Asian Journal of Pharmaceutical Sciences最新文献

Bacterial biosurfactant-reinforced chitooligosaccharide/polyvinyl alcohol hydrogels accelerate methicillin-resistant Staphylococcus aureus-infected wound healing by attenuating its virulence factors 细菌生物表面活性剂增强壳寡糖/聚乙烯醇水凝胶通过减弱其毒力因子加速耐甲氧西林金黄色葡萄球菌感染的伤口愈合

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2026-02-01 DOI: 10.1016/j.ajps.2026.101118

Geum-Jae Jeong , Dong-Joo Park , Ju-Hong Kang , Se-Chang Kim , Yu-Jin Ahn , Kyung-Jin Cho , Fazlurrahman Khan , Won-Kyo Jung , Young-Mog Kim

Methicillin-resistant Staphylococcus aureus (MRSA) causes widespread infections and poses serious public health concerns. Its high level of resistance to multiple antibiotics has garnered growing interest in identifying and applying novel antibacterial compounds derived from natural sources. In this study, we purified a biosurfactant (BS) from Bacillus rugosus HH2 to develop a natural antibacterial agent. This agent was then reinforced with chitooligosaccharide (COS) and polyvinyl alcohol (PVA) to create a hydrogel that promoted healing in MRSA-infected wounds. The COS/PVA/BS hydrogel was readily fabricated via the freeze-thaw method and demonstrated excellent mechanical strength, biological activity, and biocompatibility. In vitro assays confirmed that the hydrogel significantly enhanced the proliferation, migration, angiogenesis, and extracellular matrix deposition of fibroblasts, keratinocytes, and endothelial cells. Moreover, it exhibited strong bacteriostatic and bactericidal activities against MRSA, along with potent antibiofilm activity and inhibition of virulence factors relevant to MRSA-induced wound infections. Its anti-virulence effects have been linked to the downregulation of quorum sensing and virulence-related genes in MRSA. In an in vivo model of MRSA-induced infection, the COS/PVA/BS hydrogel significantly accelerated wound healing and markedly reduced the MRSA burden. Immunofluorescence staining confirmed enhanced neovascularization and regulated macrophage responses, underscoring the angiogenic and immunomodulatory effects of the hydrogel. Overall, the COS/PVA/BS hydrogel represents a promising therapeutic strategy for addressing antibiotic-resistant bacterial infections and promoting wound repair, supported by the use of common raw materials, a simple fabrication process, and high-yield production of natural antibacterial agents.

耐甲氧西林金黄色葡萄球菌（MRSA）引起广泛感染并引起严重的公共卫生问题。它对多种抗生素的高水平耐药性引起了人们对鉴定和应用天然来源的新型抗菌化合物的兴趣。本研究从褐芽孢杆菌hb2中纯化了一种生物表面活性剂（BS），开发了一种天然抗菌剂。然后用壳寡糖（COS）和聚乙烯醇（PVA）增强这种药物，形成一种促进mrsa感染伤口愈合的水凝胶。经冻融法制备的COS/PVA/BS水凝胶具有良好的机械强度、生物活性和生物相容性。体外实验证实，水凝胶显著增强了成纤维细胞、角化细胞和内皮细胞的增殖、迁移、血管生成和细胞外基质沉积。此外，它对MRSA具有很强的抑菌和杀菌活性，同时具有有效的抗生素膜活性和对MRSA诱导的伤口感染相关毒力因子的抑制作用。其抗毒作用与MRSA中群体感应和毒力相关基因的下调有关。在MRSA诱导感染的体内模型中，COS/PVA/BS水凝胶显著加速伤口愈合，显著减轻MRSA负担。免疫荧光染色证实了增强新生血管和调节巨噬细胞反应，强调了水凝胶的血管生成和免疫调节作用。总之，COS/PVA/BS水凝胶是一种很有前途的治疗策略，用于解决抗生素耐药细菌感染和促进伤口修复，支持使用常见的原料，简单的制造工艺，高产量的天然抗菌剂。

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引用次数: 0

High-dose treatment of cathepsin B-activatable doxorubicin prodrug nanoparticles that induce tumor-specific immunogenic cell death for immunotherapy of melanoma with minimal systemic toxicity 诱导肿瘤特异性免疫原性细胞死亡的高剂量组织蛋白酶b活化阿霉素前药纳米颗粒用于黑色素瘤的免疫治疗，具有最小的全身毒性

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2026-02-01 DOI: 10.1016/j.ajps.2026.101123

Yoojeong Oh , Jinseong Kim , Nayeon Shim , Hyeonji Yoo , Hoyeon Lee , Yumin Jeong , Jagyeong Goo , Jeongyeon Lee , Mihee Jo , Hanhee Cho , Kwangmeyung Kim

Highly potent chemotherapy provides rapid therapeutic efficacy in melanoma, but is often limited by drug resistance, off-target toxicity, and systemic toxicity. Combination therapy with chemotherapy and immunotherapy has attracted much attention but still faces challenges such as inconsistent immune responses and systemic toxicity. To address these limitations, we developed cathepsin B-activatable doxorubicin (DOX) prodrug nanoparticles (CatB-NPs) for inducing tumor-specific immunogenic cell death (ICD), while minimizing off-target toxicity in normal tissues with low cathepsin B expression. The cathepsin B-activatable DOX prodrug was synthesized by conjugating the cathepsin B-cleavable peptide (FRRL) to DOX, yielding FRRL-DOX. The amphiphilic FRRL-DOX formed stable nanoparticles (163.6 ± 13.5 nm) through intermolecular hydrophobic interaction and π-π stacking. In melanoma cells overexpressing cathepsin B, CatB-NPs effectively induced cancer cell-specific ICD, while sparing normal cells and immune cells. When CatB-NPs-treated B16F10 cells were co-cultured with immune cells, CatB-NPs enhanced the phagocytic activity of macrophages and induced the maturation of dendritic cells (DCs). In melanoma models, CatB-NPs passively accumulated at tumor tissues through the enhanced permeability and retention effect and were selectively activated by intratumoral cathepsin B, enabling high-dose treatment that induced robust ICD. Importantly, combination therapy with CatB-NPs and anti-PD-L1 antibody enhanced ICD, DC maturation and T-cell activation, resulting in complete tumor regression in 50% of treated mice by converting the immunosuppressive tumor environment into an immune-responsive state. In a lung metastasis model, high-dose CatB-NPs with anti-PD-L1 also suppressed metastatic burden without systemic toxicity, supporting their potential as a safe and effective chemo-immunotherapy for melanoma.

高效化疗对黑色素瘤的治疗效果迅速，但往往受到耐药性、脱靶毒性和全身毒性的限制。化疗和免疫联合治疗已引起广泛关注，但仍面临免疫反应不一致和全身毒性等挑战。为了解决这些局限性，我们开发了可激活组织蛋白酶B的阿霉素（DOX）前药纳米颗粒（CatB-NPs），用于诱导肿瘤特异性免疫原性细胞死亡（ICD），同时最大限度地减少组织蛋白酶B低表达的正常组织中的脱靶毒性。通过将组织蛋白酶b可切割肽（FRRL）与DOX偶联，合成组织蛋白酶b可活化的DOX前药，得到FRRL-DOX。两亲性的FRRL-DOX通过分子间疏水相互作用和π-π堆积形成稳定的纳米颗粒（163.6±13.5 nm）。在过表达组织蛋白酶B的黑色素瘤细胞中，CatB-NPs有效地诱导癌细胞特异性ICD，而不影响正常细胞和免疫细胞。当CatB-NPs处理的B16F10细胞与免疫细胞共培养时，CatB-NPs增强了巨噬细胞的吞噬活性，诱导树突状细胞（dc）成熟。在黑色素瘤模型中，CatB-NPs通过增强的渗透性和滞留效应在肿瘤组织中被动积累，并被瘤内组织蛋白酶B选择性激活，从而实现高剂量治疗，诱导强效ICD。重要的是，CatB-NPs和抗pd - l1抗体联合治疗增强了ICD、DC成熟和t细胞活化，通过将免疫抑制的肿瘤环境转化为免疫应答状态，50%的治疗小鼠的肿瘤完全消退。在肺转移模型中，高剂量抗pd - l1的CatB-NPs也抑制了转移负担，没有全身毒性，支持它们作为黑色素瘤安全有效的化学免疫疗法的潜力。

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引用次数: 0

A novel mRNA nanovaccine with dual immunoregulation ameliorates rheumatoid arthritis and associated pneumonia 一种具有双重免疫调节的新型mRNA纳米疫苗改善类风湿关节炎和相关肺炎

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2026-02-01 DOI: 10.1016/j.ajps.2026.101120

Jingjing Su , Wenguang Huang , Wenying Zhang , Ziyi Wang , Hongzhou Gu , Pengchao Sun , Yongxing Zhao

Rheumatoid arthritis (RA) as a systemic autoimmune disease, frequently triggers various extra-articular symptoms, particularly the RA-associated pneumonia. Unfortunately, the RA-associated pneumonia has garnered insufficient attention, and conventional RA therapies may exacerbate pneumonia-related complications, thereby complicating the treatment process. Herein, a novel dual immunoregulatory mRNA nanovaccine (MPDA@RC@HM) is designed for the efficient treatment of RA and RA-associated pneumonia simultaneously. This innovative mRNA nanovaccine represents a highly organized nanostructure that integrates the rapamycin-loaded mesoporous polydopamine (MPDA) with mRNA encoding the epitope of type Ⅱ collagen, and the surface is modified with hyaluronic acid and dendritic cell membrane. After intravenous injection into collagen-induced arthritis mice, the mRNA nanovaccine exhibits effective distribution and transfection within the spleen and lung, subsequently exerting potent immunoregulation in both organs, thereby yielding a dual therapeutic effect. This study presents a versatile mRNA nanovaccine platform for the treatment of autoimmune diseases and provides an innovative approach for addressing RA and RA-associated pneumonia.

类风湿关节炎（RA）作为一种全身性自身免疫性疾病，经常引发各种关节外症状，特别是RA相关的肺炎。不幸的是，RA相关性肺炎没有得到足够的重视，传统的RA治疗可能加剧肺炎相关并发症，从而使治疗过程复杂化。本文设计了一种新型双免疫调节mRNA纳米疫苗（MPDA@RC@HM），可同时有效治疗RA和RA相关性肺炎。这种创新的mRNA纳米疫苗代表了一种高度组织化的纳米结构，将负载雷帕霉素的介孔聚多巴胺（MPDA）与编码Ⅱ型胶原表位的mRNA结合在一起，表面用透明质酸和树突状细胞膜修饰。在静脉注射胶原诱导关节炎小鼠后，mRNA纳米疫苗在脾脏和肺内表现出有效的分布和转染，随后在这两个器官中发挥有效的免疫调节作用，从而产生双重治疗效果。本研究提出了一种用于自身免疫性疾病治疗的多功能mRNA纳米疫苗平台，并为治疗RA和RA相关肺炎提供了一种创新方法。

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引用次数: 0

Integrating CRISPR/Cas technology with clinical trials: Principles, progress and challenges CRISPR/Cas技术与临床试验的整合：原理、进展与挑战

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.ajps.2025.101068

Piao Yang , Mohadeseh Khoshandam , Iman Bhia , Sevil Raji , Hossein Soltaninejad , Saman Hosseinkhani , Mehdi Sani , Amir Ali Hamidieh , Mohsen Sheykhhasan

CRISPR represent a groundbreaking genome-editing technology that has revolutionized genetic modification. This innovative tool offers an unparalleled revolution in the future treatment of genetic disorders, neurological diseases, infectious diseases and cancer. Despite the rapid expansion of CRISPR applications, its clinical use in humans is still relatively limited, with only 69 active clinical trials and 6 completed studies reported so far. This review examined current clinical trials and their processes in addressing various diseases via the CRISPR/Cas system. While earlier literatures have focused mainly on delivery methods and materials for CRISPR/Cas9, our review emphasized innovative targeting conditions and approaches for novel and functional therapeutic designs. In addition, we reviewed recent research to increase the efficiency of CRISPR editing in the management of genetic disorders and cancer, while exploring their future challenges and potential. This review provided a unique perspective on the advancement of CRISPR technology. By addressing these aspects, we aim to contribute to ongoing efforts to improve CRISPR-based therapies and expand their clinical applications, ultimately striving to transform the future of medical treatment.

CRISPR代表了一项突破性的基因组编辑技术，它彻底改变了基因修饰。这种创新的工具为未来治疗遗传疾病、神经系统疾病、传染病和癌症提供了一场无与伦比的革命。尽管CRISPR的应用范围迅速扩大，但其在人体中的临床应用仍然相对有限，目前仅报道了69项正在进行的临床试验和6项已完成的研究。本综述审查了目前通过CRISPR/Cas系统解决各种疾病的临床试验及其过程。虽然早期的文献主要集中在CRISPR/Cas9的递送方法和材料上，但我们的综述强调了创新的靶向条件和方法，以实现新颖和功能性的治疗设计。此外，我们回顾了最近的研究，以提高CRISPR编辑在遗传疾病和癌症管理中的效率，同时探索它们未来的挑战和潜力。这篇综述为CRISPR技术的发展提供了一个独特的视角。通过解决这些方面的问题，我们的目标是为正在进行的改进基于crispr的疗法和扩大其临床应用的努力做出贡献，最终努力改变医疗的未来。

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引用次数: 0

Exploring the frontier of oral nanomedicine in colorectal cancer therapy: Folate-targeted 5FU-Nisin-Selenium conjugates and probiotic-rich diets as a novel approach 探索口服纳米药物在结直肠癌治疗中的前沿：叶酸靶向5fu - nisin -硒缀合物和富含益生菌的饮食是一种新方法

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.ajps.2025.101106

Mozhgan Derakhshan-sefidi , Bita Bakhshi , Aliakbar Rasekhi , Roya Saeidnejad

This study aimed to assess the therapeutic potential of nisin, 5-fluorouracil (5FU) and selenium encapsulated in folate-conjugated thiolated chitosan nanoparticles (N/5FU/Se@FTCsNPs), combined with a probiotic cocktail of Lactobacillus acidophilus and Bifidobacterium bifidum, against colorectal cancer (CRC). The nanoparticles (277 nm, +9.2 mV) exhibited high drug loading efficiencies (5FU: 89.11 %, nisin: 70.68 %) and pH-responsive release, with minimal drug release under gastric conditions and ∼60.7 % release at colonic pH, facilitating targeted delivery. The formulation remained stable for over 40 d at −20 °C and 4 °C, demonstrating excellent biocompatibility (<2 % hemolysis) and exhibiting strong mucoadhesive and mucus-penetrating abilities. In vitro, N/5FU/Se@FTCsNPs selectively targeted CT26 colon cancer cells (IC₅₀: 1.57 µg/ml) with minimal effects on healthy cells, enhanced cellular uptake, and induced ROS-mediated apoptosis. In vivo, oral administration—especially with probiotics—significantly reduced tumor volume, improved survival rates and alleviated chemotherapy-related side effects such as diarrhea and weight loss. Biodistribution studies confirmed increased tumor targeting and decreased off-target exposure. Mechanistically, the treatment downregulated oncogenes and inflammatory markers (2- to 12.5-fold), including β-catenin, mTOR, COX-2 and VEGF-α, while upregulating tumor suppressors and protective genes (4 to 14.8 fold), such as PTEN, CASP9 and Mucin 2 (P < 0.0001). This indicates inhibition of proliferation, metastasis, inflammation, and angiogenesis, along with improved gut barrier function. Cytokine profiling and histological analysis further confirmed reduced systemic inflammation and maintained hematological safety. These findings highlight N/5FU/Se@FTCsNPs combined with probiotics as a promising, safe and effective oral therapy for CRC, leveraging microbiota modulation and targeted delivery.

本研究旨在评估乳酸链球菌素、5-氟尿嘧啶（5FU）和硒包封在叶酸偶联巯基壳聚糖纳米颗粒（N/5FU/Se@FTCsNPs）中的治疗潜力，并与嗜酸乳杆菌和两歧双歧杆菌混合益生菌联合治疗结直肠癌（CRC）。纳米颗粒（277 nm, +9.2 mV）具有较高的载药效率（5FU: 89.11 %,nisin: 70.68 %）和pH响应释放，在胃条件下药物释放最小，在结肠pH下释放约60.7 %，有利于靶向递送。该制剂在- 20°C和4°C下保持稳定超过40 d，表现出优异的生物相容性（<；2 %溶血），并表现出强大的黏附和黏液穿透能力。在体外，N/5FU/Se@FTCsNPs选择性靶向CT26结肠癌细胞（IC₅₀：1.57 μ g/ml），对健康细胞的影响最小，增强细胞摄取，并诱导ros介导的细胞凋亡。在体内，口服给药-特别是益生菌-显著减少肿瘤体积，提高生存率，减轻化疗相关的副作用，如腹泻和体重减轻。生物分布研究证实肿瘤靶向性增加，脱靶暴露减少。机制上，治疗下调癌基因和炎症标志物（2- 12.5倍），包括β-catenin， mTOR， COX-2和VEGF-α，而上调肿瘤抑制基因和保护基因（4 - 14.8倍），如PTEN， CASP9和Mucin 2 （P < 0.0001）。这表明抑制了增殖、转移、炎症和血管生成，同时改善了肠道屏障功能。细胞因子分析和组织学分析进一步证实了全身炎症的减少和血液安全的维持。这些发现强调了N/5FU/Se@FTCsNPs联合益生菌作为一种有前景的、安全有效的CRC口服治疗方法，利用微生物群调节和靶向给药。

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引用次数: 0

Biomaterials-mediated sequential drug delivery: Emerging trends for wound healing 生物材料介导的顺序给药：伤口愈合的新趋势

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.ajps.2025.101088

Yuchuan Shi , Shuaichen Guo , Jiayi Tian , Xi Xie , Jie Shi , Xing Zhang , Chenchao Wang

Wound healing is a series of complex biological events that are tightly coordinated by the body. However, this physiological process is compromised in a pathological setting and underlie conditions including diabetic complications, infectious diseases and chronic inflammatory conditions. Clinically, this translates to multiple pathological features collectively exhibited (microbial colonization, chronic inflammation and impaired regenerative processes). Due to these pathological features, modern wound care approaches have changed from simple passive coverage products to advanced dressing systems which incorporate multifunctional therapies. To comprehensively elucidate recent advancements in advanced wound dressings for drug delivery applications, this review systematically examines material-driven drug release strategies through multiple analytical dimensions. The discussion encompasses structurally engineered controlled-release systems featuring bilayer architectures, layer-by-layer assembly techniques and porous matrix designs, as well as intelligent stimulus-responsive mechanisms based on physicochemical properties, including physical condition modulation, swelling/degradation behavior control, dynamic chemical bond engineering and crosslinking network optimization. Through critical analysis of these cutting-edge technologies, this article provides insightful perspectives on their clinical translation potential and future trajectories.

伤口愈合是机体紧密协调的一系列复杂生物事件。然而，这一生理过程在病理环境和潜在条件下受到损害，包括糖尿病并发症、传染病和慢性炎症条件。在临床上，这转化为多种病理特征（微生物定植，慢性炎症和再生过程受损）。由于这些病理特征，现代伤口护理方法已经从简单的被动覆盖产品转变为包含多功能治疗的先进敷料系统。为了全面阐明用于给药应用的高级伤口敷料的最新进展，本综述通过多个分析维度系统地研究了材料驱动的药物释放策略。讨论内容包括结构工程化的控制释放系统，包括双层结构、层层组装技术和多孔基质设计，以及基于物理化学性质的智能刺激响应机制，包括物理条件调节、膨胀/降解行为控制、动态化学键工程和交联网络优化。通过对这些前沿技术的批判性分析，本文提供了对其临床转化潜力和未来发展轨迹的深刻见解。

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引用次数: 0

The strategies and advances of mRNA translation booster mRNA翻译促进剂的策略与进展

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.ajps.2025.101090

Yingying Shi , Kedong Sun , Yilong Hu , Zeliang Lou , Yi Wang , Jian You

The therapeutic efficacy and safety of mRNA-based drugs in immunological and nonimmunological applications are critically dependent on the translated protein yield, which requires precise modulation of mRNA expression kinetics. Among the factors influencing mRNA translation, immunogenicity and stability are pivotal in determining the longevity of protein production. Current optimization strategies have integrated (1) molecular engineering (e.g., modified nucleotides), (2) advanced delivery systems (e.g., lipid nanoparticles), and (3) adjuvant drug synergy. This review focuses on co-delivered adjuvant drugs and introduces the concept of "mRNA translation boosters" for the first time. mRNA translation boosters are classified as small-molecule compounds and macromolecular agents that improve translational fidelity through mechanisms including blockade of pattern recognition receptors, modulation of inflammatory cascades, facilitation of endosomal escape, and protection against enzymatic degradation. As clinically validated with COVID-19 mRNA vaccines, these boosters have now demonstrated expanded utility in gene editing therapies and protein replacement applications. This review addresses the immunological challenges encountered during mRNA transfection and translation while summarizing existing mRNA translation boosters that optimize protein expression kinetics. By establishing a mechanistic framework for booster selection and employment, this work provides translational guidance for advancing nucleic acid therapeutics towards their maximum clinical potential.

基于mRNA的药物在免疫学和非免疫学应用中的疗效和安全性严重依赖于翻译蛋白的产量，这需要精确调节mRNA的表达动力学。在影响mRNA翻译的因素中，免疫原性和稳定性是决定蛋白质生产寿命的关键。目前的优化策略包括(1)分子工程（例如，修饰核苷酸），(2)先进的递送系统（例如，脂质纳米颗粒），以及(3)辅助药物协同作用。本文综述了共递送辅助药物，并首次介绍了“mRNA翻译助推器”的概念。mRNA翻译促进剂分为小分子化合物和大分子药物，它们通过阻断模式识别受体、调节炎症级联反应、促进内体逃逸和防止酶降解等机制来提高翻译保真度。随着COVID-19 mRNA疫苗的临床验证，这些增强剂现已在基因编辑疗法和蛋白质替代应用中显示出更大的效用。本文综述了mRNA转染和翻译过程中遇到的免疫学挑战，同时总结了现有的优化蛋白质表达动力学的mRNA翻译促进剂。通过建立促进剂选择和使用的机制框架，本工作为推进核酸治疗发挥其最大的临床潜力提供了翻译指导。

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引用次数: 0

A ROS/photo dual-responsive prodrug unimolecular micelle for boosted cancer immunotherapy 一种ROS/光双反应的前药单分子胶束用于增强癌症免疫治疗

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.ajps.2025.101104

Zeqian Huang , Congjun Xu , Yaqing Ding , Zishan Zeng , Huanxin Lin , Yong Luo , Xiaoyu Xu , Yanjuan Huang , Chunshun Zhao

Integrating photodynamic therapy (PDT) with immunosuppression reversal represents a promising synergistic approach to boost cancer immunotherapy. However, the complicated components and cumbersome preparation procedures of the currently developed nano drug delivery systems heavily hinder their further clinical translation. Herein, a reactive oxygen species (ROS)/photo dual-responsive amphipathic prodrug (denoted as PPTN) was designed and synthesized by linking NLG919, an indoleamine-2,3-dioxygenase (IDO) inhibitor, with the photosensitizer protoporphyrin IX (PpIX) by a thioketal moiety, and further modifying with mPEG_2k. PPTN could self-assemble into nanoscale unimolecular micelles in aqueous solution without additional excipients, increasing tumor accumulation while effectively addressing the pronounced hydrophobicity challenge of PpIX. Upon light exposure, PPTN generated ROS, not only directly damaging cancer cells, but also trigger the breakage of thioketal bond to accelerate simultaneous release of NLG919. Therefore, PPTN potentially act as a promising ROS/photo dual-responsive carrier-free prodrug delivery system for controllable drug release and specific tumor therapy. Moreover, PPTN induced simultaneous PDT-triggered immunogenic cell death (ICD) effect and specific IDO blockade to boost immune response, exhibiting potent suppression efficacy against primary and distant tumors. Overall, with the superiorities of easily controllable preparation procedures, synchronous drug delivery and ROS/photo dual-responsiveness, such a prodrug unimolecular micelle may represent a promising nanoplatform for photoactivated-immunotherapy.

将光动力疗法（PDT）与免疫抑制逆转相结合，是一种很有前途的增强癌症免疫治疗的协同方法。然而，目前开发的纳米给药系统的复杂成分和繁琐的制备过程严重阻碍了其进一步的临床转化。本文设计并合成了一种活性氧(ROS)/光双响应的两亲性前药（PPTN），将吲哚胺-2,3-双加氧酶（IDO）抑制剂NLG919与光敏剂原卟啉IX （PpIX）通过硫酮段连接，再用mPEG2k修饰。PPTN可以在水溶液中自组装成纳米级单分子胶束，无需额外的赋形剂，增加肿瘤积累，同时有效解决PpIX明显的疏水性挑战。PPTN在光照下产生ROS，不仅可以直接损伤癌细胞，还可以触发硫酮键断裂，加速NLG919的同步释放。因此，PPTN有可能作为一种有前景的ROS/光双响应无载体前药递送系统，用于可控药物释放和特异性肿瘤治疗。此外，PPTN同时诱导pdt触发的免疫原性细胞死亡（ICD）效应和特异性IDO阻断来增强免疫反应，对原发性和远处肿瘤表现出强有力的抑制作用。总之，这种药物前单分子胶束具有制备过程易于控制、药物同步传递和ROS/光双响应性等优点，可能是一种很有前途的光激活免疫治疗纳米平台。

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引用次数: 0

Development and preclinical evaluation of a novel FGFR3-targeted antibody-drug conjugate in bladder cancer 一种新型靶向fgfr3的膀胱癌抗体-药物偶联物的开发和临床前评估

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.ajps.2025.101095

Guangrui Fan , Xiongfei Luo , Kun Li , Ze Zhang , Chaohu Chen , Yibo Shi , Shu Cui , Yingru Wang , Dengtuo Wang , Zhijun Zhang , Zhilong Dong , Junqiang Tian , Liang Cheng , Juan Wang , Zhenxing Zhai , Yingqian Liu , Zhiping Wang

Given the critical shortage of antibody-drug conjugates (ADCs) for bladder cancer (BCa), we developed a novel FGFR3-targeted ADC, LZU-WZLYFG001, composed of a humanized anti-FGFR3 IgG1 monoclonal antibody, a cleavable GGFG linker, and the payload DXD. The antibody was engineered in 293 cells and conjugated via thiol-based chemistry, achieving a drug-to-antibody ratio (DAR) of eight. Comprehensive preclinical assessments, including in vitro and in vivo studies using BCa cells, organoids, cell-derived xenograft and patient-derived xenograft (PDX) models, were conducted to evaluate efficacy, targeting ability, mechanism, safety and tissue distribution. LZU-WZLYFG001 demonstrated high purity, targeting specificity and low endotoxin levels, and it significantly inhibited BCa cell proliferation, migration and invasion at nanomolar concentrations, with efficacy strongly associated with FGFR3 expression levels. Mechanistic studies showed binding to FGFR3, internalization and lysosomal release of LZU-WZLYFG001. In organoid and xenograft models, LZU-WZLYFG001 exhibited superior efficacy compared with the gemcitabine + cisplatin (GC) regimen, particularly in GC-resistant PDX tumors, while also showing robust 3D penetration, a bystander effect, and no significant short-term toxicity. Collectively, these findings demonstrate that LZU-WZLYFG001 exhibits excellent preclinical efficacy and safety, and its superiority over GC, together with its activity in resistant tumors, highlights its potential as a novel therapeutic option for BCa.

鉴于膀胱癌（BCa）的抗体-药物偶联物（ADC）严重短缺，我们开发了一种新的fgfr3靶向ADC LZU-WZLYFG001，由人源化抗fgfr3 IgG1单克隆抗体、可切割的GGFG连接物和有效载荷DXD组成。该抗体在293细胞中工程化，并通过巯基化学偶联，获得了8的药抗比（DAR）。全面的临床前评估，包括体外和体内研究，使用BCa细胞、类器官、细胞源异种移植物和患者源异种移植物（PDX）模型，评估疗效、靶向能力、机制、安全性和组织分布。LZU-WZLYFG001具有高纯度、靶向特异性和低内毒素水平，在纳摩尔浓度下显著抑制BCa细胞的增殖、迁移和侵袭，其疗效与FGFR3表达水平密切相关。机制研究显示LZU-WZLYFG001与FGFR3结合，内化和溶酶体释放。在类器官和异种移植模型中，与吉西他滨+顺铂（GC）方案相比，lju - wzlyfg001表现出更好的疗效，特别是在GC耐药的PDX肿瘤中，同时也表现出强大的3D穿透性、旁观者效应和无明显的短期毒性。总之，这些发现表明LZU-WZLYFG001具有出色的临床前疗效和安全性，其优于GC的优势，以及其在耐药肿瘤中的活性，突出了其作为BCa新治疗选择的潜力。

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引用次数: 0

Ginseng-derived exosome-like nanovesicles protect against liver fibrosis by regulating TIMP2 pathways and gut dysbiosis 人参来源的外泌体样纳米囊泡通过调节TIMP2通路和肠道生态失调来防止肝纤维化

IF 11.9 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.ajps.2025.101105

Ji-Su Kim , Yejin Sim , Dong-ha Kim , Jae-Hee Kwon , Sang-Hoon Lee , Wiramon Rungratanawanich , Jihoon Kim , JinSun Jung , Yong Yook Lee , Sun Hee Hyun , Seung-Ho Lee , Hyo-Jung Kwon , Byoung-Joon Song , Kwang-Won Seo , Do-Kyun Kim , Young-Eun Cho

Metabolic dysfunction-associated fatty liver disease (MASLD) and alcohol-associated liver disease (ALD) are prevalent chronic liver diseases that can progress to steatohepatitis, fibrosis, cirrhosis, and ultimately liver failure. Here, we demonstrated that oral administration of GNVs provided substantial protection against liver injury and fibrosis in MASLD and ALD mouse models. In a Western-style high-fat diet-induced MASLD model and a chronic binge alcohol-induced ALD model, GNVs treatment significantly reduced gut leakiness by restoring intestinal junctional complex proteins and rebalancing the gut microbiome. GNVs attenuated hepatic lipid accumulation, oxidative stress and fibrogenic markers. GNV treatment downregulated the fibrosis-associated tissue inhibitor of metalloproteinase-2 (TIMP2) pathway in hepatic stellate cells, which is linked to enhanced matrix degradation and reduced fibrogenesis. GNVs prevent MASLD- and ALD-associated gut barrier dysfunction and liver fibrosis through modulation of the gut–liver axis and the TIMP2 pathway. Edible GNVs represent a novel, multifaceted therapeutic strategy for managing chronic liver diseases.

代谢功能障碍相关脂肪性肝病（MASLD）和酒精性肝病（ALD）是常见的慢性肝病，可发展为脂肪性肝炎、纤维化、肝硬化，并最终导致肝功能衰竭。在这里，我们证明了口服gnv对MASLD和ALD小鼠模型的肝损伤和纤维化具有实质性的保护作用。在西式高脂肪饮食诱导的MASLD模型和慢性狂饮酒精诱导的ALD模型中，gnv治疗通过恢复肠道连接复合物蛋白和重新平衡肠道微生物组显著减少了肠道渗漏。gnv可减轻肝脏脂质积累、氧化应激和纤维化标志物。GNV治疗下调肝星状细胞中纤维化相关组织金属蛋白酶-2 （TIMP2）通路，这与增强基质降解和减少纤维生成有关。gnv通过调节肠-肝轴和TIMP2途径预防MASLD和ald相关的肠道屏障功能障碍和肝纤维化。可食用gnv代表了一种新的、多方面的治疗慢性肝病的策略。

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引用次数: 0