Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University , No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China.
ACS Appl Mater Interfaces. 2017 Aug 23;9(33):27563-27574. doi: 10.1021/acsami.7b09693. Epub 2017 Aug 11.
Mitochondrial-oriented delivery of anticancer drugs has been considered as a promising strategy to improve the antitumor efficiency of chemotherapeutics. However, the physiological and biological barriers from the injection site to the final mitochondrial action site remain great challenges. Herein, a novel mitochondrial-targeted multifunctional nanocomplex based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers (MPC) is designed to enhance drug accumulation in mitochondria. MPC possesses various functions such as extracellular pH response, superior cellular uptake, lysosomal escape, and mitochondrial targeting. In detail, MPC was formed by two oppositely charged HPMA copolymers, that is, positively charged mitochondrial-targeting guanidine group-modified copolymers and charge-reversible 2,3-dimethylmaleic anhydride (DMA)-modified copolymers (P-DMA). It was validated that MPC could remain stable in the blood circulation (pH 7.4) but could be cleaved to expose the positive charge of the guanidine group immediately in response to the mild acidity of tumor tissues (pH 6.5). The gradual exposure of positively charged guanidine will simultaneously facilitate endocytosis, endosomal/lysosomal escape, and mitochondrial targeting. The in vitro experiments showed that compared with copolymers without guanidine modification, the cellular uptake and mitochondrial-targeting ability of MPC in the simulated tumor environment (MPC@pH6.5) separately increased 4.3- and 23.8-fold, respectively. The in vivo experiments were processed on B16F10 tumor-bearing C57 mice, and MPC showed the highest accumulation in the tumor site and a peak tumor inhibition rate of 82.9%. In conclusion, multifunctional mitochondrial-targeting HPMA copolymers provide a novel and versatile approach for cancer therapy.
基于 N-(2-羟丙基)甲基丙烯酰胺（HPMA）共聚物的新型线粒体靶向多功能纳米复合物被设计用于增强药物在线粒体中的积累，以提高化疗药物的抗肿瘤效率。该共聚物具有细胞摄取能力强、溶酶体逃逸能力好、对外界环境 pH 值敏感和靶向线粒体等多种功能。具体来说，MPC 由两种带相反电荷的 HPMA 共聚物组成，即带正电荷的靶向线粒体的胍基改性共聚物和电荷可逆的 2,3-二甲基马来酸酐（DMA）改性共聚物（P-DMA）。实验验证了 MPC 在血液循环中（pH7.4）保持稳定，但在响应肿瘤组织的轻度酸性（pH6.5）时可以迅速被切割，暴露出胍基的正电荷。逐渐暴露的正电荷将同时促进内吞作用、内体/溶酶体逃逸和线粒体靶向。在模拟肿瘤环境（MPC@pH6.5）中，与没有胍基修饰的共聚物相比，MPC 的细胞摄取和线粒体靶向能力分别增加了 4.3 倍和 23.8 倍。在 B16F10 荷瘤 C57 小鼠上进行的体内实验表明，MPC 在肿瘤部位的积累最高，肿瘤抑制率峰值达到 82.9%。总之，多功能线粒体靶向 HPMA 共聚物为癌症治疗提供了一种新颖且多功能的方法。
