首页 > 最新文献

International Journal of Pharmaceutics最新文献

英文 中文
Development and characterization of metformin hydrochloride hydrogels as potential wound dressings for diabetic foot ulcers. 盐酸二甲双胍水凝胶作为糖尿病足溃疡潜在创面敷料的研制与表征。
IF 5.2 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2026-03-10 Epub Date: 2026-02-02 DOI: 10.1016/j.ijpharm.2026.126638
Anna Górska, Mateusz Kurek, Arkadiusz Migdał, Maja Kudrycka, Joanna Zemła, Gniewomir Latacz, Małgorzata Lekka, Karolina Witek, Aleksander Mendyk

Diabetic foot ulcers are a severe complication of diabetes mellitus, characterized by chronicity and high risk of infection. Their effective management requires wound-specific dressings, as no universal system adequately addresses the full spectrum of wounds. Hydrogel dressings offer promising local therapeutic strategies; however, materials combining mechanical robustness, prolonged drug release, and microenvironment modulation remain limited. Herein, we present a rational design strategy for a physically crosslinked, multi-component PVA-based hydrogel membrane incorporating metformin hydrochloride (MET) as the active pharmaceutical ingredient. Although conventionally administered orally, MET has been increasingly recognized for its anti-inflammatory and pro-regenerative properties, supporting its repurposing for localized wound applications. The developed dressings were comprehensively characterized in terms of rheology, pH modulation, morphology (optical microscopy, SEM), mechanical performance, liquid uptake, MET release, cytocompatibility, and in vitro antibacterial and anti-inflammatory activity. An optimized hydrogel formulation based on PVA (Mw ∼ 195,000 Da) and six freeze-thaw cycles (-80 °C/∼22 °C) exhibited high elasticity (ε > 380%), tensile strength (σ ∼ 0.23 MPa), and minimal permanent deformation (ε ≤ 3%). It enabled prolonged MET release over 72 h while maintaining a mildly acidic environment (pH ∼ 5.5-6.3) favorable for wound healing. Compared with commercial drug-free hydrogel dressings, the optimized formulation showed superior mechanical strength, pH-modulating capacity, antibacterial activity against Escherichia coli and Pseudomonas aeruginosa, as well as attenuation of IL-6 expression in LPS-stimulated keratinocytes, indicating anti-inflammatory activity. Collectively, these findings highlight the early-stage potential of MET-loaded solid-sheet hydrogels as multifunctional dressings for chronic, low-exudate diabetic foot ulcers.

糖尿病足溃疡是糖尿病的严重并发症,其特点是慢性和感染风险高。它们的有效管理需要伤口专用敷料,因为没有一种通用系统能充分处理所有类型的伤口。水凝胶敷料提供了有希望的局部治疗策略;然而,结合机械稳健性,延长药物释放和微环境调节的材料仍然有限。在此,我们提出了一种合理的设计策略,以物理交联,多组分聚乙烯醇为基础的水凝胶膜,以盐酸二甲双胍(MET)为活性药物成分。虽然传统上是口服给药,但MET因其抗炎和促进再生的特性而越来越受到认可,支持其重新用于局部伤口应用。从流变学、pH调节、形态学(光学显微镜、扫描电镜)、机械性能、液体吸收、MET释放、细胞相容性、体外抗菌和抗炎活性等方面对所研制的敷料进行了全面表征。一个优化的基于PVA水凝胶配方(Mw ∼ 195000 Da)和六个冻融循环(-80 22°C /∼ °C)表现出高弹性(ε > 380%),抗拉强度(σ ∼  0.23 MPa),和最小永久变形(ε ≤ 3%)。它可以延长MET释放时间超过72 h,同时保持有利于伤口愈合的温和酸性环境(pH ~ 5.5-6.3)。与市产无药水凝胶敷料相比,优化后的配方表现出更强的机械强度、ph调节能力、对大肠杆菌和铜绿假单胞菌的抑菌活性,以及抑制lps刺激的角质形成细胞中IL-6的表达,具有抗炎活性。总的来说,这些发现突出了met负载的固体薄片水凝胶作为慢性、低渗出性糖尿病足溃疡的多功能敷料的早期潜力。
{"title":"Development and characterization of metformin hydrochloride hydrogels as potential wound dressings for diabetic foot ulcers.","authors":"Anna Górska, Mateusz Kurek, Arkadiusz Migdał, Maja Kudrycka, Joanna Zemła, Gniewomir Latacz, Małgorzata Lekka, Karolina Witek, Aleksander Mendyk","doi":"10.1016/j.ijpharm.2026.126638","DOIUrl":"10.1016/j.ijpharm.2026.126638","url":null,"abstract":"<p><p>Diabetic foot ulcers are a severe complication of diabetes mellitus, characterized by chronicity and high risk of infection. Their effective management requires wound-specific dressings, as no universal system adequately addresses the full spectrum of wounds. Hydrogel dressings offer promising local therapeutic strategies; however, materials combining mechanical robustness, prolonged drug release, and microenvironment modulation remain limited. Herein, we present a rational design strategy for a physically crosslinked, multi-component PVA-based hydrogel membrane incorporating metformin hydrochloride (MET) as the active pharmaceutical ingredient. Although conventionally administered orally, MET has been increasingly recognized for its anti-inflammatory and pro-regenerative properties, supporting its repurposing for localized wound applications. The developed dressings were comprehensively characterized in terms of rheology, pH modulation, morphology (optical microscopy, SEM), mechanical performance, liquid uptake, MET release, cytocompatibility, and in vitro antibacterial and anti-inflammatory activity. An optimized hydrogel formulation based on PVA (Mw ∼ 195,000 Da) and six freeze-thaw cycles (-80 °C/∼22 °C) exhibited high elasticity (ε > 380%), tensile strength (σ ∼ 0.23 MPa), and minimal permanent deformation (ε ≤ 3%). It enabled prolonged MET release over 72 h while maintaining a mildly acidic environment (pH ∼ 5.5-6.3) favorable for wound healing. Compared with commercial drug-free hydrogel dressings, the optimized formulation showed superior mechanical strength, pH-modulating capacity, antibacterial activity against Escherichia coli and Pseudomonas aeruginosa, as well as attenuation of IL-6 expression in LPS-stimulated keratinocytes, indicating anti-inflammatory activity. Collectively, these findings highlight the early-stage potential of MET-loaded solid-sheet hydrogels as multifunctional dressings for chronic, low-exudate diabetic foot ulcers.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126638"},"PeriodicalIF":5.2,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119063","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
Engineered nanomaterials for targeted therapy of vascular calcification: mechanisms and applications. 靶向治疗血管钙化的工程纳米材料:机制和应用。
IF 5.2 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2026-02-27 DOI: 10.1016/j.ijpharm.2026.126707
Di Chang, Jingrong Xu, Chenhao Yang, Yanli An, Dongfang Liu

Vascular calcification (VC), a critical pathological complication in chronic kidney disease, type 2 diabetes mellitus, and atherosclerosis, is also a major risk factor for adverse cardiovascular events. Once considered a passive age-related process, VC is now recognized as a highly dynamic and multifactorial process involving an array of biological events, including oxidative stress, cellular phenotypic differentiation, and disruptions in calcium-phosphate homeostasis, among others. To date, no specific pharmacological therapies for VC have been established. Existing drug candidates in VC clinical trials often exhibit limitations like short half-lives and poor targeting efficiency, and systemic drug administration is limited by low efficacy and a high risk of adverse effects, which hinders clinical translation. In recent years, nanomaterials have emerged as promising therapeutic strategies to mitigate the dynamic pathological process of VC by virtue of microenvironment-responsive release, multi-target synergistic regulation, and precise enrichment at lesion sites, with the potential to overcome barriers to clinical translation. This review consolidates the pathophysiological mechanisms of VC, systematically evaluates recent advances in nanomaterial-based VC therapies, and analyzes future research directions based on existing evidence, with the goal of providing a theoretical foundation and innovative strategies to overcome current clinical barriers in VC management.

血管钙化(VC)是慢性肾脏疾病、2型糖尿病和动脉粥样硬化的重要病理并发症,也是心血管不良事件的主要危险因素。VC曾经被认为是一个被动的年龄相关过程,现在被认为是一个高度动态和多因素的过程,涉及一系列生物事件,包括氧化应激、细胞表型分化和磷酸钙稳态的破坏等。迄今为止,尚无针对VC的特异性药物治疗方法。VC临床试验中现有的候选药物往往存在半衰期短、靶向效率差等局限性,而且由于疗效低、不良反应风险高,全身给药受到限制,阻碍了临床转化。近年来,纳米材料凭借其微环境响应性释放、多靶点协同调节和病变部位的精确富集,成为缓解VC动态病理过程的有前景的治疗策略,具有克服临床转化障碍的潜力。本文综述了VC的病理生理机制,系统评价了基于纳米材料的VC治疗的最新进展,并基于现有证据分析了未来的研究方向,旨在为克服当前VC治疗的临床障碍提供理论基础和创新策略。
{"title":"Engineered nanomaterials for targeted therapy of vascular calcification: mechanisms and applications.","authors":"Di Chang, Jingrong Xu, Chenhao Yang, Yanli An, Dongfang Liu","doi":"10.1016/j.ijpharm.2026.126707","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2026.126707","url":null,"abstract":"<p><p>Vascular calcification (VC), a critical pathological complication in chronic kidney disease, type 2 diabetes mellitus, and atherosclerosis, is also a major risk factor for adverse cardiovascular events. Once considered a passive age-related process, VC is now recognized as a highly dynamic and multifactorial process involving an array of biological events, including oxidative stress, cellular phenotypic differentiation, and disruptions in calcium-phosphate homeostasis, among others. To date, no specific pharmacological therapies for VC have been established. Existing drug candidates in VC clinical trials often exhibit limitations like short half-lives and poor targeting efficiency, and systemic drug administration is limited by low efficacy and a high risk of adverse effects, which hinders clinical translation. In recent years, nanomaterials have emerged as promising therapeutic strategies to mitigate the dynamic pathological process of VC by virtue of microenvironment-responsive release, multi-target synergistic regulation, and precise enrichment at lesion sites, with the potential to overcome barriers to clinical translation. This review consolidates the pathophysiological mechanisms of VC, systematically evaluates recent advances in nanomaterial-based VC therapies, and analyzes future research directions based on existing evidence, with the goal of providing a theoretical foundation and innovative strategies to overcome current clinical barriers in VC management.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126707"},"PeriodicalIF":5.2,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326085","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
Engineering aerogel particles as next-generation drug delivery systems: a comprehensive review of recent advances. 工程气凝胶颗粒作为下一代药物输送系统:最新进展的全面回顾。
IF 5.2 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2026-02-27 DOI: 10.1016/j.ijpharm.2026.126722
Susana M Gomes, Carlos Illanes-Bordomás, Carlos A García-González, Işık Sena Akgün

Aerogels, defined as low-density solid materials with high porosities, open pore structures, and high specific surface areas, have shown increasing interest among the scientific and industrial communities. The engineering of aerogels in the form of spherical particles has been well documented for several applications and recent studies have highlighted the promising potential of use them as new drug delivery systems. Therefore, this review article consolidates the recent progress on aerogel particle technology by providing a comprehensive and focused synthesis of the state-of-the-art of aerogel particle design specifically intended to enhance biocompatibility, stability, and targeted drug delivery. The engineering technologies presented, based on droplets production and on the milling technology, are critically discussed, highlighting critical aspects used to control their features. Moreover, surface modification and coating techniques are critically examined as tools to enhance biocompatibility, colloidal stability, and targeted delivery. Then, key results in the diverse biomedical applications, namely for oral, skin and pulmonary drug delivery, were discussed. In oral delivery, their capacity to improve drug loading and enable sustained release is emphasized. In skin delivery, aerogels show potential to enhance dermal permeation and provide a sustained release. For pulmonary administration, their low density and aerodynamic properties make them ideal for deep lung deposition. By bridging particle engineering with therapeutic functionality, this review highlights the unique features and advantages of aerogel particles to become the next-generation aerogel-based therapeutic systems. Finally, the current challenges to be addressed and future trends are identified.

气凝胶被定义为具有高孔隙率、开孔结构和高比表面积的低密度固体材料,越来越受到科学界和工业界的关注。球形颗粒形式的气凝胶工程已经有了很好的应用记录,最近的研究强调了它们作为新型药物输送系统的巨大潜力。因此,这篇综述文章整合了气凝胶颗粒技术的最新进展,提供了一个全面和集中的最先进的气凝胶颗粒设计的合成,专门用于提高生物相容性,稳定性和靶向药物传递。介绍了基于液滴生产和铣削技术的工程技术,重点讨论了用于控制液滴特征的关键方面。此外,表面改性和涂层技术被严格检查作为工具,以提高生物相容性,胶体稳定性和靶向递送。然后,讨论了各种生物医学应用的关键结果,即口服,皮肤和肺部给药。在口服给药,他们的能力,以提高药物负荷和使持续释放被强调。在皮肤输送中,气凝胶显示出增强皮肤渗透和提供持续释放的潜力。对于肺给药,它们的低密度和空气动力学特性使其成为肺深部沉积的理想选择。通过将颗粒工程与治疗功能相结合,本文强调了气凝胶颗粒的独特特征和优势,将成为下一代基于气凝胶的治疗系统。最后,确定了当前需要解决的挑战和未来的趋势。
{"title":"Engineering aerogel particles as next-generation drug delivery systems: a comprehensive review of recent advances.","authors":"Susana M Gomes, Carlos Illanes-Bordomás, Carlos A García-González, Işık Sena Akgün","doi":"10.1016/j.ijpharm.2026.126722","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2026.126722","url":null,"abstract":"<p><p>Aerogels, defined as low-density solid materials with high porosities, open pore structures, and high specific surface areas, have shown increasing interest among the scientific and industrial communities. The engineering of aerogels in the form of spherical particles has been well documented for several applications and recent studies have highlighted the promising potential of use them as new drug delivery systems. Therefore, this review article consolidates the recent progress on aerogel particle technology by providing a comprehensive and focused synthesis of the state-of-the-art of aerogel particle design specifically intended to enhance biocompatibility, stability, and targeted drug delivery. The engineering technologies presented, based on droplets production and on the milling technology, are critically discussed, highlighting critical aspects used to control their features. Moreover, surface modification and coating techniques are critically examined as tools to enhance biocompatibility, colloidal stability, and targeted delivery. Then, key results in the diverse biomedical applications, namely for oral, skin and pulmonary drug delivery, were discussed. In oral delivery, their capacity to improve drug loading and enable sustained release is emphasized. In skin delivery, aerogels show potential to enhance dermal permeation and provide a sustained release. For pulmonary administration, their low density and aerodynamic properties make them ideal for deep lung deposition. By bridging particle engineering with therapeutic functionality, this review highlights the unique features and advantages of aerogel particles to become the next-generation aerogel-based therapeutic systems. Finally, the current challenges to be addressed and future trends are identified.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126722"},"PeriodicalIF":5.2,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326112","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
Translating in vitro buccal permeation to in vivo and whole‑body exposure using in silico cell‑based and physiologically-based pharmacokinetic modelling. 利用基于硅细胞和生理的药代动力学模型,将体外口腔渗透转化为体内和全身暴露。
IF 5.2 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2026-02-27 DOI: 10.1016/j.ijpharm.2026.126701
Sean M Edwards, Amy L Harding, Joseph A Leedale, Steven D Webb, Helen E Colley, Robert A Byers, Rachel N Bearon, Craig Murdoch

There is increasing interest in the delivery of chemicals to or through the oral buccal mucosa to avoid first-pass metabolism by the liver or the use of needles, which are associated with oral or parenteral administration. Moreover, buccal mucosa is several times more permeable than skin, making it an attractive route for controlled drug delivery via mucoadhesive films, tablets, and patches. Developing in silico models to predict rates of chemical permeation would greatly expediate experimental discovery to clinical use. However, predicting chemical permeation through the buccal mucosa is challenging due to limited availability of ex vivo human tissue for experimentation. Previously, we used tissue engineered buccal mucosa to parameterise an in silico model of buccal chemical permeation using partial differential equations, fitted to in vitro generated chemical permeation data of chemicals with known physiochemical properties. Here, we describe a new approach to predict in vivo permeation from in vitro data. The importance of the permeability barrier is included explicitly in the in silico models by parameterising from in vitro permeation experiments on buccal epithelium with fully formed or deficient permeability barriers. In vivo predictions are made by mapping mechanistic parameters, fitted to in vitro data, to in vivo cell geometry including cell layer thicknesses, cell-sizes and extracellular space. The predictions are tied to a physiologically-based pharmacokinetic model for whole-body chemical distribution that is validated against in vivo data. This combined in vitro-in silico approach has the potential to reduce animal experimentation and improve in vivo predictions for human buccal mucosa.

人们越来越关注将化学物质输送到或通过口腔颊粘膜,以避免肝脏的首次代谢或使用针,这与口服或肠外给药有关。此外,颊粘膜的渗透性是皮肤的几倍,这使其成为通过黏附膜、片剂和贴剂来控制药物递送的有吸引力的途径。开发计算机模型来预测化学物质的渗透速率将大大加快实验发现的临床应用。然而,由于离体人体组织的可用性有限,预测化学物质通过口腔粘膜的渗透是具有挑战性的。之前,我们使用组织工程口腔黏膜,使用偏微分方程参数化口腔化学渗透的硅模型,拟合体外生成的具有已知理化性质的化学物质的化学渗透数据。在这里,我们描述了一种从体外数据预测体内渗透的新方法。渗透性屏障的重要性通过对完全形成或缺乏渗透性屏障的口腔上皮进行体外渗透实验的参数化,明确地包括在硅模型中。体内预测是通过将机制参数映射到体内细胞几何结构,包括细胞层厚度、细胞大小和细胞外空间,以适应体外数据。这些预测与基于生理的全身化学分布的药代动力学模型相关联,该模型根据体内数据进行验证。这种体外硅片结合的方法有可能减少动物实验并改善人类口腔黏膜的体内预测。
{"title":"Translating in vitro buccal permeation to in vivo and whole‑body exposure using in silico cell‑based and physiologically-based pharmacokinetic modelling.","authors":"Sean M Edwards, Amy L Harding, Joseph A Leedale, Steven D Webb, Helen E Colley, Robert A Byers, Rachel N Bearon, Craig Murdoch","doi":"10.1016/j.ijpharm.2026.126701","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2026.126701","url":null,"abstract":"<p><p>There is increasing interest in the delivery of chemicals to or through the oral buccal mucosa to avoid first-pass metabolism by the liver or the use of needles, which are associated with oral or parenteral administration. Moreover, buccal mucosa is several times more permeable than skin, making it an attractive route for controlled drug delivery via mucoadhesive films, tablets, and patches. Developing in silico models to predict rates of chemical permeation would greatly expediate experimental discovery to clinical use. However, predicting chemical permeation through the buccal mucosa is challenging due to limited availability of ex vivo human tissue for experimentation. Previously, we used tissue engineered buccal mucosa to parameterise an in silico model of buccal chemical permeation using partial differential equations, fitted to in vitro generated chemical permeation data of chemicals with known physiochemical properties. Here, we describe a new approach to predict in vivo permeation from in vitro data. The importance of the permeability barrier is included explicitly in the in silico models by parameterising from in vitro permeation experiments on buccal epithelium with fully formed or deficient permeability barriers. In vivo predictions are made by mapping mechanistic parameters, fitted to in vitro data, to in vivo cell geometry including cell layer thicknesses, cell-sizes and extracellular space. The predictions are tied to a physiologically-based pharmacokinetic model for whole-body chemical distribution that is validated against in vivo data. This combined in vitro-in silico approach has the potential to reduce animal experimentation and improve in vivo predictions for human buccal mucosa.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126701"},"PeriodicalIF":5.2,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326120","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
Tumor-educated platelets: from molecular mechanisms to liquid biopsy and therapeutic applications. 肿瘤诱导血小板:从分子机制到液体活检和治疗应用。
IF 5.2 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2026-02-27 DOI: 10.1016/j.ijpharm.2026.126708
Zhuqian Li, Jingze Liu, Man Yan, Zhikui Deng

Platelets, once regarded solely as mediators of hemostasis and thrombosis, are now recognized as active participants in tumor biology. A growing body of evidence indicates that tumors can reprogram circulating platelets into tumor-educated platelets (TEPs) through molecular cargo exchange, intraplatelet RNA processing, and receptor remodeling. These processes reshape platelet transcriptomic and proteomic profiles and endow TEPs with functional properties that support tumor progression. This review critically examines the molecular mechanisms underlying platelet education, including extracellular vesicle-mediated biomolecule transfer, spliceosome-associated RNA reprogramming, and tumor-induced alterations in platelet surface receptors. We then analyze how these molecular changes translate into key pro-tumorigenic functions, such as promotion of angiogenesis, induction of anoikis resistance via the RhoA-MYPT1-PP1-YAP1 axis, facilitation of immune evasion, and enhancement of metastatic dissemination. Beyond mechanistic insights, we evaluate the translational relevance of TEPs as a liquid biopsy biosource and as a potential therapeutic target. Particular attention is given to current limitations, including the specificity of TEP RNA signatures across cancer types, methodological heterogeneity in platelet isolation and profiling, and the unresolved distinction between causal reprogramming and passive biomolecule uptake. Collectively, this review positions TEPs as a biologically informative but methodologically challenging interface between tumor biology and clinical oncology, highlighting both their diagnostic promise and the critical barriers that must be overcome for their integration into precision cancer management.

血小板,曾经仅仅被认为是止血和血栓形成的介质,现在被认为是肿瘤生物学的积极参与者。越来越多的证据表明,肿瘤可以通过分子货物交换、血小板内RNA加工和受体重塑将循环血小板重编程为肿瘤诱导血小板(TEPs)。这些过程重塑血小板转录组学和蛋白质组学特征,并赋予TEPs支持肿瘤进展的功能特性。本文综述了血小板教育的分子机制,包括细胞外囊泡介导的生物分子转移、剪接体相关RNA重编程和血小板表面受体肿瘤诱导的改变。然后,我们分析了这些分子变化如何转化为关键的促肿瘤功能,如促进血管生成、通过RhoA-MYPT1-PP1-YAP1轴诱导anoikis耐药性、促进免疫逃避和增强转移性传播。除了机制方面的见解,我们还评估了TEPs作为液体活检生物源和潜在治疗靶点的翻译相关性。特别关注当前的局限性,包括跨癌症类型TEP RNA特征的特异性,血小板分离和分析的方法异质性,以及因果重编程和被动生物分子摄取之间未解决的区别。总的来说,本综述将TEPs定位为肿瘤生物学和临床肿瘤学之间的生物学信息,但在方法上具有挑战性的接口,强调了它们的诊断前景和必须克服的关键障碍,以便将其整合到精确的癌症管理中。
{"title":"Tumor-educated platelets: from molecular mechanisms to liquid biopsy and therapeutic applications.","authors":"Zhuqian Li, Jingze Liu, Man Yan, Zhikui Deng","doi":"10.1016/j.ijpharm.2026.126708","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2026.126708","url":null,"abstract":"<p><p>Platelets, once regarded solely as mediators of hemostasis and thrombosis, are now recognized as active participants in tumor biology. A growing body of evidence indicates that tumors can reprogram circulating platelets into tumor-educated platelets (TEPs) through molecular cargo exchange, intraplatelet RNA processing, and receptor remodeling. These processes reshape platelet transcriptomic and proteomic profiles and endow TEPs with functional properties that support tumor progression. This review critically examines the molecular mechanisms underlying platelet education, including extracellular vesicle-mediated biomolecule transfer, spliceosome-associated RNA reprogramming, and tumor-induced alterations in platelet surface receptors. We then analyze how these molecular changes translate into key pro-tumorigenic functions, such as promotion of angiogenesis, induction of anoikis resistance via the RhoA-MYPT1-PP1-YAP1 axis, facilitation of immune evasion, and enhancement of metastatic dissemination. Beyond mechanistic insights, we evaluate the translational relevance of TEPs as a liquid biopsy biosource and as a potential therapeutic target. Particular attention is given to current limitations, including the specificity of TEP RNA signatures across cancer types, methodological heterogeneity in platelet isolation and profiling, and the unresolved distinction between causal reprogramming and passive biomolecule uptake. Collectively, this review positions TEPs as a biologically informative but methodologically challenging interface between tumor biology and clinical oncology, highlighting both their diagnostic promise and the critical barriers that must be overcome for their integration into precision cancer management.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126708"},"PeriodicalIF":5.2,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326077","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
Tofacitinib citrate nanoemulgel induced repigmentation in vitiligo: Assessment of oxidative stress, protein, immunohistochemistry, and mRNA expressions. 托法替尼柠檬酸纳米凝胶诱导白癜风重色素沉着:氧化应激,蛋白质,免疫组织化学和mRNA表达的评估。
IF 5.2 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2026-02-26 DOI: 10.1016/j.ijpharm.2026.126719
Harithasree Veerabomma, Saptarshee Bhattacharjee, Kalali Sridivya Goud, Jitendra Kumar, Dinesh Kumar Chandanapalli, Nagesh A Bhale, Chandraiah Godugu, Amol G Dikundwar, Jitender Madan

Tofacitinib citrate (TC), a selective inhibitor of Janus kinase 1/3 (JAK1/3), has gained attention as a potential treatment option for vitiligo, although systemic adverse effects remain a concern with oral therapy. To address this limitation, the current study focused on the development of a tofacitinib citrate-loaded nanoemulsion (TC-NE) incorporating black seed oil (BSO), a major source of thymoquinone (TQ), which was engineered under the shed of D-Optimal statistical mixture design using a high-energy ultrasonication method. TC-NE exhibited a droplet size of 41.68 ± 0.2  nm, a PDI of 0.132 ± 0.004, and a zeta (ζ) potential of -31.9 ± 0.057  mV. Later, TC-NE was transformed into tofacitinib citrate-loaded nanoemulgel (TC-NEG) and characterized under a set of stringent in vitro and in vivo parameters for pharmaceutical and therapeutic efficacy analysis. Additionally, molecular docking studies revealed strong binding affinities of TC and TQ with JAK1 and JAK3 receptors, yielding docking scores of -8.339 kcal/mol and 6.092 kcal/mol for TC, and -9.36 kcal/mol and -7.31 kcal/mol for TQ, respectively. Next, the therapeutic efficacy of TC-NEG was tested against monobenzone-induced experimental vitiligo in C57BL/6 male mice. It demonstrated superior worth in the vitiligo area scoring index (VASI), melanogenesis, and attenuation of oxidative stress markers. Following this, TC-NEG also demonstrated noteworthy melanogenic activity in histological sections, Fontana-Masson (F-M) staining, and Lillie staining. TC-NEG caused significant down-regulation of JAK1 (One-way ANOVA, P < 0.001) and JAK3 (One-way ANOVA, P < 0.0001) in experimental vitiligo. Next, the relative transcriptional levels of JAK1, JAK3, and IFN-γ were also measured using the RT-PCR technique. Treatment with TC-NEG produced marked suppression of JAK1, JAK3, and IFN-γ gene expressions by 3.47-fold, 4.3-fold, and 3.65-fold in experimental vitiligo. Hence, TC-NEG enriched with TQ provided synergistic efficacy against experimental vitiligo due to diminution of oxidative stress, reduction in melanocyte damage, and augmentation of anti-inflammatory activity owing to inhibition of pro-inflammatory JAK/STAT pathway. In conclusion, TC-NEG may be a promising therapeutic modality for translating into a clinically viable pharmaceutical product.

柠檬酸托法替尼(TC)是一种Janus激酶1/3 (JAK1/3)的选择性抑制剂,作为白癜风的潜在治疗选择而受到关注,尽管口服治疗的全身副作用仍然是一个问题。为了解决这一问题,本研究重点开发了一种负载柠檬酸托法替尼的纳米乳(TC-NE),该纳米乳含有百里醌(TQ)的主要来源黑籽油(BSO),该纳米乳在D-Optimal统计混合设计的框架下使用高能超声方法进行了工程设计。TC-NE的粒径为41.68 ± 0.2  nm, PDI为0.132 ± 0.004,ζ (ζ)电位为-31.9 ± 0.057  mV。随后,将TC-NE转化为负载柠檬酸托法替尼的纳米凝胶(TC-NEG),并在一套严格的体外和体内参数下进行表征,用于药物和治疗效果分析。此外,分子对接研究显示TC和TQ与JAK1和JAK3受体具有很强的结合亲和力,TC和TQ的对接分数分别为-8.339 kcal/mol和6.092 kcal/mol, TQ的对接分数分别为-9.36 kcal/mol和-7.31 kcal/mol。接下来,研究TC-NEG对C57BL/6雄性小鼠单苯诱导的实验性白癜风的治疗效果。它在白癜风区域评分指数(VASI)、黑色素生成和氧化应激标志物的衰减方面表现出优越的价值。在此之后,TC-NEG在组织切片、Fontana-Masson (F-M)染色和Lillie染色中也显示出明显的黑色素生成活性。TC-NEG导致JAK1显著下调(One-way ANOVA, P
{"title":"Tofacitinib citrate nanoemulgel induced repigmentation in vitiligo: Assessment of oxidative stress, protein, immunohistochemistry, and mRNA expressions.","authors":"Harithasree Veerabomma, Saptarshee Bhattacharjee, Kalali Sridivya Goud, Jitendra Kumar, Dinesh Kumar Chandanapalli, Nagesh A Bhale, Chandraiah Godugu, Amol G Dikundwar, Jitender Madan","doi":"10.1016/j.ijpharm.2026.126719","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2026.126719","url":null,"abstract":"<p><p>Tofacitinib citrate (TC), a selective inhibitor of Janus kinase 1/3 (JAK1/3), has gained attention as a potential treatment option for vitiligo, although systemic adverse effects remain a concern with oral therapy. To address this limitation, the current study focused on the development of a tofacitinib citrate-loaded nanoemulsion (TC-NE) incorporating black seed oil (BSO), a major source of thymoquinone (TQ), which was engineered under the shed of D-Optimal statistical mixture design using a high-energy ultrasonication method. TC-NE exhibited a droplet size of 41.68 ± 0.2  nm, a PDI of 0.132 ± 0.004, and a zeta (ζ) potential of -31.9 ± 0.057  mV. Later, TC-NE was transformed into tofacitinib citrate-loaded nanoemulgel (TC-NEG) and characterized under a set of stringent in vitro and in vivo parameters for pharmaceutical and therapeutic efficacy analysis. Additionally, molecular docking studies revealed strong binding affinities of TC and TQ with JAK1 and JAK3 receptors, yielding docking scores of -8.339 kcal/mol and 6.092 kcal/mol for TC, and -9.36 kcal/mol and -7.31 kcal/mol for TQ, respectively. Next, the therapeutic efficacy of TC-NEG was tested against monobenzone-induced experimental vitiligo in C57BL/6 male mice. It demonstrated superior worth in the vitiligo area scoring index (VASI), melanogenesis, and attenuation of oxidative stress markers. Following this, TC-NEG also demonstrated noteworthy melanogenic activity in histological sections, Fontana-Masson (F-M) staining, and Lillie staining. TC-NEG caused significant down-regulation of JAK1 (One-way ANOVA, P < 0.001) and JAK3 (One-way ANOVA, P < 0.0001) in experimental vitiligo. Next, the relative transcriptional levels of JAK1, JAK3, and IFN-γ were also measured using the RT-PCR technique. Treatment with TC-NEG produced marked suppression of JAK1, JAK3, and IFN-γ gene expressions by 3.47-fold, 4.3-fold, and 3.65-fold in experimental vitiligo. Hence, TC-NEG enriched with TQ provided synergistic efficacy against experimental vitiligo due to diminution of oxidative stress, reduction in melanocyte damage, and augmentation of anti-inflammatory activity owing to inhibition of pro-inflammatory JAK/STAT pathway. In conclusion, TC-NEG may be a promising therapeutic modality for translating into a clinically viable pharmaceutical product.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126719"},"PeriodicalIF":5.2,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147321746","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
From permeability to prediction: evolving strategies for evaluating oral drug absorption. 从渗透性到预测:评估口服药物吸收的演变策略。
IF 5.2 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2026-02-26 DOI: 10.1016/j.ijpharm.2026.126725
Zhenhua Yang, Kaidong Chen, Yansong Wang, Jiayang Li, Ying He, Jie Zhuang, Jianping Qi

Oral drug administration, preferred for patient compliance and convenience, encounters significant bioavailability challenges arising from complex physicochemical, physiological, and formulation-related barriers. Traditional models for evaluating absorption exhibit limitations in physiological relevance and predictive accuracy. This review critically examines evolving methodologies for oral drug absorption assessment, from classical permeability assays to emerging predictive platforms, emphasizing integration of mechanistic research with predictive modeling to advance intelligent platforms and clinical translation. While classical permeability models including parallel artificial membrane permeability assay (PAMPA), Caco-2, Ussing chambers, and intestinal perfusion remain indispensable for early screening, their limited physiological relevance and inability to elucidate mechanistic pathways constrain predictive accuracy. Mechanistic approaches such as lymphatic transport studies and advanced tracking techniques using fluorescence, Single Photon Emission Computed Tomography (SPECT), or Positron Emission Tomography (PET) imaging reveal critical biological pathways but suffer from scalability challenges. Emerging platforms provide transformative potential, as organoid-on-a-chip offer physiologically relevant and high-throughput alternatives, while integrated computational modeling enables multiscale prediction, from molecular interactions to systemic pharmacokinetics. Future oral absorption assessment requires converging in vitro biomimetics, computational modeling, and Artificial intelligence (AI) within unified platforms. Achieving this requires standardized in vitro models, robust data integration, and alignment with regulatory to accelerate translational drug development.

口服给药是患者依从性和便利性的首选,但由于复杂的物理化学、生理和配方相关障碍,面临着重大的生物利用度挑战。评估吸收的传统模型在生理相关性和预测准确性方面存在局限性。本文回顾了口服药物吸收评估的发展方法,从经典的渗透性分析到新兴的预测平台,强调了机制研究与预测建模的整合,以推进智能平台和临床翻译。虽然经典的渗透性模型包括平行人工膜渗透性测定(PAMPA)、Caco-2、Ussing chambers和肠灌注在早期筛查中仍然不可或缺,但它们有限的生理相关性和无法阐明机制途径限制了预测的准确性。机械方法,如淋巴运输研究和先进的跟踪技术,使用荧光、单光子发射计算机断层扫描(SPECT)或正电子发射断层扫描(PET)成像揭示了关键的生物途径,但受到可扩展性的挑战。新兴平台提供了变革的潜力,因为类器官芯片提供了生理学上相关的高通量替代方案,而集成的计算建模可以实现从分子相互作用到系统药代动力学的多尺度预测。未来的口服吸收评估需要在统一的平台内融合体外仿生学、计算建模和人工智能(AI)。实现这一目标需要标准化的体外模型,强大的数据整合,并与监管机构保持一致,以加速转化药物的开发。
{"title":"From permeability to prediction: evolving strategies for evaluating oral drug absorption.","authors":"Zhenhua Yang, Kaidong Chen, Yansong Wang, Jiayang Li, Ying He, Jie Zhuang, Jianping Qi","doi":"10.1016/j.ijpharm.2026.126725","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2026.126725","url":null,"abstract":"<p><p>Oral drug administration, preferred for patient compliance and convenience, encounters significant bioavailability challenges arising from complex physicochemical, physiological, and formulation-related barriers. Traditional models for evaluating absorption exhibit limitations in physiological relevance and predictive accuracy. This review critically examines evolving methodologies for oral drug absorption assessment, from classical permeability assays to emerging predictive platforms, emphasizing integration of mechanistic research with predictive modeling to advance intelligent platforms and clinical translation. While classical permeability models including parallel artificial membrane permeability assay (PAMPA), Caco-2, Ussing chambers, and intestinal perfusion remain indispensable for early screening, their limited physiological relevance and inability to elucidate mechanistic pathways constrain predictive accuracy. Mechanistic approaches such as lymphatic transport studies and advanced tracking techniques using fluorescence, Single Photon Emission Computed Tomography (SPECT), or Positron Emission Tomography (PET) imaging reveal critical biological pathways but suffer from scalability challenges. Emerging platforms provide transformative potential, as organoid-on-a-chip offer physiologically relevant and high-throughput alternatives, while integrated computational modeling enables multiscale prediction, from molecular interactions to systemic pharmacokinetics. Future oral absorption assessment requires converging in vitro biomimetics, computational modeling, and Artificial intelligence (AI) within unified platforms. Achieving this requires standardized in vitro models, robust data integration, and alignment with regulatory to accelerate translational drug development.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126725"},"PeriodicalIF":5.2,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147321683","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
Synthesis, catalytic mechanisms, and biomedical applications of manganese-based nanozymes: A review. 锰基纳米酶的合成、催化机理及生物医学应用综述
IF 5.2 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2026-02-26 DOI: 10.1016/j.ijpharm.2026.126723
Huan Luo, Qi Zhang, Chenran Zhen, Haiyan Xiao, Longgang Wang

Manganese-based nanozymes have garnered significant research interest owing to their unique physicochemical properties. Their structures and morphologies can be precisely tailored, offering broad applicability. These materials exhibit novel magnetic and optical characteristics, endowing them with substantial potential in magnetic and optical applications. Furthermore, they have demonstrated excellent catalytic activity alongside favorable biodegradability, establishing a robust foundation for their utilization in catalysis and biomedicine. This review systematically summarizes the synthesis methodologies, catalytic mechanisms, biomedical applications, and future prospects of manganese-based nanozymes. It particularly highlights their applications and underlying mechanisms in tumor therapy and biosensing and detection. Future research endeavors should prioritize optimizing synthesis protocols, expanding the scope of application domains, and exploring their potential in areas such as drug delivery, biosensing, and environmental monitoring.

锰基纳米酶因其独特的物理化学性质而引起了广泛的研究兴趣。它们的结构和形态可以精确定制,具有广泛的适用性。这些材料表现出新的磁性和光学特性,赋予它们在磁性和光学应用方面的巨大潜力。此外,它们还具有优异的催化活性和良好的生物降解性,为其在催化和生物医学中的应用奠定了坚实的基础。本文系统地综述了锰基纳米酶的合成方法、催化机理、生物医学应用及未来前景。它特别强调了它们在肿瘤治疗和生物传感和检测中的应用和潜在机制。未来的研究工作应优先优化合成方案,扩大应用范围,并探索其在药物传递、生物传感和环境监测等领域的潜力。
{"title":"Synthesis, catalytic mechanisms, and biomedical applications of manganese-based nanozymes: A review.","authors":"Huan Luo, Qi Zhang, Chenran Zhen, Haiyan Xiao, Longgang Wang","doi":"10.1016/j.ijpharm.2026.126723","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2026.126723","url":null,"abstract":"<p><p>Manganese-based nanozymes have garnered significant research interest owing to their unique physicochemical properties. Their structures and morphologies can be precisely tailored, offering broad applicability. These materials exhibit novel magnetic and optical characteristics, endowing them with substantial potential in magnetic and optical applications. Furthermore, they have demonstrated excellent catalytic activity alongside favorable biodegradability, establishing a robust foundation for their utilization in catalysis and biomedicine. This review systematically summarizes the synthesis methodologies, catalytic mechanisms, biomedical applications, and future prospects of manganese-based nanozymes. It particularly highlights their applications and underlying mechanisms in tumor therapy and biosensing and detection. Future research endeavors should prioritize optimizing synthesis protocols, expanding the scope of application domains, and exploring their potential in areas such as drug delivery, biosensing, and environmental monitoring.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126723"},"PeriodicalIF":5.2,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147321706","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
Fully synthetic, nature-inspired exosome-mimetics for melanoma therapy. 完全合成,自然启发的外泌体模拟黑色素瘤治疗。
IF 5.2 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2026-02-25 DOI: 10.1016/j.ijpharm.2026.126715
Nahide Zeren Arda Ozturk, Oliwia Barbara Majchrzak, Gianluca Ulivi, Petek Ballar Kirmizibayrak, Gerrit Borchard, Viorica Patrulea, Ozgen Ozer

Fully synthetic exosome-mimetics (FSEMs) represent a nature-inspired drug delivery system designed to replicate the key physicochemical and biological properties of natural exosomes, while offering the potential to address limitations in scalability and reproducibility associated with natural exosomes. In this study, we prepared FSEMs at the laboratory scale. We loaded them with (-)-epigallocatechin-3-gallate (EGCG) and microRNA-23a (miR-23a), aiming to co-deliver therapeutic small molecules and nucleic acids for the treatment of melanoma. FSEMs were fabricated using three methods: thin-film hydration, ethanol injection, and microfluidics. They were surface-functionalized with either CD9, a tetraspanin involved in membrane fusion, or TSP-1, an adhesion protein promoting cellular interactions. Through physicochemical characterization via dynamic light scattering, we found that FSEMs were ∼ 100 nm in size, of low polydispersity (∼0.2) and showed a negative zeta potential (∼-55 mV). Both EGCG and miR-23a were efficiently encapsulated. SDS-PAGE analysis confirmed successful protein incorporation and correct positioning. In vitro release studies showed minimal premature leakage, supporting their suitability for cellular uptake-mediated delivery. When tested on melanoma cells (MDA-MB-435) and progenitor human dermal fibroblasts (FE002-SK2), FSEMs selectively killed melanoma cells while sparing fibroblasts. Importantly, EGCG within FSEMs was more effective than the free compound. Compared to conventional DOTAP-based liposomes, FSEMs were more selective and induced less off-target cytotoxicity. This study presents a proof-of-concept for fully synthetic, protein-functionalized FSEMs as dual carriers for both chemical and gene-based agents, offering a safer and potentially more effective alternative to traditional cationic liposomes. These results lay the groundwork for future in vivo validation and translational cancer research.

完全合成的外泌体模拟物(FSEMs)是一种受自然启发的药物传递系统,旨在复制天然外泌体的关键物理化学和生物学特性,同时提供解决与天然外泌体相关的可扩展性和可重复性限制的潜力。在这项研究中,我们在实验室规模上制备了fsem。我们将它们装载(-)-表没食子儿茶素-3-没食子酸酯(EGCG)和microRNA-23a (miR-23a),旨在共同递送治疗性小分子和核酸,用于治疗黑色素瘤。采用薄膜水化、乙醇注射和微流体三种方法制备FSEMs。它们被CD9(一种参与膜融合的四联蛋白)或TSP-1(一种促进细胞相互作用的粘附蛋白)表面功能化。通过动态光散射的物理化学表征,我们发现fsem的尺寸为 ~ 100 nm,具有低多分散性(~ 0.2),并表现出负的zeta电位(~ -55 mV)。EGCG和miR-23a均被有效封装。SDS-PAGE分析证实了成功的蛋白结合和正确的定位。体外释放研究显示最小的过早泄漏,支持其适合细胞摄取介导的递送。当对黑色素瘤细胞(MDA-MB-435)和祖人类真皮成纤维细胞(FE002-SK2)进行测试时,FSEMs选择性地杀死黑色素瘤细胞,同时保留成纤维细胞。重要的是,fsem中的EGCG比游离化合物更有效。与传统的dotap脂质体相比,fsem具有更强的选择性和更少的脱靶细胞毒性。这项研究提出了一种概念验证,即完全合成的、蛋白质功能化的fsem作为化学和基因制剂的双重载体,提供了一种比传统阳离子脂质体更安全、更有效的替代品。这些结果为未来的体内验证和转化性癌症研究奠定了基础。
{"title":"Fully synthetic, nature-inspired exosome-mimetics for melanoma therapy.","authors":"Nahide Zeren Arda Ozturk, Oliwia Barbara Majchrzak, Gianluca Ulivi, Petek Ballar Kirmizibayrak, Gerrit Borchard, Viorica Patrulea, Ozgen Ozer","doi":"10.1016/j.ijpharm.2026.126715","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2026.126715","url":null,"abstract":"<p><p>Fully synthetic exosome-mimetics (FSEMs) represent a nature-inspired drug delivery system designed to replicate the key physicochemical and biological properties of natural exosomes, while offering the potential to address limitations in scalability and reproducibility associated with natural exosomes. In this study, we prepared FSEMs at the laboratory scale. We loaded them with (-)-epigallocatechin-3-gallate (EGCG) and microRNA-23a (miR-23a), aiming to co-deliver therapeutic small molecules and nucleic acids for the treatment of melanoma. FSEMs were fabricated using three methods: thin-film hydration, ethanol injection, and microfluidics. They were surface-functionalized with either CD9, a tetraspanin involved in membrane fusion, or TSP-1, an adhesion protein promoting cellular interactions. Through physicochemical characterization via dynamic light scattering, we found that FSEMs were ∼ 100 nm in size, of low polydispersity (∼0.2) and showed a negative zeta potential (∼-55 mV). Both EGCG and miR-23a were efficiently encapsulated. SDS-PAGE analysis confirmed successful protein incorporation and correct positioning. In vitro release studies showed minimal premature leakage, supporting their suitability for cellular uptake-mediated delivery. When tested on melanoma cells (MDA-MB-435) and progenitor human dermal fibroblasts (FE002-SK2), FSEMs selectively killed melanoma cells while sparing fibroblasts. Importantly, EGCG within FSEMs was more effective than the free compound. Compared to conventional DOTAP-based liposomes, FSEMs were more selective and induced less off-target cytotoxicity. This study presents a proof-of-concept for fully synthetic, protein-functionalized FSEMs as dual carriers for both chemical and gene-based agents, offering a safer and potentially more effective alternative to traditional cationic liposomes. These results lay the groundwork for future in vivo validation and translational cancer research.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126715"},"PeriodicalIF":5.2,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147317072","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
Effect of formulation composition on stability and aerosol performance of respirable high load monoclonal antibody powders. 剂型组成对可吸入高负荷单克隆抗体粉剂稳定性和雾化性能的影响。
IF 5.2 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2026-02-25 DOI: 10.1016/j.ijpharm.2026.126711
Varsha V Nair, Rex Moore, Li Ding, Weikun Li, Yangjie Wei, Darren L Reid, Hugh D C Smyth

Inhalation-based delivery can efficiently transport monoclonal antibodies (mAbs) to the lungs for respiratory and other diseases. While several attempts have been made to develop inhaled formulations of mAbs in the nebulized or dry powder form, these formulations typically rely on high quantities of sugar stabilizers. While sugars can stabilize the mAbs during processing and storage, they are characterized by high hygroscopicity, which could hamper product physical stability in certain drug product configurations and requires aggressive moisture protection during storage and use. The addition of stabilizing excipients like sugars may also lead to a higher powder burden for high-dose therapies. Additionally, sugars may react adversely with certain mAbs via reactions such as the Maillard reaction. This study aimed at delivering mAbs in -lipid-based formulations and abrogate potential storage issues that limit typical sugar-based formulations by reducing hygroscopicity and cohesivity while maintaining high doses of the mAb. The broader goal was to evaluate if the dry powder formulation approach could enable a patient-friendly system that allows a minimal number of inhalations to achieve therapeutic efficacy by increasing the payload of IgG, reducing excipients, in each actuation. Anti-streptavidin IgG1 antibody was used as a model biologic and a series of formulations were prepared using one representative lipid, amino acid, and surfactant in different compositions. A "mixture design of experiments" was utilized to identify stability and dose constraints using these excipients when processed via spray drying. Three formulations containing high IgG content (50 %, 73 %, and 79 % w/w) were chosen for further characterization and assessment of storage stability. The prepared IgG powders exhibited excellent aerosol performance, with over 80 % fine particle fraction and more than 85 % emitted fraction. The powders also had reduced moisture sorption relative to control powders. Additionally, size exclusion chromatography showed that the powders remained stable for at least one month under accelerated conditions (e.g., 40°C with 75 % relative humidity). These findings suggest lipid-based mAb formulations can provide enhanced physical stability to the protein, while exhibiting superior aerosol performance and hence may offer promise for dry powder inhaled therapies.

基于吸入的给药可以有效地将单克隆抗体(mab)转运到肺部,用于呼吸系统和其他疾病。虽然已经有几次尝试开发雾化或干粉形式的单克隆抗体吸入制剂,但这些制剂通常依赖于大量的糖稳定剂。虽然糖可以在加工和储存过程中稳定单克隆抗体,但它们的特点是高吸湿性,这可能会妨碍产品在某些药品结构中的物理稳定性,并且在储存和使用过程中需要积极的水分保护。添加糖等稳定赋形剂也可能导致高剂量治疗的粉末负担增加。此外,糖可能通过美拉德反应等反应与某些单克隆抗体发生不良反应。本研究旨在通过降低吸湿性和粘聚性,同时保持高剂量的单抗,以提供基于脂质的单抗制剂,并消除限制典型糖基制剂的潜在储存问题。更广泛的目标是评估干粉制剂方法是否可以使患者友好的系统,允许最少的吸入次数,通过增加IgG的有效载荷,减少辅料,在每次驱动中达到治疗效果。以抗链霉亲和素IgG1抗体为模型生物制剂,采用一种具有代表性的脂质、氨基酸和表面活性剂组成不同的系列制剂。采用“混合实验设计”来确定这些辅料在喷雾干燥过程中的稳定性和剂量限制。选择三种高IgG含量(50%、73%和79% w/w)的配方进行进一步表征和储存稳定性评估。制备的IgG粉末具有优良的气溶胶性能,细粒率大于80%,发射率大于85%。与对照粉末相比,该粉末的吸湿性也有所降低。此外,粒径排除色谱法表明,粉末在加速条件下(例如,40°C, 75%相对湿度)保持稳定至少一个月。这些发现表明,基于脂质的单抗制剂可以增强蛋白质的物理稳定性,同时表现出优越的气溶胶性能,因此可能为干粉吸入疗法提供希望。
{"title":"Effect of formulation composition on stability and aerosol performance of respirable high load monoclonal antibody powders.","authors":"Varsha V Nair, Rex Moore, Li Ding, Weikun Li, Yangjie Wei, Darren L Reid, Hugh D C Smyth","doi":"10.1016/j.ijpharm.2026.126711","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2026.126711","url":null,"abstract":"<p><p>Inhalation-based delivery can efficiently transport monoclonal antibodies (mAbs) to the lungs for respiratory and other diseases. While several attempts have been made to develop inhaled formulations of mAbs in the nebulized or dry powder form, these formulations typically rely on high quantities of sugar stabilizers. While sugars can stabilize the mAbs during processing and storage, they are characterized by high hygroscopicity, which could hamper product physical stability in certain drug product configurations and requires aggressive moisture protection during storage and use. The addition of stabilizing excipients like sugars may also lead to a higher powder burden for high-dose therapies. Additionally, sugars may react adversely with certain mAbs via reactions such as the Maillard reaction. This study aimed at delivering mAbs in -lipid-based formulations and abrogate potential storage issues that limit typical sugar-based formulations by reducing hygroscopicity and cohesivity while maintaining high doses of the mAb. The broader goal was to evaluate if the dry powder formulation approach could enable a patient-friendly system that allows a minimal number of inhalations to achieve therapeutic efficacy by increasing the payload of IgG, reducing excipients, in each actuation. Anti-streptavidin IgG1 antibody was used as a model biologic and a series of formulations were prepared using one representative lipid, amino acid, and surfactant in different compositions. A \"mixture design of experiments\" was utilized to identify stability and dose constraints using these excipients when processed via spray drying. Three formulations containing high IgG content (50 %, 73 %, and 79 % w/w) were chosen for further characterization and assessment of storage stability. The prepared IgG powders exhibited excellent aerosol performance, with over 80 % fine particle fraction and more than 85 % emitted fraction. The powders also had reduced moisture sorption relative to control powders. Additionally, size exclusion chromatography showed that the powders remained stable for at least one month under accelerated conditions (e.g., 40°C with 75 % relative humidity). These findings suggest lipid-based mAb formulations can provide enhanced physical stability to the protein, while exhibiting superior aerosol performance and hence may offer promise for dry powder inhaled therapies.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"126711"},"PeriodicalIF":5.2,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147317128","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
期刊
International Journal of Pharmaceutics
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1