Molecular Pharmaceutics最新文献

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Verticillin A-Loaded Surgical Buttresses Prevent Local Pancreatic Cancer Recurrence in a Murine Model. 含橘皮霉素 A 的手术栓在小鼠模型中可防止局部胰腺癌复发
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-01-27 DOI: 10.1021/acs.molpharmaceut.4c00589
Zeinab Y Al Subeh, Herma C Pierre, Cedric J Pearce, Mark W Grinstaff, Aaron H Colby, Kebin Liu, Nicholas H Oberlies
{"title":"Verticillin A-Loaded Surgical Buttresses Prevent Local Pancreatic Cancer Recurrence in a Murine Model.","authors":"Zeinab Y Al Subeh, Herma C Pierre, Cedric J Pearce, Mark W Grinstaff, Aaron H Colby, Kebin Liu, Nicholas H Oberlies","doi":"10.1021/acs.molpharmaceut.4c00589","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00589","url":null,"abstract":"<p><p>The fungal metabolite verticillin A is a potent and selective histone methyltransferase inhibitor. It regulates apoptosis, the cell cycle, and stress response, and displays potent activity in the suppression of tumor cell growth in several different in vivo models. Verticillin A sensitizes pancreatic cancer cells to anti-PD-1 immunotherapy by regulating PD-L1 expression. However, as with many natural products, delivery and systemic toxicity are challenges that must be overcome to advance their use as a chemotherapeutic. To both reduce systemic toxicity and improve delivery, we report a verticillin A-loaded surgical buttress, which is well-tolerated at a dose as high as 40 mg/kg. In contrast, free verticillin A administered systemically results in toxicity at a dose of 3 mg/kg. The verticillin A-loaded buttress suppresses tumor recurrence in vivo in a safe and dose-dependent manner against a highly aggressive and metastatic model of pancreatic cancer.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Antitumor Research Based on Drug Delivery Carriers: Reversing the Polarization of Tumor-Associated Macrophages.
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-01-27 DOI: 10.1021/acs.molpharmaceut.4c01277
Xinyu Cao, Shen Wan, Bingyu Wu, Zhikuan Liu, Lixing Xu, Yu Ding, Haiqin Huang
{"title":"Antitumor Research Based on Drug Delivery Carriers: Reversing the Polarization of Tumor-Associated Macrophages.","authors":"Xinyu Cao, Shen Wan, Bingyu Wu, Zhikuan Liu, Lixing Xu, Yu Ding, Haiqin Huang","doi":"10.1021/acs.molpharmaceut.4c01277","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01277","url":null,"abstract":"<p><p>The development of malignant tumors is a complex process that involves the tumor microenvironment (TME). An immunosuppressive TME presents significant challenges to current cancer therapies, serving as a key mechanism through which tumor cells evade immune detection and play a crucial role in tumor progression and metastasis. This impedes the optimal effectiveness of immunotherapeutic approaches, including cytokines, immune checkpoint inhibitors, and cancer vaccines. Tumor-associated macrophages (TAMs), a major component of tumor-infiltrating immune cells, exhibit dual functionalities: M1-like TAMs suppress tumorigenesis, while M2-like TAMs promote tumor growth and metastasis. Consequently, the development of various nanocarriers aimed at polarizing M2-like TAMs to M1-like phenotypes through distinct mechanisms has emerged as a promising therapeutic strategy to inhibit tumor immune escape and enhance antitumor responses. This Review covers the origin and types of TAMs, common pathways regulating macrophage polarization, the role of TAMs in tumor progression, and therapeutic strategies targeting TAMs, aiming to provide a comprehensive understanding and guidance for future research and clinical applications.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Atomic Insights into pH-Dependent and Water Permeation of mRNA-Lipid Nanoparticles. mrna -脂质纳米颗粒的ph依赖性和水渗透的原子见解。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-01-21 DOI: 10.1021/acs.molpharmaceut.4c01239
Shao-Jun Feng, Guang-Wen Chu, Hui Li, Jian-Feng Chen
{"title":"Atomic Insights into pH-Dependent and Water Permeation of mRNA-Lipid Nanoparticles.","authors":"Shao-Jun Feng, Guang-Wen Chu, Hui Li, Jian-Feng Chen","doi":"10.1021/acs.molpharmaceut.4c01239","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01239","url":null,"abstract":"<p><p>The exposure of mRNA to water is likely to contribute to the instability of RNA vaccines upon storage under nonfrozen conditions. Using atomistic molecular dynamics (MD) simulations, we investigated the pH-dependent structural transition and water penetration behavior of mRNA-lipid nanoparticles (LNPs) with the compositions of Moderna and Pfizer vaccines against COVID-19 in an aqueous solution. It was revealed that the ionizable lipid (IL) membranes of LNPs were extremely sensitive to pH, and the increased acidity could cause a rapid membrane collapse and hydration swelling of LNP, confirming the high releasing efficiency of both LNP vaccines. The free energy profiles of water penetration showed that the conical structure of IL played a key role in obstructing water from entering the inner core of LNPs: the molecular geometry with more tail chains, lower linearity, and looser packing structure resulted in higher water permeability, leading to lower stability in nonfrozen liquid environment. On the other hand, the geometry of IL also dominated the fusion behavior of LNP with endosomal membrane during the endosomal escape. Thus, for LNP-based vaccines with both high release efficiency and high stability, a suitable molecular structure of ILs should be selected to seek a balance between the packing tightness and fusion rate of membranes.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Photosensitizable ZIF-8 BioMOF for Stimuli-Responsive Antimicrobial Phototherapy. 用于刺激反应性抗菌光疗的光敏性ZIF-8 BioMOF。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-01-21 DOI: 10.1021/acs.molpharmaceut.4c00981
Angana De, Yeddula Nikhileshwar Reddy, Shatabdi Paul, Vaibhav Sharma, Vamshi Krishna Tippavajhala, Jayeeta Bhaumik
{"title":"Photosensitizable ZIF-8 BioMOF for Stimuli-Responsive Antimicrobial Phototherapy.","authors":"Angana De, Yeddula Nikhileshwar Reddy, Shatabdi Paul, Vaibhav Sharma, Vamshi Krishna Tippavajhala, Jayeeta Bhaumik","doi":"10.1021/acs.molpharmaceut.4c00981","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00981","url":null,"abstract":"<p><p>Resistant pathogens are increasingly posing a heightened risk to healthcare systems, leading to a growing concern due to the lack of effective antimicrobial treatments. This has prompted the adoption of antimicrobial photodynamic therapy (aPDT), which eradicates microorganisms by generating reactive oxygen species (ROS) through the utilization of a photosensitizer, photons, and molecular oxygen. However, a challenge arises from the inherent characteristics of photosensitizers, including photobleaching, aggregation, and self-quenching. Consequently, a strategy has been devised to adsorb or bind photosensitizers to diverse carriers to facilitate their delivery. Notably, metal-organic frameworks (MOFs) have emerged as a promising means of transporting photosensitizers, even though achieving uniform particle sizes through room-temperature synthesis remains a complex task. In this work, we have tackled the issue of heterogeneous particle size distribution in MOFs, achieving a particle size of 150 ± 50 nm. Subsequently, we harnessed Zeolite Imidazolate Framework 8 (ZIF-8), an excellent subclass of biocompatible MOF, to effectively load two distinct categories of photosensitizers, namely, Rose Bengal (RB) and porphyrin, using a simple, straightforward, and single-step process. Our findings indicate that the prepared RB@ZIF-8 complex generates a more substantial amount of reactive singlet oxygen species when subjected to photoirradiation (using green light-emitting diode (LED)) at low concentrations, in comparison with porphyrin@ZIF-8, as demonstrated in <i>in vitro</i> experiments. Additionally, we investigated the pH-responsive behavior of the complex to ascertain its implications under biological conditions. Correspondingly, the RB@ZIF-8 complex exhibited a more favorable IC<sub>50</sub> value against <i>Escherichia coli</i> compared to bare photosensitizers, ZIF-8 alone, and other photosensitizer-loaded ZIF-8 complexes. This underscores the potential of BioMOF as a promising strategy for combatting multidrug-resistant bacteria across a spectrum of infection scenarios, complemented by its responsiveness to stimuli.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Formulation and Evaluation of Lipid/Soluplus-Stabilized Nanocrystals of Paclitaxel and Bosutinib for a Synergistic Effect in Non-Small Cell Lung Cancer Therapy. 脂质/溶质稳定的紫杉醇和博舒替尼纳米晶体在非小细胞肺癌治疗中的协同作用的配方和评价。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-01-21 DOI: 10.1021/acs.molpharmaceut.4c01334
Manish Kumar, Pooja Goswami, Abhishek Jha, Vividha Dhapte-Pawar, Biplob Koch, Brahmeshwar Mishra
{"title":"Formulation and Evaluation of Lipid/Soluplus-Stabilized Nanocrystals of Paclitaxel and Bosutinib for a Synergistic Effect in Non-Small Cell Lung Cancer Therapy.","authors":"Manish Kumar, Pooja Goswami, Abhishek Jha, Vividha Dhapte-Pawar, Biplob Koch, Brahmeshwar Mishra","doi":"10.1021/acs.molpharmaceut.4c01334","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01334","url":null,"abstract":"<p><p>Tyrosine kinase inhibitors have been employed for the treatment of lung cancer, owing to their role in regulating irregulated pathways or mutated genes. Bosutinib, a nonreceptor tyrosine kinase, has been recently investigated for lung cancer treatment. Bosutinib can also be used with paclitaxel as a combinatorial approach to receive a synergistic effect for the effective management of lung cancer. Furthermore, the nanocrystals of each can also be prepared and in combination can produce a more pronounced impact than the drug combination. Herein, the prepared Soluplus/lipid-stabilized nanocrystals of paclitaxel and bosutinib were rod to cubic in shape of about 150-250 nm. The nanocrystals were stable, provided controlled drug release, and exhibited a higher aerosolization performance. The nanocrystal combination demonstrated higher anticancer activity than the drug combination synergy against A549 cancer cells. The nanocrystals increased the level of cellular internalization in cancer cells, thereby inducing higher ROS generation and apoptosis of cancer cells. Furthermore, the lipid/Soluplus-stabilized nanocrystals exhibited higher translocation potential compared with only Soluplus-stabilized nanocrystals. The nanocrystals administered intratracheally showed a lower drug distribution to other organs, with prolonged drug retention in the lungs, suggesting the higher efficacy of developed nanocrystals in targeting the lungs. In conclusion, lipid-modified nanocrystals can be a novel approach for the effective management of lung cancer.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Opto-Laser-Responsive Smart NanoGel with Mild Hyperthermia, Vascularization, and Anti-Inflammatory Potential for Boosting Hard-to-Heal Wounds in a Diabetic Mice Model. 光激光响应智能纳米凝胶具有轻度高温、血管化和抗炎潜力,可促进糖尿病小鼠模型中难以愈合的伤口。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-01-20 DOI: 10.1021/acs.molpharmaceut.4c01466
Bhakti Pawar, Shivam Otavi, Amrita Singh, Suryanarayana Polaka, Nupur Vasdev, Tanisha Gupta, Rakesh K Tekade
{"title":"Opto-Laser-Responsive Smart NanoGel with Mild Hyperthermia, Vascularization, and Anti-Inflammatory Potential for Boosting Hard-to-Heal Wounds in a Diabetic Mice Model.","authors":"Bhakti Pawar, Shivam Otavi, Amrita Singh, Suryanarayana Polaka, Nupur Vasdev, Tanisha Gupta, Rakesh K Tekade","doi":"10.1021/acs.molpharmaceut.4c01466","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01466","url":null,"abstract":"<p><p>It is well known that impaired wound healing associated with diabetes mellitus has led to a challenging problem as well as a global economic healthcare burden. Conventional wound care therapies like films, gauze, and bandages fail to cure diabetic wounds, thereby demanding a synergistic and promising wound care therapy. This investigation aimed to develop a novel, greener synthesis of a laser-responsive silver nanocolloid (LR-SNC) prepared using hyaluronic acid as a bioreductant. The prepared LR-SNC was embedded into a stimuli-responsive <i>in situ</i> gel (LR-SNC<i>-in situ</i> gel) for easy application to the wound region. The physicochemical characterization of LR-SNC revealed a nanometric hydrodynamic particle size of 25.59 ± 0.72 nm with an -31.8 ± 0.7 mV surface ζ-potential. The photothermal conversion efficiency of LR-SNC was observed up to 62.9 ± 0.1 °C. <i>In vitro</i> evaluation of LR-SNC with and without NIR laser irradiation exhibited >70% cell viability, confirming its cytocompatibility for human keratinocyte cells. The <i>in vitro</i> scratch assay showed significant wound closure of 75.50 ± 0.02%. Further, the addition of cytocompatible LR-SNC into an <i>in situ</i> gel followed by laser irradiation resulted in substantial <i>in vivo</i> wound closure (86.69 ± 2.48%) in a diabetic wound-bearing mouse. Histological evaluation demonstrated salient features of the healed wounds, such as increased neovascularization, collagen density, migration of keratinocytes, as well as growth of hair follicles. Additionally, the findings showed a decrease in the levels of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) and enhanced angiogenesis gene expression (VEGF and CD31), thereby healing the diabetic wound efficiently. The present study confirmed the potential role of silver nanocolloids followed by laser irradiation in treating diabetic wound mouse models.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Enhancement of Transdermal Drug Delivery: Integrating Microneedles with Biodegradable Microparticles. 增强经皮给药:整合微针与可生物降解微粒。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-01-17 DOI: 10.1021/acs.molpharmaceut.4c01202
Hiep X Nguyen, Thomas Kipping, Ajay K Banga
{"title":"Enhancement of Transdermal Drug Delivery: Integrating Microneedles with Biodegradable Microparticles.","authors":"Hiep X Nguyen, Thomas Kipping, Ajay K Banga","doi":"10.1021/acs.molpharmaceut.4c01202","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01202","url":null,"abstract":"<p><p>This investigation aimed to enhance transdermal methotrexate delivery through human skin by employing Dr. Pen microneedles and poly(d,l-lactide-<i>co</i>-glycolide) acid microparticles formulated from eight polymer grades (Expansorb DLG 95-4A, DLG 75-5A, DLG 50-2A, DLG 50-5A, DLG 50-8A, DLG 50-6P, DLG 50-7P, and DLL 10-15A). A comprehensive characterization of the microparticles was performed, encompassing various parameters such as size, charge, morphology, microencapsulation efficiency, yield, release kinetics, and chemical composition. The efficacy of microneedles in disrupting skin integrity was demonstrated by scanning electron microscopy, dye binding, histological examination, confocal laser microscopy, and pore size analysis. Microneedle-mediated skin microporation led to a substantial reduction in skin electrical resistance and a concomitant increase in transepidermal water loss. <i>In vitro</i> permeation experiments using human skin delivered microparticles into microporated skin and demonstrated a considerable difference in methotrexate delivery among the polymer groups. Microneedle treatment significantly amplified cumulative drug delivery, steady-state flux, diffusion coefficient, permeability coefficient, and drug concentration within skin layers while concurrently diminishing lag time (<i>p</i> < 0.05). Furthermore, a robust correlation was established between microparticle properties (cumulative release, release rate, encapsulation efficiency) and drug deposition in the skin. In conclusion, the synergistic combination of Dr. Pen microneedles and PLGA microparticles facilitated enhanced and regulated transdermal methotrexate delivery.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Nano-Based Strategies Aiming at Tumor Microenvironment for Improved Cancer Therapy. 靶向肿瘤微环境的纳米策略改善癌症治疗。
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-01-17 DOI: 10.1021/acs.molpharmaceut.4c01267
Tianhui Liu, Changshun Lu, Xue Jiang, Yutong Wang, Zhengrong Chen, Chunshuang Qi, Xiaoru Xu, Xiangru Feng, Qingshuang Wang
{"title":"Nano-Based Strategies Aiming at Tumor Microenvironment for Improved Cancer Therapy.","authors":"Tianhui Liu, Changshun Lu, Xue Jiang, Yutong Wang, Zhengrong Chen, Chunshuang Qi, Xiaoru Xu, Xiangru Feng, Qingshuang Wang","doi":"10.1021/acs.molpharmaceut.4c01267","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01267","url":null,"abstract":"<p><p>Malignant tumors pose a considerable threat to human life and health. Traditional treatments, such as radiotherapy and chemotherapy, often lack specificity, leading to collateral damage to normal tissues. Tumor microenvironment (TME) is characterized by hypoxia, acidity, redox imbalances, and elevated ATP levels factors that collectively promote tumor growth and metastasis. This review provides a comprehensive overview of the nanoparticles developed in recent years for TME-responsive strategies or TME-modulating methods for tumor therapy. The TME-responsive strategies focus on designing and synthesizing nanoparticles that can interact with the tumor microenvironment to achieve precisely controlled drug release. These nanoparticles activate drug release under specific conditions within the tumor environment, thereby enhancing the efficacy of the drugs while reducing toxicity to normal cells. Moreover, simply eliminating tumor cells does not fundamentally solve the problem. Only by comprehensively regulating the TME to make it unsuitable for tumor cell survival and proliferation can we achieve more thorough therapeutic effects and reduce the risk of tumor recurrence. TME regulation strategies aim to suppress the growth and metastasis of tumor cells by modulating various components within the TME. These strategies not only improve treatment outcomes but also have the potential to lay the foundation for future personalized cancer therapies.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
PEGylation Improves the Therapeutic Index of Dexamethasone To Treat Acute Respiratory Distress Syndrome with Obesity Background in Mouse. 聚乙二醇化提高地塞米松治疗小鼠肥胖背景急性呼吸窘迫综合征的治疗指标
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-01-17 DOI: 10.1021/acs.molpharmaceut.4c00954
Xian Wu, Hong Guo, Xiangxiang Hu, Yiqin Li, Mitchell A Kowalke, Wenjuan Zhang, Ju-Hee Oh, William F Elmquist, Hong-Bo Pang
{"title":"PEGylation Improves the Therapeutic Index of Dexamethasone To Treat Acute Respiratory Distress Syndrome with Obesity Background in Mouse.","authors":"Xian Wu, Hong Guo, Xiangxiang Hu, Yiqin Li, Mitchell A Kowalke, Wenjuan Zhang, Ju-Hee Oh, William F Elmquist, Hong-Bo Pang","doi":"10.1021/acs.molpharmaceut.4c00954","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00954","url":null,"abstract":"<p><p>With increasing prevalence globally, obesity presents unique challenges to the clinical management of other diseases. In the case of acute respiratory distress syndrome (ARDS), glucocorticoid therapy (e.g., dexamethasone (DEX)) represents one of the few pharmacological treatment options, but it comes with severe adverse effects, especially when long-term usage (>1 week) is required. One important reason for the adverse effects of DEX is its nonspecific accumulation in healthy tissues upon systemic administration. Therefore, we hypothesize that refining its pharmacokinetics (PK) and in vivo biodistribution may improve its therapeutic index (higher efficacy, lower toxicity) and thus make it safer for obese populations. To achieve this goal, DEX was conjugated with polyethylene glycol (PEG) with three different molecular weights (<i>M</i><sub>w</sub>, 2K, 5K, and 10K) via a reactive oxygen species (ROS)-cleavable linker. Their anti-inflammatory efficacy and long-term adverse effects were evaluated in a murine obesity-ARDS model. Strikingly, DEX-PEG-2K (conjugates with 2K PEG <i>M</i><sub>w</sub>) provided the optimal therapeutic index compared to free DEX and to the other two conjugates with longer PEGs (<i>M</i><sub>w</sub> of 5K and 10K): While retaining the comparable therapeutic efficacy to DEX, DEX-PEG-2K significantly reduced the accumulation of free DEX in the liver and spleen, which led to a 51% reduction of fatty area in liver and a 32% reduction of blood triglycerides concentration. DEX-induced apoptosis of the thymus was also rescued by DEX-PEG-2K under normal conditions. The PK and biodistribution were also investigated to elicit the underlying mechanism. In summary, we provided here a chemical modification strategy to improve the therapeutic index of dexamethasone and possibly other glucocorticoid drugs for ARDS treatment with an obesity background.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
ALC-0315 Lipid-Based mRNA LNP Induces Stronger Cellular Immune Responses Postvaccination. ALC-0315基于脂质的mRNA LNP诱导接种后更强的细胞免疫应答
IF 4.5 2区 医学
Molecular Pharmaceutics Pub Date : 2025-01-15 DOI: 10.1021/acs.molpharmaceut.4c00995
Zuchen Song, Lan Jin, Lina Jiao, Ruihong Yu, Huina Liu, Shun Zhang, Yaoren Hu, Yuechao Sun, Entao Li, Guofang Zhao, Zhenguang Liu, Ting Cai
{"title":"ALC-0315 Lipid-Based mRNA LNP Induces Stronger Cellular Immune Responses Postvaccination.","authors":"Zuchen Song, Lan Jin, Lina Jiao, Ruihong Yu, Huina Liu, Shun Zhang, Yaoren Hu, Yuechao Sun, Entao Li, Guofang Zhao, Zhenguang Liu, Ting Cai","doi":"10.1021/acs.molpharmaceut.4c00995","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00995","url":null,"abstract":"<p><p>At the end of 2019, SARS-CoV-2 emerged and rapidly spread, having a profound negative impact on human health and socioeconomic conditions. In response to this unprecedented global health crisis, significant advancements were made in the mRNA vaccine technology. In this study, we have compared the difference between two SARS-CoV-2 receptor-binding domain (RBD) mRNA-Lipid nanoparticle (LNP) vaccines prepared from two different ionizable cationic lipids: ALC-0315 and MC3. Characterization of RBD mRNA-LNPs showed that both MC3-LNP and ALC-0315-LNP are highly uniform and stable. Furthermore, we assessed the humoral immune response in mice after immunization; our findings indicated that both vaccine formulations effectively enhanced the formation and differentiation of germinal center (GC). Notably, the mice immunized with the ALC-0315-LNP vaccine elicited higher levels of IgG and its subclasses and significantly enhanced the activation of dendritic cells and T cells in draining lymph nodes (dLNs) compared to those immunized with the MC3-LNP vaccine. Further analysis of the T cell phenotype after splenic restimulation showed that mice injected with both LNP mRNA vaccines had significantly increased activation of the splenic T cells and Th1-type cytokine production. In addition, our finding showed that both LNP mRNA vaccines significantly increased the proportions of follicular helper T cells (Tfh) and long-lasting plasma cells in the dLNs of mice on day 14 postimmunization compared to control. In conclusion, both ALC-0315 and MC3 exhibited good stability and immunogenicity as mRNA-LNP recipes, but the ALC-0315-based mRNA-LNP vaccine showed higher efficacy in humoral and cellular immune responses compared to MC3.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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