PO.CH01.07 · 化学
通过GSH响应性互益前药靶向共递送gemcitabine和atRA，经氧化还原失衡和Pin1抑制增强细胞毒性
Targeted co-delivery of gemcitabine and atRA via a GSH-responsive mutual prodrug enhances cytotoxicity through redox imbalance and Pin1 inhibition
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摘要 Abstract
中文摘要
联合治疗在增强抗癌疗效方面具有强大潜力，但其成功依赖于多种药物的同步靶向递送。为应对这一挑战，我们设计了一种自组装三聚体互益前药RqGem，它通过一个消耗谷胱甘肽（GSH）的连接臂将gemcitabine（GEM）和全反式维甲酸（atRA）共价连接。这种结构实现了无需辅料的纳米组装，达到100%的载药量，并确保两种药物的同步递送。RqGem纳米组装体在生理条件下保持稳定，并经酯酶介导激活，释放GEM和atRA以及一种醌甲基化物中间体，后者可迅速消耗细胞内GSH。这种GSH消耗驱动的氧化还原调节通过提升氧化应激并使细胞对DNA损伤和分化信号敏感，增强了两种药物的细胞毒性机制。使用细胞培养和小鼠模型评估了RqGem纳米组装体的多重协同治疗作用。RqGem纳米组装体相比等量的游离GEM和atRA混合物，展现出显著更强的细胞毒性、增强的细胞摄取和更强的凋亡诱导，反映了atRA介导的信号调节与GEM诱导的DNA损伤之间的强协同作用。自组装、100%载药量、同步药物释放和氧化还原依赖性敏化的联合作用共同促成了RqGem的高效力。鉴于atRA在靶向Pin1（一种在癌症中过表达且与不良预后相关的肽基脯氨酰异构酶）中的作用，我们进一步评估了RqGem对Pin1表达的影响。在AsPC-1和CFPAC-1胰腺癌细胞中的Western blot分析显示，RqGem处理后Pin1明显下调，支持其递送GEM和atRA介导致癌通路抑制的双重机制。正在进行的原位胰腺肿瘤模型研究旨在阐明RqGem驱动的Pin1抑制的信号通路及其对治疗协同作用的贡献。总体而言，这些发现确立了RqGem作为一种经合理设计的自协同互益前药，它整合了药物自递送、受控激活和氧化还原调节，以实现强效的靶向抗癌活性。该平台在胰腺癌及其他癌症的联合治疗中具有强大的转化前景。
查看英文原文 English abstract
Combination therapy offers strong potential to enhance anticancer efficacy, yet its success depends on the concurrent and targeted delivery of multiple agents. To address this challenge, we designed a self-assembling trimeric mutual prodrug, RqGem, which covalently links gemcitabine (GEM) and all-trans retinoic acid (atRA) through a glutathione (GSH)-depleting linker. This architecture enables excipients-free nanoassembly, achieving 100% drug loading and ensuring simultaneous delivery of both agents. RqGem nanoassemblies remained stable under physiological conditions and underwent esterase-mediated activation, releasing GEM and atRA along with a quinone methide intermediate that rapidly depletes intracellular GSH. This GSH depletion-driven redox modulation potentiated the cytotoxic mechanisms of both drugs by elevating oxidative stress and sensitizing cells to DNA damage and differentiation cues.The multiple and synergistic therapeutic actions of RqGem nanoassemblies were evaluated using cell culture and mouse models. RqGem nanoassemblies demonstrated significantly greater cytotoxicity, enhanced cellular uptake, and stronger apoptosis induction than the equivalent mixture of free GEM and atRA, reflecting robust synergy between atRA-mediated signaling modulation and GEM-induced DNA damage. The combined actions of self-assembly, 100% drug loading, concurrent drug release, and redox-dependent sensitization collectively contributed to the high potency of RqGem. Given that the role of atRA in targeting Pin1, a peptidyl-prolyl isomerase overexpressed in cancers and associated with poor prognosis, we further evaluated the impact of RqGem on Pin1 expression. Western blot analyses in AsPC-1 and CFPAC-1 pancreatic cancer cells showed marked Pin1 downregulation following RqGem treatment, supporting its dual mechanism of GEM delivery and atRA-mediated oncogenic pathway inhibition. Ongoing studies in orthotopic pancreatic tumor models aim to define the signaling pathways underlying RqGem-driven Pin1 suppression and its contribution to treatment synergy. Collectively, these findings establish RqGem as a rationally engineered, self-synergistic mutual prodrug that integrates drug self-delivery, controlled activation, and redox regulation to achieve potent and targeted anticancer activity. This platform holds strong translational promise for combination therapy in pancreatic cancer and beyond.
利益披露 Disclosure
N. Song, None..
I. Kim, None..
C. Lim, None..
D. Lee, None.