatible materials; deacetylated chitin; inflammation; skin regeneration; tissue engineering; wound healing
  37. J Clin Biochem Nutr. 2022 Nov;71(3): 206-211
    Acetic acid enhances the effect of photodynamic therapy in gastric cancer cells via the production of reactive oxygen species.
    Hiromi Kurokawa, Hiromu Ito, Daisuke Matano, Masahiko Terasaki, Hirofumi Matsui.
      Acetic acid is a major component of vinegar and is reported to have beneficial health effects. Notably, it causes oxidative stress and enhances the production of reactive oxygen species (ROS) in gastric cancer cells. ROS play important roles in cellular signal transduction, resulting in the regulation of protein expression and apoptosis. We previously reported that ROS upregulate heme carrier protein 1 (HCP1). Moreover, ROS increase the cellular uptake of porphyrins, which are precursors of heme and substrates for uptake by HCP1. Therefore, we hypothesized that photodynamic therapy (PDT) for cancer treatment using laser irradiation and photosensitizers, such as porphyrin, is enhanced via ROS produced by acetic acid. Herein, we used the rat gastric mucosal cells, RGM1, its cancer-like mutated cells, RGK1, and a manganese superoxide dismutase (MnSOD)-overexpressing RGK cell line, RGK-MnSOD. We confirmed that cancer-specific cellular uptake of porphyrin is increased upon acetic acid treatment and enhances the PDT cytotoxicity in RGK-1, not in RGM-1 and RGK-MnSOD. We believe that this occurs because of the overproduction of ROS and subsequent upregulation of HCP1 in cancerous cells. In conclusion, acetic acid can elevate the effect of PDT by inducing cancer-specific HCP1 expression via ROS production.
    Keywords:  ABCG2; HCP1; acetic acid; photodynamic therapy; reactive oxygen species
    DOI:  https://doi.org/10.3164/jcbn.22-34
  38. J Nutr Sci Vitaminol (Tokyo). 2022 ;68(Supplement): S121-S124
    Polyphenols for the Prevention and Treatment of Cognitive Impairment.
    Masahito Yamada.
      Epidemiological studies have suggested that diets rich in polyphenols/phenolic compounds are associated with reduced risk of cognitive impairment and Alzheimer's disease (AD). Experimental studies have indicated that these compounds have specific effects on AD pathogenesis as well as anti-oxidant and anti-inflammatory effects. For clinical use, several compounds have been investigated by clinical trials to establish their efficacy for prevention and treatment of AD or cognitive impairment.
    Keywords:  Alzheimer’s disease; cognitive impairment; dementia; polyphenols; prevention
    DOI:  https://doi.org/10.3177/jnsv.68.S121
  39. Cell Biochem Biophys. 2022 Nov 28.
    Advances in the Biological Functions of Extracellular Vesicles and their Potential Use in Treating Oral Cancer.
    Jingwen Liu, Luyi Chai, Xia Zhang.
      Extracellular vesicles (EVs) are membranous spheroid organelles secreted by various cells during their development. Previous studies have proved that the elimination of metabolic waste products from the cells is one of the key biological functions of EVs. Besides, recent studies suggest that EVs also promote intercellular information transmission thus further regulating the external environment of cells, especially during the development of cancer. Different EVs are produced by tumor cells and tumor-related cells during the development of tumors. Based on their sources and contents, different EVs may promote the proliferation of tumor cells, interfere with the function of immune cells, or destroy normal tissue barriers. As a landmark component in the occurrence and development of tumors, EVs can be used to solve the biological behaviors that hinder tumor treatment, such as drug resistance and immune escape. Oral cancer is a highly prevalent cancer type in clinic and current therapies often fail to effectively inhibit its deterioration. Based on their essential roles in cancer development, EVs therefore possess great potential to be a target for oral cancer treatment. In this review, we focused on the origin and classification of vesicles in oral cancer tissues around the tumor microenvironment, described their biological functions, and discussed their potential for cancer treatment in combination with existing research methods. In addition, we highlighted the current challenges and recommendations of EVs for the treatment of oral cancer in clinic.
    Keywords:  Biological components; Drug resistance; Extracellular vesicles; Immune escape; Oral cancer
    DOI:  https://doi.org/10.1007/s12013-022-01120-1
  40. Eur J Pharm Biopharm. 2022 Nov 23. pii: S0939-6411(22)00275-2. [Epub ahead of print]
    Development of nanoparticle loaded microneedles for drug delivery to a brain tumour resection site.
    Paula Muresan, Phoebe McCrorie, Fiona Smith, Catherine Vasey, Vincenzo Taresco, David J Scurr, Stefanie Kern, Stuart Smith, Pavel Gershkovich, Ruman Rahman, Maria Marlow.
      Systemic drug delivery to the central nervous system (CNS) has been historically impeded by the presence of the blood brain barrier rendering many therapies inefficacious to any cancer cells residing within the brain. Therefore, local drug delivery systems are being developed to overcome this shortfall. Here we have manufactured polymeric microneedle (MN) patches, which can be anchored within a resection cavity site following surgical removal of a tumour such as isocitrate dehydrogenase wild type glioblastoma (GBM). These biodegradable MN patches have been loaded with polymer coated nanoparticles (NPs) containing cannabidiol (CBD) or olaparib (OLA) and applied to an in vitro brain simulant and ex vivo rat brain tissue to assess drug release and distance of penetration. MN patches loaded with methylene blue dye were placed into a cavity of 0.6% agarose to simulate brain tissue. The results showed that clear channels were generated by the MNs and the dye spread laterally throughout the agarose. When loaded with CBD-NPs, the agarose showed a CBD concentration of 12.5 µg/g at 0.5 cm from the MN insertion site. Furthermore, high performance liquid chromatography of ex vivo brain tissue following CBD-NP/MN patch insertion showed successful delivery of 59.6 µg/g into the brain tissue. Similarly, OLA-NP loaded MN patches showed delivery of 5.2 µg/g OLA into agarose gel at 0.5 cm distance from the insertion site. Orbitrap secondary ion mass spectrometry (OrbiSIMS) analysis confirmed the presence of OLA and the MN patch at up to 6 mm away from the insertion site following its application to a rat brain hemisphere. This data has provided insight into the capabilities and versatility of MN patches for use in local brain drug delivery, giving promise for future research.
    Keywords:  Microneedles; isocitrate dehydrogenase wild type glioblastoma; nanoparticles
    DOI:  https://doi.org/10.1016/j.ejpb.2022.11.016
  41. Appl Biochem Biotechnol. 2022 Nov 28.
    Regulatory Components of Oxidative Stress and Inflammation and Their Complex Interplay in Carcinogenesis.
    Loganathan Chandramani Priya Dharshini, Rajan Radha Rasmi, Chinnadurai Kathirvelan, Kalavathi Murugan Kumar, K M Saradhadevi, Kunnathur Murugesan Sakthivel.
      Cancer progression is closely linked to oxidative stress (OS) inflammation. OS is caused by an imbalance between the amount of reactive oxygen species produced and antioxidants present in the body. Excess ROS either oxidizes biomolecules or activates the signaling cascade, resulting in inflammation. Immune cells secrete cytokines and chemokines when inflammation is activated. These signaling molecules attract a wide range of immune cells to the site of infection or oxidative stress. Similarly, increased ROS production by immune cells at the inflamed site causes oxidative stress in the affected area. A review on the role of oxidative stress and inflammation in cancer-related literature was conducted to obtain data. All of the information gathered was focused on the current state of oxidative stress and inflammation in various cancers. After gathering all relevant information, a narrative review was created to provide a detailed note on oxidative stress and inflammation in cancer. Proliferation, differentiation, angiogenesis, migration, invasion, metabolic changes, and evasion of programmed cell death are all aided by OS and inflammation in cancer. Imbalance between reactive oxygen species (ROS) and antioxidants lead to oxidative stress that damages macromolecules (nucleic acids, lipids and proteins). It causes breakdown of the biological signaling cascade. Prolonged oxidative stress causes inflammation by activating transcription factors (NF-κB, p53, HIF-1α, PPAR-γ, Nrf2, AP-1) that alter the expression of many other genes and proteins, including growth factors, tumor-suppressor genes, oncogenes, and pro-inflammatory cytokines, resulting in cancer cell survival. The present review article examines the complex relationship between OS and inflammation in certain types of cancer (colorectal, breast, lung, bladder, and gastric cancer).
    Keywords:  Cancer; Cytokines; Inflammation; Oxidative stress; Transcription factors
    DOI:  https://doi.org/10.1007/s12010-022-04266-z
  42. DNA Cell Biol. 2022 Nov 29.
    Ketogenic Diet and Beta-Hydroxybutyrate in Colorectal Cancer.
    Svetlana Khoziainova, Galina Rozenberg, Maayan Levy.
      Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the United States. Although certain genetic predispositions may contribute to one's risk for developing CRC, dietary and lifestyle factors may play an important role as well. In a recent study in Nature, Dmitrieva-Posocco et al, reveal a potential protective role of the ketogenic diet in colorectal cancer growth and progression. Administration of a ketogenic diet to CRC-bearing mice demonstrated a tumor-suppressive effect. Specifically, the ketone body β-hydroxybutyrate (BHB) exhibited the ability to suppress epithelial cell proliferation and inhibit tumor growth. BHB acts on cancer cells through regulation of homeodomain-only protein Hopx, known regulator of CRC. Furthermore, BHB requires a surface receptor Hcar to induce Hopx expression and suppress proliferation of intestinal epithelial cells. Taken together, these results describe a new therapeutic approach of using dietary intervention for the prevention and treatment of colorectal cancer.
    Keywords:  BHB; colorectal cancer; ketogenic diet; metabolites
    DOI:  https://doi.org/10.1089/dna.2022.0486
  43. Drug Metab Dispos. 2022 Nov 29. pii: DMD-MR-2022-000856. [Epub ahead of print]
    Cell and tissue specific metabolism of nucleoside and nucleotide drugs: case studies and implications for precision medicine.
    Elaine E To.
      Many clinically used antiviral drugs are nucleoside or nucleotide analogue drugs, which have a unique mechanism of action that requires intracellular phosphorylation. This dependence on intracellular activation presents novel challenges for the discovery and development of nucleoside/nucleotide analogue drugs. Contrary to many small molecule drug development programs that rely on plasma pharmacokinetics and systemic exposures, the precise mechanisms that result in efficacious intracellular nucleoside triphosphate concentrations must be understood in the process of nucleoside/nucleotide drug development. The importance is highlighted here, using the following as case studies: the herpes treatment acyclovir, the cytomegalovirus therapy ganciclovir, and human immunodeficiency virus (HIV) treatments based on tenofovir, which are also in use for HIV prophylaxis. For each drug, the specificity of metabolism that results in its activation in different cells or tissues is discussed, and the implications explored. Acyclovir's dependence on a viral enzyme for activation provides selective pressure for resistance mutations. Ganciclovir is also dependent on a viral enzyme for activation, and suicide gene therapy capitalizes on that for a novel oncology treatment. The tissue of most relevance for tenofovir activation depends on its use as treatment or as prophylaxis, and the pharmacogenomics and drug-drug interactions in those tissues must be considered. Finally, differential metabolism of different tenofovir prodrugs and its effects on toxicity risk are explored. Taken together, these examples highlight the importance of understanding tissue specific metabolism for optimal use of nucleoside/nucleotide drugs in the clinic. Significance Statement Nucleoside and nucleotide analogue drugs are cornerstones in current antiviral therapy and prevention efforts that require intracellular phosphorylation for activity. Understanding their cell and tissue specific metabolism enables their rational, precision use for maximum efficacy.
    Keywords:  Nucleoside/Nucleotide derivatives; drug metabolism
    DOI:  https://doi.org/10.1124/dmd.122.000856
  44. J Biol Chem. 2022 Oct 28. pii: S0021-9258(22)01091-2. [Epub ahead of print]298(12): 102648
    Requirement of hepatic pyruvate carboxylase during fasting, high fat, and ketogenic diet.
    Ebru S Selen, Susana Rodriguez, Kyle S Cavagnini, Han-Byeol Kim, Chan Hyun Na, Michael J Wolfgang.
      Pyruvate has two major fates upon entry into mitochondria, the oxidative decarboxylation to acetyl-CoA via the pyruvate decarboxylase complex or the biotin-dependent carboxylation to oxaloacetate via pyruvate carboxylase (Pcx). Here, we have generated mice with a liver-specific KO of pyruvate carboxylase (PcxL-/-) to understand the role of Pcx in hepatic mitochondrial metabolism under disparate physiological states. PcxL-/- mice exhibited a deficit in hepatic gluconeogenesis and enhanced ketogenesis as expected but were able to maintain systemic euglycemia following a 24 h fast. Feeding a high-fat diet to PcxL-/- mice resulted in animals that were resistant to glucose intolerance without affecting body weight. However, we found that PcxL-/- mice fed a ketogenic diet for 1 week became severely hypoglycemic, demonstrating a requirement for hepatic Pcx for long-term glycemia under carbohydrate-limited diets. Additionally, we determined that loss of Pcx was associated with an induction in the abundance of lysine-acetylated proteins in PcxL-/- mice regardless of physiologic state. Furthermore, liver acetyl-proteomics revealed a biased induction in mitochondrial lysine-acetylated proteins. These data show that Pcx is important for maintaining the proper balance of pyruvate metabolism between oxidative and anaplerotic pathways.
    Keywords:  Pyruvate Carboxylase; acetylation; fasting; gluconeogenesis; mitochondria
    DOI:  https://doi.org/10.1016/j.jbc.2022.102648
  45. Biomater Sci. 2022 Nov 30.
    Light and immunostimulant mediated in situ re-education of tumor-associated macrophages using photosensitizer conjugated mannan nanoparticles for boosting immuno-photodynamic anti-metastasis therapy.
    Saji Uthaman, Shameer Pillarisetti, Youn-Mook Lim, Jin-Oh Jeong, Rizia Bardhan, Kang Moo Huh, In-Kyu Park.
      In an immunosuppressive tumor microenvironment, tumor-associated macrophages (TAMs) are the most abundant cells displaying pro-tumorigenic M2-like phenotypes, encouraging tumor growth and influencing the development of resistance against conventional therapies. TAMs are highly malleable. They can be repolarized into tumoricidal M1-like cells. In this study, we report the synthesis of novel co-operative immuno-photodynamic nanoparticles involving TAM self-targeting acrylic acid grafted mannan (a polysaccharide) conjugated with the chlorin e6 (Ce6) photosensitizer and then loaded with resiquimod (R848), a toll-like receptor (TLR7/8) agonist. The mannan conjugated Ce6 loaded with R848 (MCR) as bioconjugate nanoparticles demonstrated selective targeting of anti-inflammatory M2-like cells. Using photodynamic therapy they were repolarized to pro-inflammatory M1-like cells with combined effects of reactive oxygen species (ROS)-triggered intracellular signaling and a small-molecule immunostimulant. The MCR also demonstrated a TAM-directed adaptive immune response, inhibited tumor growth, and prevented metastasis. Our results indicate that these MCR nanoparticles can effectively target TAMs and modulate them for cancer immunotherapy.
    DOI:  https://doi.org/10.1039/d2bm01508k
  46. Virology. 2022 Nov 11. pii: S0042-6822(22)00192-1. [Epub ahead of print]578 13-21
    Targeting proteasome enhances anticancer activity of oncolytic HSV-1 in colorectal cancer.
    Xiaxi Li, Wei Hu, Jiangang Shen, Mingsong Li, Wei Gong.
      Herpes simplex virus 1 (HSV-1) has been widely used to treat various cancers, but its efficacy is limited. Studies indicated that combining HSV-1 and chemotherapy drugs can effectively improve the lethality of HSV-1 in tumor cells, which has a synergistic effect. Here, we explored the oncolytic effect and mechanism of bortezomib and HSV-1 on colorectal cancer cells, HCT116 and Caco-2. First, we selected four drugs to detect cell viability and found that the strongest HSV-1-promoting effect was achieved using bortezomib + HSV-1 treatment. Bortezomib combined with HSV-1 treatment significantly upregulated the expression of heat shock proteins, endoplasmic reticulum stress-related proteins and apoptosis-related proteins, while Bcl-2 was downregulated. JC-1 staining revealed that combining bortezomib and HSV-1 promotes cell apoptosis. In addition, bortezomib + oHSV-1 treatment effectively inhibit tumor growth. These results indicate that bortezomib combined with HSV-1 induce intense endoplasmic reticulum stress and activate the caspase-12 apoptosis pathway, killing tumor cells.
    Keywords:  Bortezomib; Colorectal cancer cells; Drug combination; HSV-1; Oncolysis
    DOI:  https://doi.org/10.1016/j.virol.2022.11.002
  47. Life Sci. 2022 Nov 28. pii: S0024-3205(22)00949-3. [Epub ahead of print] 121249
    Alterations in the omics profiles in mevalonate pathway-inhibited cancer cells.
    Tomoko Warita, Nanami Irie, Yaxuan Zhou, Jiro Tashiro, Akihiro Sugiura, Zoltán N Oltvai, Katsuhiko Warita.
       AIMS: Statins, cholesterol-lowering drugs, are potential therapeutic agents for inhibiting cancer proliferation. However, the mechanisms that mediate the effects of statins, the homeostatic responses of tumor cells to statin therapy, and the modes underlying the antitumor effects of statins remain unclear.
    MAIN METHODS: To uncover the effects of statins on cancer cells in vitro, we performed transcriptome and metabolome analyses on atorvastatin-treated statin-resistant and statin-sensitive lung cancer cells.
    KEY FINDINGS: The results of Gene Ontology terms and pathway enrichment analyses showed that after 24 h of atorvastatin treatment, the expression of cell cycle- and DNA replication-related genes was significantly decreased in the statin-sensitive cancer cells. The results of metabolome analysis showed that the components of polyamine metabolism and purine metabolism, glycolysis, and pentose phosphate pathway were decreased in the statin-sensitive cancer cells.
    SIGNIFICANCE: Differences in cellular properties between statin-sensitive and statin-resistant cancer cells revealed additional candidates for therapeutic targets in statin-treated cancer cells and suggested that inhibiting these metabolic pathways could improve efficacy. In conclusion, combining statins with inhibitors of polyamine metabolism (cell proliferation and protein translation), purine metabolism (DNA synthesis), glycolytic system (energy production), and pentose phosphate pathway (antioxidant stress) might enhance the anticancer effects of statins.
    Keywords:  Cancer cells; Glycolysis; Metabolome; Polyamine metabolism; Statins; Transcriptome
    DOI:  https://doi.org/10.1016/j.lfs.2022.121249
  48. Front Oncol. 2022 ;12 1081171
    Editorial: Metabolic reprogramming in breast cancer.
    Cristian Scatena, Antonio Giuseppe Naccarato, Bela Ozsvari, Domenica Scumaci.
      
    Keywords:  breast cancer; breast cancer treatment; metabolic reprogramming; metabolic therapy; resistance mechanisms
    DOI:  https://doi.org/10.3389/fonc.2022.1081171
  49. EMBO Mol Med. 2022 Dec 01. e17042
    Repurposing immunosuppressants for antileukemia therapy.
    Maiko Sezaki, Gang Huang.
      Drug repurposing, the strategy to identify new therapeutic use for clinically approved drugs has attracted much attention in recent years. This strategy offers various advantages over traditional approaches to develop new drugs, including shorter development timelines, low cost, and reduced risk of failure. In this issue of EMBO Molecular Medicine, Liu et al show that inosine monophosphate dehydrogenase (IMPDH) inhibitors, the well-known immunosuppressants have a potent therapeutic effect on the aggressive blood cancer, acute myeloid leukemia with MLL rearrangements. Intriguingly, the antileukemia effect of IMPDH inhibitors is mediated, at least in part through the overactivation of TLR signaling and Vcam1 upregulation. The robust antileukemia effect of IMPDH inhibitors, both in vitro and in vivo, together with their mechanistic findings provides a rational basis for repurposing IMPDH inhibitors for antileukemia therapy.
    DOI:  https://doi.org/10.15252/emmm.202217042
  50. Med Oncol. 2022 Dec 02. 40(1): 31
    Exosomes: special nano-therapeutic carrier for cancers, overview on anticancer drugs.
    Leila Rezakhani, Kiavash Fekri, Gelavizh Rostaminasab, Shima Rahmati.
      Chemotherapy drugs are the first line of cancer treatment, but problems such as low intratumoral delivery, poor bioavailability, and off-site toxicity must be addressed. Cancer-specific drug delivery techniques could improve the therapeutic outcome in terms of patient survival. The current study investigated the loading of chemotherapy drugs loaded into exosomes for cancer treatment. Exosomes are the smallest extracellular vesicles found in body fluids and can be used to transfer information by moving biomolecules from cell to cell. This makes them useful as carriers. As the membranes of these nanoparticles are similar to cell membranes, they can be easily transported to carry different components. As most chemotherapy drugs are not easily soluble in liquid, loading them into exosomes can be a suitable solution to this problem. This cancer treatment could avert the injection of high doses of drugs and provide a more appropriate release mechanism.
    Keywords:  Cancer; Carrier; Chemotherapy drugs; Exosome
    DOI:  https://doi.org/10.1007/s12032-022-01887-6
  51. J Mater Chem B. 2022 Dec 02.
    A thermo-responsive hydrogel loaded with an ionic liquid microemulsion for transdermal delivery of methotrexate.
    Yang Shu, Rong Xue, Yiru Gao, Wenxin Zhang, Jianhua Wang.
      Systemic administration of methotrexate (MTX), the gold standard for the treatment of psoriasis, can cause adverse side effects. To address this issue, a thermally responsive hydrogel loaded with an ionic liquid microemulsion (IL-ME) was developed for the transdermal delivery of MTX. The microemulsion was prepared using water, Tween 20 and choline and geranic acid (CAGE) ionic liquid. The solubility of methotrexate in the IL-ME was 9-fold higher than that in phosphate buffer (PBS). The hydrogel (Gel) based on isopropylacrylamide and silk fibroin acts as a drug reservoir to achieve temperature-responsive drug release in the human epidermis. The loading of the IL-ME or MTX-containing IL-ME on the Gel produced a ME@Gel or MTX/ME@Gel. In vitro permeation experiments showed that the MTX/ME@Gel exhibited a 27.6% increase in MTX permeation. In addition, IL-ME exhibits strong antibacterial activity. In vivo studies indicated that when compared with the results obtained in PBS medium, the MTX/ME@Gel could effectively treat skin redness, swelling and scaling caused by imiquimod (IMQ). In general, the present study demonstrated that the MTX/ME@Gel provides vast potential to serve as a biocompatible drug carrier for the efficient delivery of poorly soluble drugs, i.e., MTX in this particular case.
    DOI:  https://doi.org/10.1039/d2tb02189g
  52. J Mater Sci Mater Med. 2022 Dec 03. 33(12): 78
    Polymeric Nanofibers for Drug Delivery Applications: A Recent Review.
    Xiaoge Duan, Hai-Lan Chen, Chunxian Guo.
      With the rapid development of biomaterials and biotechnologies, various functional materials-based drug delivery systems (DDS) are developed to overcome the limitations of traditional drug release formulations, such as uncontrollable drug concentration in target organs/tissues and unavoidable adverse reactions. Polymer nanofibers exhibit promising characteristics including easy preparation, adjustable features of wettability and elasticity, tailored surface and interface properties, and surface-to-volume ratio, and are used to develop new DDS. Different kinds of drugs can be incorporated into the polymer nanofibers. Additionally, their release kinetics can be modulated via the preparation components, component proportions, and preparation processes, enabling their applications in several fields. A timely and comprehensive summary of polymeric nanofibers for DDS is thus highly needed. This review first describes the common methods for polymer nanofiber fabrication, followed by introducing controlled techniques for drug loading into and release from polymer nanofibers. Thus, the applications of polymer nanofibers in drug delivery were summarized, particularly focusing on the relation between the physiochemical properties of polymeric nanofibers and their DDS performance. It is ended by listing future perspectives. Graphical abstract.
    DOI:  https://doi.org/10.1007/s10856-022-06700-4
  53. Med Oncol. 2022 Nov 29. 40(1): 22
    Atorvastatin induces downregulation of matrix metalloproteinase-2/9 in MDA-MB-231 triple negative breast cancer cells.
    Filiz Bakar-Ates, Erva Ozkan.
      Matrix metalloproteinases (MMPs) are a family of endopeptidases, mainly responsible of extracellular tissue remodeling. Abundant expression of MMPs leads to a number of tumorigenic processes including proliferation, angiogenesis, metastasis and invasion. Therefore, suppressing MMP expression is particularly important in cancer. Atorvastatin is a member of statin family, with cholesterol-lowering properties. Recently, it has emerged as a potential anticancer agent. Multiple researchers have reported promising results of atorvastatin use in cancer therapies. However, its effect on the expression of matrix metalloproteinases in breast cancer is unknown. In the present study, we have confirmed the apoptotic activity of atorvastatin on highly metastatic MDA-MB-231 triple negative breast cancer cells and investigated the gene expression of MMP-2/9. In this regard, MTT analysis was performed to evaluate cytotoxicity. Apoptotic activity was assessed by Annexin V binding and multicaspase assays. Western blot analysis was used to detect the apoptosis-related proteins. RT-PCR analysis was performed to evaluate the mRNA expression levels of MMP-2/9. Results indicated that atorvastatin reduces cell viability significantly at 5 µM after 48 h of treatment (p < 0.0001). It also induces caspase-dependent apoptosis, alters the expression of Bax and Bcl-2 in favour of apoptosis and stimulates cell cycle arrest at S phase (p < 0.05). Moreover, atorvastatin downregulates the mRNA expression of MMP-2 and MMP-9 significantly (p < 0.05). In conclusion, these results demonstrate for the first time that atorvastatin inhibits MMP-2 and MMP-9 gene expression in MDA-MB-231 cells, in addition to inducing caspase-dependent apoptosis.
    Keywords:  Apoptosis; Atorvastatin; Breast cancer; MMP-2; MMP-9
    DOI:  https://doi.org/10.1007/s12032-022-01880-z
  54. Pharm Res. 2022 Nov 30.
    Lipid Microparticles Show Similar Efficacy With Lipid Nanoparticles in Delivering mRNA and Preventing Cancer.
    Afang Ji, Minghao Xu, Yunzhi Pan, Lu Diao, Lin Ma, Li Qian, Junping Cheng, Mi Liu.
       PURPOSE: Messenger RNA (mRNA) has shown great promise for vaccine against both infectious diseases and cancer. However, mRNA is unstable and requires a delivery vehicle for efficient cellular uptake and degradation protection. So far, lipid nanoparticles (LNPs) represent the most advanced delivery platform for mRNA delivery. However, no published studies have compared lipid microparticles (LMPs) with lipid nanoparticles (LNPs) in delivering mRNA systematically, therefore, we compared the impact of particle size on delivery efficacy of mRNA vaccine and subsequent immune responses.
    METHODS: Herein, we prepared 3 different size lipid particles, from nano-sized to micro-sized, and they loaded similar amounts of mRNA. These lipid particles were investigated both in vitro and in vivo, followed by evaluating the impact of particle size on inducing cellular and humoral immune responses.
    RESULTS: In this study, all mRNA vaccines showed a robust immune response and lipid microparticles (LMPs) show similar efficacy with lipid nanoparticles (LNPs) in delivering mRNA and preventing cancer. In addition, immune adjuvants, either toll like receptors or active molecules from traditional Chinese medicine, can improve the efficacy of mRNA vaccines.
    CONCLUSIONS: Considering the efficiency of delivery and endocytosis, besides lipid nanoparticles with size smaller than 150 nm, lipid microparticles (LMPs) also have the potential to be an alternative and promising delivery system for mRNA vaccines.
    Keywords:  LMP; LNP; lipid microparticles; lipid nanoparticles; mRNA vaccine; particle size
    DOI:  https://doi.org/10.1007/s11095-022-03445-1
  55. Comput Biol Med. 2022 Nov 24. pii: S0010-4825(22)01021-6. [Epub ahead of print]151(Pt B): 106313
    Knowledge-driven design and optimization of potent symmetric anticancer molecules: A case study on PKM2 activators.
    Eshika Jaiswal, Christoph Globisch, Alok Jain.
       BACKGROUND: Pyruvate kinase M2 (PKM2) is preferentially expressed as a low-activity dimer over the active tetramer in proliferating tumor cells, resulting in metabolic reprogramming to achieve high energy requirements and nutrient uptake. This leads to a shift from the normal glycolytic pathway causing tumor cells to proliferate uncontrollably. This study utilizes knowledge-based drug discovery to determine the critical features from experimentally known PKM2 activators and design compounds that would significantly confer a stable structural and functional edge over the known compounds which are still at the preclinical stage.
    METHODS: Conscientious molecular modeling studies were carried out and critical structural features were identified and validated from the knowledge of experimentally known PKM2 activators to confer high-binding affinities. A virtual library of 200 palindromic and non-palindromic activators was designed based on these identified critical features to target a distinct activator binding-site. This binding would favor specific dimer-dimer association and subsequent protein tetramerization. The resultant compounds strongly correlated with identified structural features and binding affinities which further strengthened our findings. The designed activators were then subjected to pharmacokinetic profiling and toxicity prediction, followed by free-binding energy calculations and MD simulations.
    RESULTS: All the virtually designed activators comprising the identified critical features were observed to confer high-binding affinities ranging from -9.1 to -15.0 kcal/mol to the receptor protein. The designed activators also demonstrated optimum pharmacokinetic and toxicity profiles.
    CONCLUSION: The best activators selected for MD simulations studies were conclusively observed to stabilize the required tetrameric conformation suggesting that these activators could potentially target PKM2 tetramerization that might restore the normal glycolytic pathway and suppress tumor progression.
    Keywords:  Knowledge-based drug discovery; MD Simulations; Molecular docking; PKM2 activators; Palindromic molecules
    DOI:  https://doi.org/10.1016/j.compbiomed.2022.106313
  56. Int J Biol Macromol. 2022 Nov 29. pii: S0141-8130(22)02838-0. [Epub ahead of print]
    Injectable chitosan-based self-healing supramolecular hydrogels with temperature and pH dual-responsivenesses.
    Yongyan Yang, Gangying Feng, Jingfei Wang, Ruiting Zhang, Shuangling Zhong, Jia Wang, Xuejun Cui.
      In this study, a supramolecular hydrogel was fabricated with orotic acid (OA) modified chitosan (OACS) and 2,6-diaminopurine (DAP). The obtained OACS-DAP supramolecular hydrogels have dual responsiveness to temperature and pH. Phase transition experiments indicate this is a temperature-dependent thermoreversible supramolecular hydrogel. Rheological experiments proved the formation of the supramolecular hydrogel and its thixotropic properties. FTIR spectra confirmed that hydrogen bonds and π-π interactions are the main driving forces for OACS and DAP to form hydrogels through intermolecular self-assembly. XRD pattern confirmed the amorphous morphology of OACS-DAP hydrogels. The hydrogel has excellent electrical conductivity with a conductivity of 9.48 μ S·cm-1. And can achieve the precise release of gastrointestinal drugs. OACS-DAP hydrogel is expected to have better applications in the field of gastrointestinal drug release.
    Keywords:  Dual-stimulus responsiveness; Injectable; Self-healing; Supramolecular hydrogel; Thermal reversible; Thixotropy
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.11.279
  57. Front Mol Biosci. 2022 ;9 1022725
    The application of exosomes in the treatment of triple-negative breast cancer.
    John W Weaver, Jinyu Zhang, Juan Rojas, Phillip R Musich, Zhiqiang Yao, Yong Jiang.
      Triple-negative breast cancer (TNBC) is a heterogeneous and invasive breast cancer (BC) subtype that is estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2 (Her2)-negative. So far, the treatment of TNBC is still ineffective due to the lack of well-defined molecular targets. Exosomes are nanosized extracellular vesicles composed of lipid bilayers. They originate from various types of donor cells and release a complex mixture of contents including diverse nucleic acid types (miRNA, LnRNA, siRNA, and DNA) and proteins; after binding to recipient cells the exosomes release their contents that execute their biological functions. Exosomes have been reported to play an important role in the tumorigenesis of TNBC, including tumor initiation, metastasis, angiogenesis, cell proliferation, immune escape, and drug resistance. On the other hand, exosomes can be valuable biomarkers for diagnosis, monitoring, and treatment of TNBC. More interestingly, exosomes can be harnessed as a nanosized drug-delivery system specifically targeting TNBC. In this review, we present the most recent mechanistic findings and clinical applications of exosomes in TNBC therapy, focusing on their use as diagnostic and prognostic biomarkers, nanoscale drug delivery platforms, and immunotherapeutic agents. In addition, the associated challenges and future directions of using exosomes for TNBC treatment will be discussed.
    Keywords:  TNBC; biomarker; breast cancer; exosome; metastasis
    DOI:  https://doi.org/10.3389/fmolb.2022.1022725
  58. Cell Rep. 2022 Nov 29. pii: S2211-1247(22)01619-9. [Epub ahead of print]41(9): 111741
    Vitamin B5 rewires Th17 cell metabolism via impeding PKM2 nuclear translocation.
    Chen Chen, Weiqiao Zhang, Tingyue Zhou, Qiuyuan Liu, Chao Han, Zonghui Huang, Si Chen, Qiao Mei, Cunjin Zhang, Kaiguang Zhang, Hongdi Ma, Rongbin Zhou, Wei Jiang, Wen Pan, Shu Zhu.
      Metabolic rewiring is essential for Th17 cells' functional identity to sense and interpret environmental cues. However, the environmental metabolic checkpoints with specific regulation of Th17 cells, manifesting potential therapeutic opportunities to autoimmune diseases, remain largely unknown. Here, by screening more than one hundred compounds derived from intestinal microbes or diet, we found that vitamin B5 (VB5) restrains Th17 cell differentiation as well as related autoimmune diseases such as experimental autoimmune encephalomyelitis and colitis. Mechanistically, VB5 is catabolized into coenzyme A (CoA) in a pantothenate kinase (PANK)-dependent manner, and in turn, CoA binds to pyruvate kinase isoform 2 (PKM2) to impede its phosphorylation and nuclear translocation, thus inhibiting glycolysis and STAT3 phosphorylation. In humans, reduced serum VB5 levels are found in both IBD and MS patients. Collectively, our study demonstrates a role of VB5 in Th17 cell metabolic reprograming, thus providing a potential therapeutic intervention for Th17 cell-associated autoimmune diseases.
    Keywords:  CP: Immunology; CP: Microbiology; CoA; PKM2; Th17; glucose metabolism; vitamin B5
    DOI:  https://doi.org/10.1016/j.celrep.2022.111741
  59. Drug Metab Dispos. 2022 Dec 02. pii: DMD-MR-2021-000743. [Epub ahead of print]
    Opportunities for accelerating drug discovery and development by using engineered drug-metabolizing enzymes.
    Elizabeth M J Gillam, Valerie M Kramlinger.
      The study of drug metabolism is fundamental to drug discovery and development (DDD) since by mediating the clearance of drugs, metabolic enzymes control their bioavailability and duration of action. Biotransformation can also produce pharmacologically active or toxic products, which complicates the evaluation of the therapeutic benefit vs liability of potential drugs, but also provides opportunities to explore the chemical space around a lead. The structures and relative abundance of metabolites are determined by the substrate and reaction specificity of biotransformation enzymes and their catalytic efficiency. Preclinical drug biotransformation studies are done to quantify in vitro intrinsic clearance to estimate likely in vivo pharmacokinetic parameters, to predict an appropriate dose, and to anticipate interindividual variability in response, including from drug-drug-interactions. Such studies need to be done rapidly and cheaply, but native enzymes, especially in microsomes or hepatocytes, do not always produce the full complement of metabolites seen in extrahepatic tissues or preclinical test species. Furthermore, yields of metabolites are usually limiting. Engineered recombinant enzymes can make DDD more comprehensive and systematic. Additionally, as renewable, sustainable and scalable resources, they can also be used for elegant chemoenzymatic, synthetic approaches to optimize or synthesize candidates as well as metabolites. Here we will explore how these new tools can be used to enhance the speed and efficiency of DDD pipelines, and provide a perspective on what will be possible in the future. The focus will be on cytochrome P450 enzymes to illustrate paradigms that can be extended in due course to other drug-metabolizing enzymes. Significance Statement Protein engineering can generate enhanced versions of drug-metabolizing enzymes that are more stable, better suited to industrial conditions and have altered catalytic activities, including catalyzing non-natural reactions on structurally complex lead candidates. When applied to drugs in development, libraries of engineered cytochrome P450 enzymes can accelerate the identification of active or toxic metabolites, help elucidate structure activity relationships, and, when combined with other synthetic approaches, provide access to novel structures, by regio- and stereoselective functionalization of lead compounds.
    Keywords:  CYP2C19; CYP2C9; CYP2D6; CYP3A4; Cytochrome P450 (CYP); drug development/discovery; drug metabolism; extrahepatic drug metabolism; in vitro toxicity assays; reactive metabolites/intermediates
    DOI:  https://doi.org/10.1124/dmd.121.000743
  60. ACS Omega. 2022 Nov 22. 7(46): 41872-41881
    Epigallocatechin-3-gallate Delivered in Nanoparticles Increases Cytotoxicity in Three Breast Carcinoma Cell Lines.
    Fulvia Farabegoli, Andreia Granja, Joana Magalhães, Stefania Purgato, Manuela Voltattorni, Marina Pinheiro.
      The anticancer activity of epigallocatechin-3-gallate (EGCG), orally administrated, is limited by poor bioavailability, absorption, and unpredictable distribution in human tissues. EGCG charged nanoparticles may represent an opportunity to overcome these limitations. We assayed two different kinds of lipid nanoparticles (LNPs and LNPs functionalized with folic acid) charged with EGCG on three breast carcinoma cell lines (MCF-7, MDA-MB-231, and MCF-7TAM) and the human normal MCF10A mammary epithelial cells. Both LNPs loaded with EGCG, at low concentrations, induced a significant cytotoxicity in the three breast carcinoma cells but not in MCF10A cells. In view of a future application, both LNPs and LNPs-FA were found to be very suitable for in vitro studies and useful to improve EGCG administration in vivo. Since they are produced by inexpensive procedures using bioavailable, biocompatible, and biodegradable molecules, they represent an applicable tool for a more rationale use of EGCG as an anti-cancer agent.
    DOI:  https://doi.org/10.1021/acsomega.2c01829
  61. Adv Sci (Weinh). 2022 Nov 27. e2204365
    Emerging Sonodynamic Therapy-Based Nanomedicines for Cancer Immunotherapy.
    Yunrong Yang, Jia Huang, Min Liu, Yige Qiu, Qiaohui Chen, Tianjiao Zhao, Zuoxiu Xiao, Yuqi Yang, Yitian Jiang, Qiong Huang, Kelong Ai.
      Cancer immunotherapy effect can be greatly enhanced by other methods to induce immunogenic cell death (ICD), which has profoundly affected immunotherapy as a highly efficient paradigm. However, these treatments have significant limitations, either by causing damage of the immune system or limited to superficial tumors. Sonodynamic therapy (SDT) can induce ICD to promote immunotherapy without affecting the immune system because of its excellent spatiotemporal selectivity and low side effects. Nevertheless, SDT is still limited by low reactive oxygen species yield and the complex tumor microenvironment. Recently, some emerging SDT-based nanomedicines have made numerous attractive and encouraging achievements in the field of cancer immunotherapy due to high immunotherapeutic efficiency. However, this cross-cutting field of research is still far from being widely explored due to huge professional barriers. Herein, the characteristics of the tumor immune microenvironment and the mechanisms of ICD are firstly systematically summarized. Subsequently, the therapeutic mechanism of SDT is fully summarized, and the advantages and limitations of SDT are discussed. The representative advances of SDT-based nanomedicines for cancer immunotherapy are further highlighted. Finally, the application prospects and challenges of SDT-based immunotherapy in future clinical translation are discussed.
    Keywords:  cancer immunotherapy; immune adjuvants; immune checkpoint blockade therapy; immunogenic cell death; sonodynamic therapy
    DOI:  https://doi.org/10.1002/advs.202204365
  62. Cell Mol Bioeng. 2022 Oct;15(5): 355-366
    High-Density Branched PEGylation for Nanoparticle Drug Delivery.
    Devorah Cahn, Gregg A Duncan.
       Introduction: The surface modification of nanoparticles (NP) with a dense layer of polyethylene glycol (PEG) has been widely used to improve NP circulation time, bioavailability, and diffusion through biological barriers [e.g. extracellular matrix (ECM), mucus]. While linear PEG coatings are commonly used, branched PEG coatings have not been widely explored as a design parameter for NP drug delivery systems.
    Methods: NPs were densely coated with either linear 2, 5, 10 kDa linear PEG or with 10 kDa star-shaped, 4-arm branched PEG. NP cellular uptake was evaluated in HEK-293T and A549 cells. NP stability was evaluated in fetal bovine serum over 24 h using dynamic light scattering. Diffusion of NPs within a Matrigel ECM model and sputum (mucus) collected from individuals with cystic fibrosis (CF) lung disease were analyzed through multiple particle tracking.
    Results: PEG-coated NPs appeared more stable in serum compared to uncoated NPs, but the reduction in total protein adsorbed was most significant for branched PEG coated NP. All PEGylated NPs had similar cellular uptake in HEK-293T and A549 cells. Interestingly, branched-PEG coated NPs had the largest diffusion coefficient and moved most rapidly through Matrigel. However in CF mucus, linear 2 and 5 kDa PEG coated NPs had the largest fraction of rapidly diffusing particles while branched PEG coated NPs had less hindered mobility compared to linear 10 kDa PEG coated NPs.
    Conclusion: Branched PEGylation may have the potential to increase NP efficiency in reaching target cells based on an apparent increase in diffusion through an ECM model while maintaining NP stability and uptake in target cells comparable to their linear PEG counterparts.
    Keywords:  Extracellular matrix; Nanomedicine; PEGylation
    DOI:  https://doi.org/10.1007/s12195-022-00727-x
  63. Front Genet. 2022 ;13 1065320
    Retinoids in cancer chemoprevention and therapy: Meta-analysis of randomized controlled trials.
    Shuting Chen, Qinchao Hu, Xiaoan Tao, Juan Xia, Tong Wu, Bin Cheng, Juan Wang.
      Retinoids, natural and synthetic derivatives of vitamin A, have many regulatory functions in human body, including regulating cellular proliferation, differentiation, apoptosis. Moreover, retinoids have been used successfully for the treatment of certain malignancies, especially acute promyelocytic leukemia (APL) in adults and neuroblastoma in children. However, retinoids have not yet been translated into effective systemic treatments for most solid cancers. Some recent studies have shown that retinoids promote tumorigenesis. Therefore, we performed this meta-analysis to systematically evaluate the efficacy of retinoids in the chemoprevention and treatment of cancers. We performed literature search of several electronic databases, including PubMed, Embase and Cochrane Library from 2000 January to 2021 November. Various outcomes were applied to investigate the potential of retinoids for prevention and treatment of cancers. The primary outcomes in this study were disease recurrence and clinical response. The secondary outcomes included overall survival (OS), cancer development, disease progression and event-free survival. We identified 39 randomized controlled trials with 15,627 patients in this study. Our results showed that lower recurrence rate and better clinical response were obtained in retinoids treated patients with cancer or premalignancy as compared with control. The differences were statistically significant (RR = 0.85, 95% CI = 0.74-0.96, p = 0.01; RR = 1.24, 95% CI = 1.03-1.49, p = 0.02, respectively). Retinoids treatment was not associated with improvement in overall survival, cancer development, disease progression or event-free survival. Subgroup analysis conducted based on cancer type showed that patients benefited from retinoids treatment in APL, renal cell carcinoma, hepatocellular carcinoma, lung cancer, Kaposi sarcoma, and complete hydatidiform mole. No significant therapeutic effect was noted in head and neck cancer, acute myeloid leukemia (AML), melanoma, breast cancer, bladder cancer, cervical intraepithelial neoplasia (CIN) or cervical carcinoma. Subgroup analysis based on tumor classification demonstrated that retinoids group obtained a lower recurrence rate and better clinical response than control group in solid cancers. In conclusion, clinical application of retinoids was associated with reduction in disease recurrence and improvement in clinical response, illustrating that retinoids play a key role in cancer prevention and therapy. Further research is needed to broaden the utility of retinoids in other types of cancers. Systematic Review Registration: PROSPERO, identifier CRD42022296706.
    Keywords:  cancer; prevention; retinoids; treatment; vitamin A
    DOI:  https://doi.org/10.3389/fgene.2022.1065320
  64. Nat Prod Res. 2022 Nov 28. 1-6
    Resveratrol induces the production of reactive oxygen species, interferes with the cell cycle, and inhibits the cell migration of bladder tumour cells with different TP53 status.
    Tamires Cunha Almeida, André Sacramento Melo, Ana Paula Braga Lima, Renata Tupinambá Branquinho, Glenda Nicioli da Silva.
      Resveratrol is a polyphenolic compound whose antitumor activity has been demonstrated in several types of cancer. However, there are few studies on its molecular mechanisms of action in bladder cancer. Therefore, we aimed to evaluate resveratrol activity in bladder tumour cells with different TP53 gene status. Cytotoxicity, cell proliferation, reactive oxygen species (ROS) production, cell migration, mutagenicity, and CDH1, CTNNBIP1, HAT1, HDAC1, MYC, and SMAD4 gene expression were evaluated. An increase in ROS after resveratrol treatment was accompanied by reduced cell viability and proliferation in all cell lines. In TP53 wild-type cells, the inhibition of cell migration was accompanied by CDH1 and SMAD4 modulation. In TP53 mutated cells, cell migration inhibition with CDH1 and CTNNB1P1 upregulation was observed. In conclusion, resveratrol has antiproliferative effect in bladder tumour cells and its mechanism of action occurred through ROS production, interference with cell cycle, and inhibition of cell migration, independent of TP53 status.
    Keywords:  TP53 gene; bladder cancer; cell migration; cell proliferation; reactive oxygen species; resveratrol
    DOI:  https://doi.org/10.1080/14786419.2022.2151007
  65. Nat Rev Endocrinol. 2022 Nov 29.
    Metabolic determinants of tumour initiation.
    Julia S Brunner, Lydia W S Finley.
      Tumours exhibit notable metabolic alterations compared with their corresponding normal tissue counterparts. These metabolic alterations can support anabolic growth, enable survival in hostile environments and regulate gene expression programmes that promote malignant progression. Whether these metabolic changes are selected for during malignant transformation or can themselves be drivers of tumour initiation is unclear. However, intriguingly, many of the major bottlenecks for tumour initiation - control of cell fate, survival and proliferation - are all amenable to metabolic regulation. In this article, we review evidence demonstrating a critical role for metabolic pathways in processes that support the earliest stages of tumour development. We discuss how cell-intrinsic factors, such as the cell of origin or transforming oncogene, and cell-extrinsic factors, such as local nutrient availability, promote or restrain tumour initiation. Deeper insight into how metabolic pathways control tumour initiation will improve our ability to design metabolic interventions to limit tumour incidence.
    DOI:  https://doi.org/10.1038/s41574-022-00773-5
  66. Int J Pharm. 2022 Nov 24. pii: S0378-5173(22)00991-7. [Epub ahead of print]630 122436
    Co-delivery of ibrutinib and hydroxychloroquine by albumin nanoparticles for enhanced chemotherapy of glioma.
    Zhihang Yang, Yufan Du, Lei Lei, Xue Xia, Xiaorong Wang, Fan Tong, Yuan Li, Huile Gao.
      Ibrutinib (IBR) is an oral covalent inhibitor of Bruton's tyrosine kinase (BTK) that has been approved for the treatment of hematological malignancies. It was reported that IBR exhibited great therapeutic potential for glioma. However, the poor water solubility and high hepatic first-pass effect restrict its anti-glioma application. Meanwhile, IBR induces cytoprotective autophagy through Akt/mTOR signaling pathway, thus leading to a compromised antitumor effect. Herein, we aimed to develop a human serum albumin (HSA) based co-delivery system (IBR&HCQ HSA NPs) encapsulating IBR and hydroxychloroquine (HCQ). The bioavailability of IBR was largely improved, and enhanced sensitivity of glioma to IBR was achieved due to inhibition effect of HCQ on IBR-induced pro-survival autophagy. The physicochemical properties of IBR&HCQ HSA NPs were characterized to optimize the formulation. Biodistribution investigation revealed that HSA NPs (20 mg/kg, i.v.) dramatically increased the accumulation of IBR in glioma, which was 5.59 times higher than that of free IBR (100 mg/kg, i.g.). CCK-8 and apoptosis assays demonstrated that IBR&HCQ HSA NPs showed maximal cytotoxicity to C6 cells. In vivo studies indicated that the survival time was significantly prolonged in IBR&HCQ HSA NPs treated mice compared to those treated with IBR HSA NPs. Taken together, the HSA-based drug delivery system of IBR and HCQ opens a new avenue for efficient treatment of glioma.
    Keywords:  Albumin nanoparticles; Autophagy inhibition; Combined therapy; Glioma; Ibrutinib
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122436
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