Department of Hematology and Research Laboratory of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Department of Hematology and Research Laboratory of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
J Control Release. 2019 Feb 28;296:93-106. doi: 10.1016/j.jconrel.2019.01.016. Epub 2019 Jan 19.
At present, chemotherapy remains to be one of the most important therapeutic approaches for malignant tumors. The tumor microenvironment(TME)-responsive intelligent drug delivery systems are still the hot research topics in delivering chemotherapeutic drugs. Camptothecin (CPT) possesses very strong antitumor activities, but its clinical application is hindered by its poor water-solubility and serious toxic side effects. Herein, a new intelligent and TME-responsive P(CPT-MAA) prodrug nanogel was developed for delivering CPT and reducing its side effects. P(CPT-MAA) prodrug nanogels were prepared with methacrylic acid (MAA), CPT monomer (CPTM) and N,N'-methylenebisacrylamide (Bis) via distillation-precipitation polymerization, in which CPT was covalently conjugated into the nanogels via redox-responsive disulfide linker. The as-prepared nanogels were spherical shapes with uniform size and narrow size distribution. With the help of redox-responsive property of disulfide linker and pH-responsive property of PMAA, the release of CPT from prodrug nanogels was redox/pH-dual dependent and could be accelerated by the increased concentration of GSH and the decreased pH value, which were favorable to realize the "on-demand" drug release in tumor cell and tumor tissue microenvironment. Furthermore, P(CPT-MAA) prodrug nanogels exhibited superior antitumor activity both in vitro and in vivo without observed side effects. Hence, the prepared P(CPT-MAA) prodrug nanogels may be a promise delivery system for chemotherapeutic agents.
目前，化疗仍然是治疗恶性肿瘤的最重要方法之一。肿瘤微环境（TME）响应智能药物传递系统仍然是传递化疗药物的热门研究课题。喜树碱（CPT）具有很强的抗肿瘤活性，但由于其水溶性差和严重的毒副作用，其临床应用受到限制。在此，开发了一种新的智能 TME 响应 P（CPT-MAA）前药纳米凝胶用于递送 CPT 并降低其副作用。P（CPT-MAA）前药纳米凝胶是通过蒸馏沉淀聚合用甲基丙烯酸（MAA）、CPT 单体（CPTM）和 N，N'-亚甲基双丙烯酰胺（Bis）制备的，其中 CPT 通过氧化还原响应性二硫键连接子共价连接到纳米凝胶中。所制备的纳米凝胶呈球形，具有均匀的尺寸和较窄的尺寸分布。借助二硫键的氧化还原响应性和 PMAA 的 pH 响应性，CPT 从前药纳米凝胶中的释放具有氧化还原/pH 双重依赖性，并可以通过增加 GSH 的浓度和降低 pH 值来加速，这有利于在肿瘤细胞和肿瘤组织微环境中实现“按需”药物释放。此外，P（CPT-MAA）前药纳米凝胶在体外和体内均表现出优异的抗肿瘤活性，而没有观察到副作用。因此，所制备的 P（CPT-MAA）前药纳米凝胶可能是一种有前途的化疗药物传递系统。
