2025-08-08 作者：ZJ 来源：文献：ROS-responsive dimeric prodrug-based nanomedicine targeted therapy for gastric cancer
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作者：Jiachi Ma, Yuzhong Chen , Wanqing Liang , Lei Li , Jun Du , Chengwu Pan and Chensong
Zhang
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原文摘要：Gastric cancer (GC) remains a major public health problem. Ursolic acid (UA) is reported to be effective in inhibiting GC; however, its low solubility and poor biocompatibility have greatly hindered its clinical application. Herein, an innovative reactive oxygen species (ROS)-sensitive UA dimeric prodrug is developed by coupling two UA molecules via a ROS-cleavable linkage, which can self-assemble into stable nanoparticles in the presence of surfactant. This new UA-based delivery system comprises the following major components: (I) dimeric prodrug inner core that can achieve high drug-loading (55%, w/w) and undergo rapid and selective conversion into intact drug molecules in response to ROS; (II) a polyethylene glycol (PEG) shell to improve colloid stability and extend blood circulation, and (III) surfacemodified internalizing RGD (iRGD) to increase tumor targeting. Enhancement of the antitumor effect of this delivery system was demonstrated against GC tumors in vitro and in vivo. This novel approach offers the potential for clinical applications of UA.
DSPE-PEG-iRGD由二硬脂酰基磷脂酰乙醇胺（DSPE）、聚乙二醇（PEG）和靶向穿膜肽 iRGD 组成.DSPE 具有良好的两亲性，可自组装形成脂质体等结构，PEG 能提高水溶性和生物相容性，iRGD 是由九个氨基酸组成的环状肽，可先与 av 整合素结合，经酶解后与神经素 - 1 相互作用，促进化合物的组织渗透并靶向tumor。 主要用于胶束、囊泡的靶向研究及化合物传递。熊果酸（UA）能有效抑制GC，但其溶解度低，生物相容性差，一种创新的活性氧（ROS）敏感的UA二聚体，通过ROS可裂键偶联两个UA分子，可以在表面活性剂的存在下自组装成稳定的纳米颗粒。
图：基于ua的DPNS及其活性靶向GC和细胞内ros触发的化合物释放
载药纳米颗粒的制备
TK-UA2、DSPE-PEG-iRGD和DSPE-PEG形成的NPs标记为iRGD-TK-NPs；TK-UA2和DSPE-PEG形成的NPs命名为TK-NPs，CC-UA2、DSPE-PEG-iRG-NGD和DSPE-PEG形成的NPs称为iRGD-CCNPs，CC-UA2和DSPE-PEG形成的NPs定义为CC-NPs。采用乙醇注射法制备了这些NPs。通常，TK-UA2、 DSPE-PEGiRGD和DSPE-PEG溶解在乙醇中。随后，在剧烈搅拌下，将混合物滴加入到蒸馏水中。搅拌后，在真空下蒸发，除去乙醇。然后，用蒸馏水将胶体溶液稀释，得到iRGD-TK-NPs。
图：SGC 7901细胞分别与香豆素-6负载的iRGD-TK-NPs、TK-NPs、iRGD-CC-NPs和CC-NPs孵育后的CLSM图像。
结论：这种DSPE-PEG-iRGD参与制备的基于ua的递送系统iRGD-TK-NPs包括以下主要成分： (I)二聚体内核，可以实现高载药量（55%，w/w），并在ROS的作用下快速选择性地转化为完整的化合物分子；（II）聚乙二醇（PEG）壳以改善胶体稳定性和延长体内循环，（III）表面模块化内化RGD（iRGD）以增加tumor靶向性。
