National Engineering Research Center for Biomaterials, Sichuan University , Chengdu, Sichuan 610064, P.R. China.
College of Materials Science and Engineering, Nanjing Tech University , Nanjing, Jiangsu 210009, P.R. China.
ACS Nano. 2017 Jan 24;11(1):416-429. doi: 10.1021/acsnano.6b06161. Epub 2016 Dec 27.
Chemotherapy resistance remains a serious impediment to successful antitumor therapy around the world. However, existing chemotherapeutic approaches are difficult to cope with the notorious multidrug resistance in clinical treatment. Herein, we developed tumor-specific multiple stimuli-activated dendrimeric nanoassemblies with a metabolic blockade to completely combat both physiological barriers and cellular factors of multidrug resistance. With a sophisticated molecular and supramolecular engineering, this type of tumor-specific multiple stimuli-activated nanoassembly based on dendrimeric prodrugs can hierarchically break through the sequential physiological barriers of drug resistance, including stealthy dendritic PEGylated corona to optimize blood transportation, robust nanostructures for efficient tumor passive targeting and accumulation, enzyme-activated tumor microenvironment targeted to deepen tumor penetration and facilitate cellular uptake, cytoplasmic redox-sensitive disintegration for sufficient release of encapsulated agents, and lysosome acid-triggered nucleus delivery of antitumor drugs. In the meantime, we proposed a versatile tactic of a tumor-specific metabolism blockade for provoking several pathways (ATP restriction, apoptotic activation, and anti-apoptotic inhibition) to restrain multiple cellular factors of drug resistance. The highly efficient antitumor activity to drug-resistant MCF-7R tumor in vitro and in vivo supports this design and strongly defeats both physiological barriers and cellular factors of chemotherapy resistance. This work sets up an innovative dendrimeric nanosystem to surmount multidrug resistance, contributing to the development of a comprehensive nanoparticulate strategy for future clinical applications.
化疗耐药性仍然是全世界抗肿瘤治疗成功的严重障碍。然而，现有的化疗方法很难应对临床治疗中臭名昭著的多药耐药性。在此，我们开发了具有代谢阻断作用的肿瘤特异性多重刺激激活树状纳米组装体，以彻底克服多药耐药性的生理屏障和细胞因素。通过精细的分子和超分子工程，这种基于树状前药的肿瘤特异性多重刺激激活纳米组装体可以分层突破耐药的连续生理屏障，包括隐形树枝状聚乙二醇化冠以优化血液运输、高效的肿瘤被动靶向和积累的坚固纳米结构、酶激活的肿瘤微环境靶向以加深肿瘤渗透并促进细胞摄取、细胞质氧化还原敏感的崩解以充分释放封装的药物，以及溶酶体酸性触发的抗肿瘤药物核传递。同时，我们提出了一种肿瘤特异性代谢阻断的通用策略，以引发多种途径（ATP 限制、凋亡激活和抗凋亡抑制）来抑制多药耐药性的多个细胞因素。体外和体内对耐药 MCF-7R 肿瘤的高效抗肿瘤活性支持这一设计，并强烈克服化疗耐药性的生理屏障和细胞因素。这项工作建立了一种创新的树状纳米系统来克服多药耐药性，为未来临床应用的综合纳米粒策略的发展做出了贡献。
