Duan Xiao, Chen Heng, Fan Li, Kong Jie
MOE Key Laboratory of Space Applied Physics and Chemistry, Shaanxi Key Laboratory of Macromolecular Science and Technology, School of Science, Northwestern Polytechnical University, Xi'an 710072, P. R. China.
Department of Pharmaceutical Chemistry and Analysis, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, P. R. China.
ACS Biomater Sci Eng. 2016 Dec 12;2(12):2347-2354. doi: 10.1021/acsbiomaterials.6b00559. Epub 2016 Nov 23.
In this study, we present a novel drug self-assembled delivery system (DSDs) with pH and glutathione dual responsiveness to synergistically address the problems of traditional polymer-based carriers, i.e., their low drug loading efficiency, poor biocompatibility and nonbiodegradability. The DSD system with minimum assistant substances was developed from methotrexate (MTX) model drug copolymers and polyethylene glycol (PEG), which gives the system a higher drug loading efficiency and completely avoids the use of toxic carriers. The amphiphilic block copolymers of MTX and PEG are self-assembled into stable micelles such that MTX can be delivered to tumor tissues in vivo and controllable release can be achieved for cancer therapy via the cleavage of the reversible covalent bonds in the copolymer. The micelles overlapped with lysosomes for cellular uptake, and the in vivo distribution was higher in tumor tissues. Biological evaluation and histological analysis confirmed that the DSD micelles were more effective in killing tumor cells than free MTX. In addition, there were fewer side effects in normal tissues. As a result, tumor growth could be effectively inhibited in vivo. The DSDs concept is a perfect emerging strategy to address the problems of traditional polymer-based anticancer drug carriers in a synergetic manner and offers new potential routes of cancer therapy and clinical treatments.
在本研究中，我们提出了一种具有pH值和谷胱甘肽双重响应性的新型药物自组装递送系统（DSDs），以协同解决传统聚合物载体存在的问题，即其药物负载效率低、生物相容性差和不可生物降解。该DSD系统由甲氨蝶呤（MTX）模型药物共聚物和聚乙二醇（PEG）开发而成，辅助物质最少，这使得该系统具有更高的药物负载效率，并完全避免了使用有毒载体。MTX与PEG的两亲性嵌段共聚物自组装成稳定的胶束，从而使MTX能够在体内递送至肿瘤组织，并通过共聚物中可逆共价键的断裂实现可控释放，用于癌症治疗。胶束与溶酶体重叠以实现细胞摄取，并且在肿瘤组织中的体内分布更高。生物学评价和组织学分析证实，DSD胶束在杀死肿瘤细胞方面比游离MTX更有效。此外，正常组织中的副作用更少。因此，体内肿瘤生长可得到有效抑制。DSDs概念是一种完美的新兴策略，能够以协同方式解决传统聚合物基抗癌药物载体的问题，并为癌症治疗和临床治疗提供新的潜在途径。
