肿瘤通透型自递药纳米药物靶向线粒体以增强化疗。
Tumor permeable self-delivery nanodrug targeting mitochondria for enhanced chemotherapy.
机构信息
Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Biomass Chemical Engineering of the Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China.
Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Biomass Chemical Engineering of the Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China; ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311215, China.
出版信息
J Control Release. 2023 Sep;361:792-802. doi: 10.1016/j.jconrel.2023.08.032. Epub 2023 Aug 23.
Drug self-delivery systems (DSDSs) have been extensively exploited to enhance drug loading capacity and avoid excipient-related toxicity issues. However, deficient tumor targeting, inferior tumor permeability, prominent burst release, and nonspecific subcellular distribution remain major obstacles. Herein, we reported a ROS-responsive amphiphilic prodrug (CPT-S-NO) synthesized by the conjugation of zwitterionic tertiary amine-oxide (TAO) moiety and hydrophobic camptothecin (CPT) through a thioether linkage, which formed a nanoparticulate DSDS in an aqueous solution. CPT-S-NO, compared with CPT-11 and the water-soluble TAO-modified CPT prodrug (CPT-NO), exhibited prolonged blood circulation, enhanced tumor accumulation, deep tumor penetration, efficient mitochondrial targeting, and ROS-activated drug release to induce mitochondrial dysfunction, corporately conducing to the superior antitumor efficacy in vivo. This TAO decoration strategy promises potential applications in designing multipotent DSDSs for various drugs.
药物自传递系统（DSDSs）已被广泛用于提高药物载药量和避免赋形剂相关的毒性问题。然而，肿瘤靶向性不足、肿瘤通透性差、突释明显和非特异性亚细胞分布仍然是主要障碍。在此，我们报道了一种通过硫醚键将两性离子叔胺氧化物（TAO）部分和疏水性喜树碱（CPT）连接而成的 ROS 响应性两亲前药（CPT-S-NO），在水溶液中形成纳米级 DSDS。与 CPT-11 和水溶性 TAO 修饰的 CPT 前药（CPT-NO）相比，CPT-S-NO 具有延长的血液循环、增强的肿瘤积累、深层肿瘤渗透、有效的线粒体靶向和 ROS 激活的药物释放，以诱导线粒体功能障碍，共同导致体内更优异的抗肿瘤疗效。这种 TAO 修饰策略有望在设计用于各种药物的多功能 DSDS 中得到应用。
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