Asian Journal of Pharmaceutical Sciences最新文献_第3页

Stealth hemostatic anchors with VWF-driven navigation and plasmin-triggered tranexamic release for hematoma containment in cerebral hemorrhage vwf驱动导航和纤溶酶触发氨甲环释放的隐形止血锚用于脑出血血肿控制

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-10-01 DOI: 10.1016/j.ajps.2025.101091

Yu-E Wang , Haoqi Wang , Shanshan Han , Dong Cen , Zibin Zhang , Ke Xiao , Likun Wang , Xingjie Wu , Qianqian Guo , Ling Tao , Wei Li , Xiangchun Shen , Guofeng Wu

The high mortality and disability rates associated with spontaneous intracerebral hemorrhage (sICH) are primarily attributed to secondary injuries caused by hematoma expansion from continuous bleeding or rehemorrhage. Rapid hemostasis to prevent hematoma progression is critical in clinical emergencies for improving surgical outcomes and patient prognosis. For internal hemorrhages inaccessible to external interventions, especially for sICH, intravenous hemostatic strategies are essential regardless of ultimate surgical eligibility. This study reported a stealth hemostatic anchor system based on peptide-drug conjugates. Tranexamic acid (TXA), a clinically approved antifibrinolytic agent, served as the hemostatic component, while a Von Willebrand factor-binding peptide (VBP) enabled targeted delivery by specifically binding to von Willebrand factor exposed at vascular injury sites. A plasmin-cleavable linker was incorporated to control TXA release, ensuring site-specific drug activation. The plasmin-responsive peptide-drug conjugate (RPDC) was synthesized by covalently linking TXA to VBP via the plasmin-cleavable linker. In vitro and in vivo experiments verified the targeted hemostatic efficacy of RPDC, especially demonstrating 42 % reduction in hematoma volume (P < 0.001 vs. saline; P < 0.05 vs. free TXA) with mitigated peri‑hematomal pathology in the collagenase-induced ICR mouse ICH model. These results highlight the potential of the stealth hemostatic anchor as a precision therapeutic strategy for managing sICH, particularly in cases of internal hemorrhages inaccessible to surgical intervention or visual inspection. The plasmin-dependent targeting mechanism enables precise drug localization at cryptic hemorrhage sites, but further studies in larger animal models are needed to confirm its efficacy. This design offers a theoretical framework for advancing emergency interventions in cerebral hemorrhage and addressing challenges related to inaccessible bleeding sites.

自发性脑出血（siich）的高死亡率和致残率主要归因于持续出血或再出血引起的血肿扩张引起的继发性损伤。快速止血以防止血肿进展是改善手术效果和患者预后的关键。对于无法进行外部干预的内出血，特别是siich，无论最终手术资格如何，静脉止血策略都是必不可少的。本研究报道了一种基于肽-药物偶联物的隐形止血锚系统。氨甲环酸（TXA）是一种临床批准的抗纤溶药物，作为止血成分，而血管性血友病因子结合肽（VBP）通过特异性结合血管损伤部位的血管性血友病因子实现靶向递送。一个纤溶蛋白可切割连接被纳入控制TXA释放，确保位点特异性药物激活。通过纤溶蛋白可切割连接物将TXA与VBP共价连接，合成了纤溶蛋白响应肽-药物偶联物（RPDC）。体外和体内实验证实了RPDC的靶向止血效果，特别是在胶原酶诱导的ICR小鼠ICH模型中，RPDC的血肿体积减少42% （P <； 0.001与生理盐水相比；P <； 0.05与游离TXA相比），并减轻了血肿周围病理。这些结果强调了隐形止血锚作为治疗siich的精确治疗策略的潜力，特别是在无法进行手术干预或目视检查的内出血病例中。依赖于纤溶酶的靶向机制可以在隐蔽性出血部位精确定位药物，但需要在更大的动物模型中进一步研究以证实其有效性。该设计为推进脑出血的紧急干预和解决与无法到达的出血部位相关的挑战提供了理论框架。

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引用次数: 0

Metal-organic frameworks as therapeutic chameleons: revolutionizing the cancer therapy employing novel nanoarchitectonics 金属有机框架作为治疗变色龙：利用新型纳米结构革新癌症治疗

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-10-01 DOI: 10.1016/j.ajps.2025.101054

Sajja Bhanu Prasad , Akshay Shinde , Dadi A. Srinivasrao , Paras Famta , Saurabh Shah , Tejaswini Kolipaka , Giriraj Pandey , Deelip Gaonker , Ganesh Vambhurkar , Pooja Khairnar , Rahul Kumar , Amol G. Dikundwar , Vinaykumar Kanchupalli , Saurabh Srivastava

Cancer is one of the most complex diseases and the second leading cause of mortality worldwide. Due to its poor prognosis and challenges in diagnosis, eradicating cancer remains highly difficult. The limitations associated with conventional therapies have led to the emergence of copious therapeutic strategies such as chemotherapy, phototherapy, starvation therapy, radiotherapy and immunotherapy; however, limited therapeutic efficacy, poor tumor cell selectivity and substantial adverse effects remain significant concern. Attributed to the expeditious advancement of nanotechnology, the amalgamation of nanomaterials with therapeutic approaches provides an opportunity to address the shortcomings of conventional chemotherapy. Metal-organic frameworks (MOFs), which consist of bridging ligands and ions/clusters connected by coordination bonds, have been widely used in cancer therapy to address the limitations of currently therapeutic interventions, such as poor efficacy, low stability and severe side effects. This potential arises from their tuneable porosities, high specific surface area-to-volume ratio, tailorable diameters, tractable morphologies, variegated compositions, biocompatibility and facile functionalization. We summarized the role of MOF-based nanoplatforms along with mechanistic insights into emerging avenues—such as cuproptosis, ferroptosis, cell-penetrating and biomimetic MOFs, and tumor microenvironment-responsive MOFs— alongside recent advancements in mono- and multifunctional cancer therapeutics. Theragnostic and imaging functionalities, as well as regulatory considerations and future prospects of MOF-based nanoplatforms utilized in cancer treatment, are also discussed.

癌症是最复杂的疾病之一，也是全球第二大死亡原因。由于预后差和诊断困难，根除癌症仍然非常困难。传统疗法的局限性导致了多种治疗策略的出现，如化疗、光疗、饥饿疗法、放疗和免疫疗法；然而，治疗效果有限，肿瘤细胞选择性差和严重的不良反应仍然是值得关注的问题。由于纳米技术的迅速发展，纳米材料与治疗方法的融合为解决传统化疗的缺点提供了机会。金属有机框架（Metal-organic frameworks, mof）是一种由桥接配体和配位键连接的离子/簇组成的框架，已被广泛应用于癌症治疗中，以解决目前治疗干预措施疗效差、稳定性低和副作用严重的局限性。这种潜力来自于它们可调的孔隙率、高比表面积与体积比、可定制的直径、可处理的形态、多样化的成分、生物相容性和易于功能化。我们总结了基于mof的纳米平台的作用，以及对新兴途径的机制见解，如铜骺、铁骺、细胞穿透和仿生mof，以及肿瘤微环境响应的mof，以及单功能和多功能癌症治疗的最新进展。本文还讨论了基于mof的纳米平台在癌症治疗中的诊断和成像功能，以及监管方面的考虑和未来的前景。

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引用次数: 0

Overcoming corneal barriers: Posaconazole loaded cationic surfactant vesicles for enhanced ocular permeability and anti-fungal efficacy 克服角膜屏障：泊沙康唑负载阳离子表面活性剂囊泡增强眼通透性和抗真菌功效

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-10-01 DOI: 10.1016/j.ajps.2025.101087

Kshitija M. Phatak , Ankita N. Yawalkar , Sushant S. Sole , Pradeep R. Vavia

Posaconazole (PCZ) is a broad-spectrum anti-fungal drug approved by FDA and currently used off-label for the treatment of fungal keratitis (FK). Although ocular route serves as the most bioavailable route for treating FK, delivery of PCZ to the eye remains a challenge due to poor permeation though the cornea and rapid elimination from the eye. Here we outline a comprehensive formulation development process, beginning with in silico studies, progressing through in vitro evaluations, and ultimately achieving therapeutic benefits in vivo. We report modified niosome-like surfactant vesicles, hereafter termed as NioTherms, formulated using a novel and simple heat-mix method, encapsulating PCZ for ocular administration in the form of an in situ gel. Excipient screening performed using in silico simulations highly correlate with in vitro studies (R²=0.77), guiding optimization by Quality by Design (QbD) approach for encapsulating PCZ in NioTherms resulting in particles with an average size of 180.7 ± 2.3 nm, zeta potential of +27.5 ± 2.2 mV and entrapment efficiency of 87.6 % ± 1.7 %. A 2-fold increase in both mucin binding and cellular uptake indicates a functional role of positive surface charge in enhancing mucoadhesive properties of PCZ-NioTherms. In an in vivo murine ocular keratitis model, we demonstrate a 2-fold enhancement in trans-corneal permeability of PCZ-NioTherms and a 3-fold reduction in fungal burden compared to the control standard of care, the PCZ solution. Owing to a facile formulation process, we anticipate that PCZ-NioTherms would serve as a clinically translatable and patient compliant therapeutic intervention for treating FK.

泊沙康唑（PCZ）是FDA批准的广谱抗真菌药物，目前用于治疗真菌性角膜炎（FK）。虽然眼部途径是治疗FK的最具生物利用度的途径，但由于PCZ通过角膜的渗透性差和从眼睛中迅速消除，将PCZ输送到眼睛仍然是一个挑战。在这里，我们概述了一个全面的配方开发过程，从计算机研究开始，通过体外评估，最终在体内实现治疗效果。我们报道了改良的nio质体样表面活性剂囊泡，以下称为NioTherms，使用一种新颖简单的热混合方法配制，以原位凝胶的形式包封PCZ用于眼部给药。利用计算机模拟进行赋形剂筛选，与体外实验高度相关（R2=0.77），通过质量设计（QbD）方法对NioTherms中PCZ的包封进行优化，得到的颗粒平均尺寸为180.7±2.3 nm， zeta电位为+27.5±2.2 mV，包封效率为87.6%±1.7%。粘蛋白结合和细胞摄取均增加2倍，表明表面正电荷在增强PCZ-NioTherms粘接性能方面的功能作用。在体内小鼠角膜角膜炎模型中，我们证明了PCZ- niotherms与对照标准护理（PCZ溶液）相比，经角膜通透性增强了2倍，真菌负担减少了3倍。由于配方过程简单，我们预计PCZ-NioTherms将作为治疗FK的临床可翻译和患者依从性的治疗干预措施。

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引用次数: 0

Critical Quality Attributes of Lipid Nanoparticles and In Vivo Fate 脂质纳米颗粒的关键质量属性和体内命运

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-09-01 DOI: 10.1016/j.ajps.2025.101092

Jiaxing Di , Yuhong Xu , Tonglei Li

Lipid nanoparticles (LNPs) have emerged as versatile carriers for the delivery of genetic medicines and small-molecule drugs, offering desired benefits for therapeutic applications. Optimization of the treatment efficacy of nanocarriers necessitates a thorough understanding of the connection between pharmacokinetics and physicochemical properties. This review consolidates scientific efforts to elucidate how LNP’s physicochemical attributes influence their in vivo fate, emphasizing particle size and shape, surface electric potential and ligand-binding chemistry. By examining the interplay between LNPs and biological barriers across various administration routes, this review provides insights into tailoring LNP properties for optimal delivery and reduced off-target effects. Recommendations for future research are provided to advance the study of LNP in vivo behaviors and offer a practical framework for optimizing in vivo performance through product design parameters.

脂质纳米颗粒（LNPs）已成为遗传药物和小分子药物的多功能载体，为治疗应用提供了理想的益处。优化纳米载体的治疗效果需要深入了解药代动力学与理化性质之间的联系。本文综述了LNP的物理化学属性如何影响其体内命运的科学研究成果，重点介绍了LNP的粒径和形状、表面电位和配体结合化学。通过研究LNP与不同给药途径的生物屏障之间的相互作用，本综述为定制LNP特性以实现最佳给药和减少脱靶效应提供了见解。为进一步研究LNP在体内的行为提供了建议，并为通过产品设计参数优化LNP在体内的性能提供了实用的框架。

引用次数: 0

Targeted protein degradation with small molecules for cancer immunotherapy 靶向小分子蛋白降解用于癌症免疫治疗

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-08-01 DOI: 10.1016/j.ajps.2025.101058

Zichao Yang , Jianwei Xu , Xixiang Yang , Jianjun Chen

Immunotherapy has transformed cancer treatment, marked by the approval of numerous antibody-based drugs. However, the limitations of antibodies in pharmacokinetics including long half-lives, limited oral bioavailability and immunogenicity, have prompted the pursuit of small molecule-based immunotherapy. Traditional drug discovery strategies, which focus on blocking protein activity through inhibitors, face persistent hurdles, such as reliance on accessible binding pockets, poor selectivity, and the emergence of drug resistance. Targeted protein degradation (TPD) technologies have emerged as powerful tools to address these limitations, offering significant therapeutic advantages over conventional inhibition strategies, particularly for historically ''undruggable'' targets. In recent years, small molecule-based protein degraders have rapidly advanced in cancer immunotherapy. In this review, we highlight recent progress in TPD-driven small-molecule drug discovery and summarize the application of these technologies in cancer immunotherapy, including degraders targeting PD-1/PD-L1, chemokine receptors, IDO1, AhR, and others.

免疫疗法已经改变了癌症治疗，其标志是许多基于抗体的药物获得批准。然而，抗体在药代动力学方面的局限性，包括半衰期长、口服生物利用度和免疫原性有限，促使人们追求基于小分子的免疫治疗。传统的药物发现策略侧重于通过抑制剂阻断蛋白质活性，面临着持续的障碍，例如依赖于可获得的结合口袋，选择性差以及耐药性的出现。靶向蛋白降解（TPD）技术已经成为解决这些限制的有力工具，与传统的抑制策略相比，它提供了显著的治疗优势，特别是对于历史上“不可药物”的靶标。近年来，基于小分子的蛋白质降解剂在癌症免疫治疗中迅速发展。在这篇综述中，我们重点介绍了tpd驱动的小分子药物发现的最新进展，并总结了这些技术在癌症免疫治疗中的应用，包括靶向PD-1/PD-L1的降解物、趋化因子受体、IDO1、AhR等。

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引用次数: 0

Enhanced Cerenkov radiation induced photodynamic therapy based on GSH-responsive biomimetic nanoplatform to trigger immunogenic cell death for tumor immunotherapy 基于gsh响应仿生纳米平台的增强Cerenkov辐射诱导光动力治疗触发免疫原性细胞死亡的肿瘤免疫治疗

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-05-27 DOI: 10.1016/j.ajps.2025.101070

Ruijie Qian , Yawen Guo , Xuemei Gao , Jianzhuang Ren , Dawei Jiang , Rui An , Ruihua Wang , Xuhua Duan , Xinwei Han

Cerenkov radiation (CR) can serve as a source of internal light to overcome the limited tissue penetration of external light in conventional photodynamic therapy (PDT). However, insufficient luminescence intensity hinders the clinical application of CR-PDT. Here, we developed a glutathione-responsive biomimetic nanoplatform by fusing cancer cell membranes and liposomes loaded with photosensitizer hematoporphyrin monomethyl ether (HMME) and a radiation energy amplifier Eu³⁺, named HMME-Eu@LEV. Colloidal Eu³⁺ converts γ-radiation and CR from radioisotopes into fluorescence to enhance anti-tumor effects. Sequential administration ensures co-localization of HMME-Eu@LEV and radiopharmaceutical ¹⁸F-fluorodeoxyglucose (FDG) at the tumor site, triggering enhanced CR-PDT and immunogenic cell death. Our observations indicated that luminescence resonance energy transfer between Eu³⁺ and HMME was efficient, and Cerenkov luminescence from Eu@LEV+FDG was approximately 5.6-fold higher in intensity than that from FDG alone. As a result, abundant ROS were generated, and macrophages in the tumor microenvironment were polarized from M2 to M1. In addition, the immunosuppressive tumor microenvironment could be reversed by promoting the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes. The activated immune system effectively inhibited the growth of primary tumors and spread of distant metastases. Our work demonstrates the feasibility of CR-PDT without an external light source and the critical role of nanomaterials in personalized medicine.

在常规光动力治疗（PDT）中，切伦科夫辐射（CR）可以作为一种内部光源来克服外部光对组织的有限穿透。然而，由于发光强度不足，阻碍了CR-PDT的临床应用。在这里，我们开发了一个谷胱甘肽响应的仿生纳米平台，通过融合癌细胞膜和脂质体，脂质体负载光敏剂血卟啉单甲基醚（HMME）和辐射能量放大器Eu3+，命名为HMME-Eu@LEV。胶体Eu3+将放射性同位素中的γ辐射和CR转化为荧光，增强抗肿瘤作用。序贯给药确保HMME-Eu@LEV和放射性药物18f -氟脱氧葡萄糖（FDG）在肿瘤部位的共定位，触发增强的CR-PDT和免疫原性细胞死亡。我们的观察表明，Eu3+和HMME之间的发光共振能量转移是有效的，Eu@LEV+FDG的切伦科夫发光强度比单独使用FDG的高约5.6倍。因此产生了大量的ROS，肿瘤微环境中的巨噬细胞由M2向M1极化。此外，免疫抑制的肿瘤微环境可以通过促进树突状细胞成熟和细胞毒性T淋巴细胞浸润来逆转。激活的免疫系统有效地抑制原发肿瘤的生长和远处转移的扩散。我们的工作证明了CR-PDT在没有外部光源的情况下的可行性以及纳米材料在个性化医疗中的关键作用。

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引用次数: 0

Nanoparticles-incorporated hydrogel microneedle for biomedical applications: Fabrication strategies, emerging trends and future prospects 生物医学应用的纳米颗粒结合水凝胶微针：制造策略、新兴趋势和未来前景

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-05-24 DOI: 10.1016/j.ajps.2025.101069

Zejun Xu , Jiaying Chi , Fei Qin , Dongyan Liu , Yecai Lai , Yingxia Bao , Ruizhi Guo , Yiqiu liao , Zhoufan Xie , Jieqiong Jiang , Juyan Liu , Jianfeng Cai , Chao Lu , Jiansong Wang , Chuanbin Wu

Nanoparticles-incorporated hydrogel microneedles (NPs-HMN) have attracted significant attention due to their exceptional biomedical applications. The arrayed needle tips of NPs-HMN effectively penetrate the skin or tissue, enabling minimally invasive and painless delivery of therapeutic molecules into the tissue microenvironment. This approach has shown significant improvements in bioavailability and patient compliance. Moreover, the functionalized hydrogel materials of NPs-HMN exhibit a three-dimensional network structure resembling the extracellular matrix, along with controllable drug release, exceptional swelling ability, hydrophilicity, and biocompatibility. These characteristics broaden the potential applications of HMN in therapeutic and biosensing contexts. In addition, the incorporation of nanoparticles (NPs) has been shown to improve the solubility of hydrophobic drugs, enhance mechanical properties, enable intelligent drug release, and facilitate precise targeting of HMN. The versatility and diversity of treatment options afforded by NPs-HMN contribute to significant advancements in animal models and clinical settings, as well as offer valuable insights for biomaterial development. This review provides a comprehensive examination of the fabrication strategies of NPs-HMN and their recent advancements in biomedical applications. We also analyze the mechanisms, advantages, challenges, and future prospects of this system in enhancing drug delivery efficiency to provide theoretical references for further breakthroughs in novel delivery platforms.

纳米颗粒结合水凝胶微针（NPs-HMN）由于其特殊的生物医学应用而引起了极大的关注。NPs-HMN排列的针尖有效地穿透皮肤或组织，使治疗分子能够微创无痛地进入组织微环境。该方法在生物利用度和患者依从性方面有显著改善。此外，NPs-HMN功能化水凝胶材料具有类似于细胞外基质的三维网络结构，具有药物释放可控、优异的溶胀能力、亲水性和生物相容性。这些特点扩大了HMN在治疗和生物传感领域的潜在应用。此外，纳米颗粒（NPs）的掺入已被证明可以改善疏水药物的溶解度，增强机械性能，实现药物的智能释放，并促进HMN的精确靶向。NPs-HMN提供的治疗选择的多功能性和多样性有助于动物模型和临床设置的重大进步，并为生物材料开发提供有价值的见解。本文综述了NPs-HMN的制备策略及其在生物医学应用中的最新进展。分析该系统在提高给药效率方面的作用机制、优势、面临的挑战及未来前景，为新型给药平台的进一步突破提供理论参考。

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引用次数: 0

Penetrative biomimetic nanovehicle boosts immunotherapy in triple-negative breast cancer via SOS1 blockade 渗透性仿生纳米载体通过SOS1阻断促进三阴性乳腺癌的免疫治疗

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-05-02 DOI: 10.1016/j.ajps.2025.101064

Jiaxin Zhang , Peng Xian , Chao Wang , Xier Pan , Yaoyao Du , Yunrong Nan , Qing Pu , Linghui Zou , Donovan Green , Shuting Ni , Kaili Hu

Immunotherapy of triple-negative breast cancer (TNBC) is significantly hindered by the immunosuppressive tumor microenvironment (TME). Notably, tumor-associated macrophages (TAMs), which constitute the predominant infiltrating immune cell type in TNBC, represent a critical target for “turning off” immunosuppressive TME. Despite numerous ongoing clinical trials, current strategies exhibit limited efficacy in overcoming immunosuppressive TME. Interestingly, regulation of son of sevenless 1 (SOS1), which is overexpressed in TNBC patients, shows promising potential for TAM repolarization. Herein, we developed a biomimetic liposomal platform (CCM/Cil-lipo@TD), which integrates cilengitide (Cil)-functionalized breast cancer cell membranes (CCM) to co-deliver tetrandrine (TET) and low-dose docetaxel (DTX) for TNBC therapy. This system synergistically enhanced immunotherapy by coupling SOS1 blockade-driven TAM repolarization with immune cell death (ICD)-mediated dendritic cell (DC) maturation, thereby reshaping the highly immunosuppressive TME in TNBC. Critically, the low-density Cil-anchored, CCM-fused liposomes overcome the penetration limitations inherent to conventional CCM-based delivery systems, achieving deep intratumoral accumulation of therapeutic payloads. Mechanistically, the CCM/Cil-lipo@TD ensured that TET-mediated SOS1 inhibition in tumor cells efficiently polarized TAM2 (protumor) toward TAM1 (antitumor). Furthermore, SOS1 blockade synergized with low-dose DTX-induced ICD to remodel TME, as evidenced by sustained cytotoxic T-cell infiltration and suppression of regulatory T cells. The CCM/Cil-lipo@TD exerted superior tumor inhibition (82.9 %) in 4T1 orthotopic models and effectively inhibited postoperative local recurrence and distant metastasis. Taken together, the Cil-engineered, cell membrane-anchoring CCM/Cil-lipo@TD provides a promising approach for TNBC immunotherapy.

三阴性乳腺癌（TNBC）的免疫治疗受到免疫抑制肿瘤微环境（TME）的显著阻碍。值得注意的是，肿瘤相关巨噬细胞（tam）是TNBC中主要的浸润性免疫细胞类型，是“关闭”免疫抑制性TME的关键靶点。尽管有许多正在进行的临床试验，目前的策略在克服免疫抑制性TME方面的疗效有限。有趣的是，在TNBC患者中过表达的SOS1的调控显示出TAM复极的潜力。在此，我们开发了一种仿生脂质体平台（CCM/Cil-lipo@TD），该平台整合了西伦吉肽（Cil）功能化的乳腺癌细胞膜（CCM），共同递送粉防己碱（TET）和低剂量多西他赛（DTX）用于TNBC治疗。该系统通过将SOS1阻断驱动的TAM复极化与免疫细胞死亡（ICD）介导的树突状细胞（DC）成熟相结合，协同增强免疫治疗，从而重塑TNBC中高度免疫抑制的TME。至关重要的是，低密度的螺旋锚定、ccm融合脂质体克服了传统基于ccm的递送系统固有的渗透限制，实现了治疗有效载荷在肿瘤内的深度积累。从机制上讲，CCM/Cil-lipo@TD确保了tet介导的SOS1抑制在肿瘤细胞中有效地将TAM2（肿瘤）极化为TAM1（抗肿瘤）。此外，SOS1阻断与低剂量dtx诱导的ICD协同作用可重塑TME，这可以通过持续的细胞毒性T细胞浸润和抑制调节性T细胞来证明。CCM/Cil-lipo@TD在4T1原位模型中具有较好的肿瘤抑制作用（82.9%），有效抑制术后局部复发和远处转移。综上所述，cil工程的细胞膜锚定CCM/Cil-lipo@TD为TNBC免疫治疗提供了一种很有前途的方法。

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引用次数: 0

Small molecular chelator for comprehensive regulation of tumor lactate levels in synergy with photodynamic therapy for cancer treatment 综合调节肿瘤乳酸水平的小分子螯合剂与光动力疗法协同用于癌症治疗

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-04-23 DOI: 10.1016/j.ajps.2025.101059

Haiqing Zhong , Xufang Ying , Xiaoyan Bao , Linjie Wu , Yiying Lu , Qi Dai , Qiyao Yang , Xin Tan , Donghang Xu , Jianqing Gao , Min Han

An increasing number of studies have focused on depleting lactate and modulating the tumor's lactic microenvironment to interfere with tumor progression, particularly in breast cancer. Lactate accumulation in tumors contributes to a highly acidic microenvironment that promotes cancer cell survival and resistance to therapies. However, existing lactate depletion agents, primarily enzymes and macromolecules, fall short of clinical applications due to poor stability and their ability to only perform solitary lactate depletion without interfering with the transport process. Consequently, the development of stable molecules that deplete lactate and interfere with lactate transport is critically needed. Therefore, in this study, chlorin e6 (Ce6)-gadolinium chloride (GdCl₃)-flavin adenine dinucleotide (FAD)/tamoxifen (TAM) molecular chelates were prepared. The chelates fully interfered with lactate transport, depleted lactate in the tumor microenvironment, mitigated photodynamic therapy resistance, and realized synergistic photodynamic-hormonal therapy. FAD has promising capabilities in regulating lactate levels and mitigating acidic microenvironments. However, a strategy for depleting lactate by chelating the coenzyme FAD to form nanoparticles has not yet been reported. Tamoxifen disrupts tumor development and interferes with lactate transport by binding to estrogen receptor and inhibiting the expression of monocarboxylate transporter. In addition, coupling with Gd³⁺ increased the solubility of Ce6, thereby improving the photodynamic therapy effectiveness. This innovative strategy improves therapeutic efficacy and offers a promising approach for breast cancer treatment.

越来越多的研究集中在消耗乳酸和调节肿瘤的乳酸微环境来干扰肿瘤的进展，特别是在乳腺癌中。乳酸在肿瘤中的积累有助于形成一个高酸性微环境，促进癌细胞的存活和对治疗的抵抗。然而，现有的乳酸消耗剂，主要是酶和大分子，由于稳定性差，并且它们只能单独消耗乳酸而不干扰运输过程，因此缺乏临床应用。因此，开发稳定的消耗乳酸和干扰乳酸运输的分子是非常必要的。因此，本研究制备了氯e6 (Ce6)-氯化钆(GdCl3)-黄素腺嘌呤二核苷酸(FAD)/他莫昔芬（TAM）分子螯合剂。螯合物充分干扰乳酸转运，消耗肿瘤微环境中的乳酸，减轻光动力治疗抗性，实现光动力-激素协同治疗。FAD在调节乳酸水平和缓解酸性微环境方面具有良好的应用前景。然而，通过螯合辅酶FAD形成纳米颗粒来消耗乳酸的策略尚未被报道。他莫昔芬通过与雌激素受体结合，抑制单羧酸转运蛋白的表达，破坏肿瘤发展，干扰乳酸转运。此外，与Gd3+的偶联增加了Ce6的溶解度，从而提高了光动力治疗效果。这种创新策略提高了治疗效果，为乳腺癌治疗提供了一种有希望的方法。

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引用次数: 0

Amphiphilic lipid-peptide engineered placenta-derived mesenchymal stem cells for liver fibrosis treatment 两亲性脂肽工程胎盘源间充质干细胞用于肝纤维化治疗

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-04-22 DOI: 10.1016/j.ajps.2025.101061

Hee Won Park , Dae Hyun Lee , Sungjun Kim , Hyeri Park , Ashok Kumar Jangid , Chae Eun Lee , Jaewon Park , Gyu Tae Park , Ha Yeon Park , HyunJin Kim , Jae Ho Kim , Gi Jin Kim , Kyobum Kim

The global mortality rate due to liver diseases, particularly liver fibrosis, is increasing. Among various treatment methods, stem cell therapy using placenta-derived mesenchymal stem cells (PDMSCs) offers distinct benefits, including ease of isolation and superior proliferative potential. To enhance the therapeutic efficacy of PDMSCs, the WKYMVm peptide was selected for cell engineering. Immobilization of WKYMVm on PDMSC membranes facilitates effective peptide binding to the formyl peptide receptor 2 on adjacent PDMSCs and hepatocytes, thereby enhancing cell activation and achieving more efficient peptide utilization compared to bolus peptide treatment. Increased cell activation enhances the secretion of paracrine factors including growth factors and cytokines, which in turn improves liver function and vascular repair in both in vitro and in vivo models. This approach not only enhances the angiogenic and therapeutic capacities of stem cells, but also enables efficient peptide utilization, minimizing potential side effects and costs associated with high peptide dosages. Overall, our study demonstrates significant promise of stem cell therapy for treating liver fibrosis. Thus, stem cell therapy offers considerable prospects for clinical applications.

全球因肝脏疾病，特别是肝纤维化造成的死亡率正在上升。在各种治疗方法中，使用胎盘源性间充质干细胞（PDMSCs）的干细胞治疗具有明显的优势，包括易于分离和优越的增殖潜力。为了提高PDMSCs的治疗效果，选择WKYMVm肽进行细胞工程。将WKYMVm固定在PDMSC膜上，可以促进肽与邻近PDMSCs和肝细胞上的甲酰基肽受体2的有效结合，从而增强细胞活化，与注射肽治疗相比，实现更有效的肽利用。在体外和体内模型中，细胞活化的增加促进了包括生长因子和细胞因子在内的旁分泌因子的分泌，从而改善了肝功能和血管修复。这种方法不仅增强了干细胞的血管生成和治疗能力，而且能够有效地利用肽，最大限度地减少与高剂量肽相关的潜在副作用和成本。总的来说，我们的研究显示了干细胞治疗肝纤维化的重大前景。因此，干细胞治疗具有广阔的临床应用前景。

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