用于线粒体靶向的可逆电荷多功能HPMA共聚物,ACS Applied Materials & Interfaces

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用于线粒体靶向的可逆电荷多功能HPMA共聚物
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2017-08-11 00:00:00 , DOI: 10.1021/acsami.7b09693
Fengling Wang ₁ , Wei Sun ₁ , Lian Li ₁ , Lijia Li ₁ , Yuanyuan Liu ₁ , Zhi-rong Zhang ₁ , Yuan Huang ₁

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线粒体导向的抗癌药物被认为是提高化疗药物抗肿瘤效率的一种有前途的策略。然而，从注射部位到最终的线粒体作用部位的生理和生物学障碍仍然是巨大的挑战。本文中，一种基于N的新型线粒体靶向多功能纳米复合物-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物（MPC）用于增强线粒体中的药物蓄积。MPC具有各种功能，例如细胞外pH响应，优异的细胞摄取，溶酶体逃逸和线粒体靶向。详细地说，MPC是由两种带相反电荷的HPMA共聚物形成的，即带正电荷的线粒体靶向胍基改性的共聚物和带电荷可逆的2,3-二甲基马来酸酐（DMA）改性的共聚物（P-DMA）。已证实，MPC可以在血液循环中保持稳定（pH 7.4），但可以响应肿瘤组织的弱酸性（pH 6.5）而被裂解以立即暴露出胍基的正电荷。带正电荷的胍逐渐暴露会同时促进内吞，内体/溶酶体逸出，和线粒体靶向体外实验表明，与未经胍修饰的共聚物相比，MPC在模拟肿瘤环境（[受电子邮件保护]）中的细胞摄取和线粒体靶向能力分别提高了4.3倍和23.8倍。体内实验是在B16F10荷瘤C57小鼠上进行的，MPC显示在肿瘤部位的累积最多，肿瘤抑制率最高，为82.9％。总之，靶向线粒体的多功能HPMA共聚物为癌症治疗提供了一种新颖而通用的方法。分别是3倍和23.8倍。体内实验是在B16F10荷瘤C57小鼠上进行的，MPC显示在肿瘤部位的累积最多，肿瘤抑制率最高，为82.9％。总之，靶向线粒体的多功能HPMA共聚物为癌症治疗提供了一种新颖而通用的方法。分别是3倍和23.8倍。体内实验是在B16F10荷瘤C57小鼠上进行的，MPC显示在肿瘤部位的累积最多，肿瘤抑制率最高，为82.9％。总之，靶向线粒体的多功能HPMA共聚物为癌症治疗提供了一种新颖而通用的方法。

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Charge-Reversible Multifunctional HPMA Copolymers for Mitochondrial Targeting

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 ([email protected]) 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.

更新日期：2017-08-11

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