Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, National Demonstration Center for Experimental Chemistry Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710127, Shaanxi, P.R. China.
ACS Appl Bio Mater. 2021 Apr 19;4(4):3246-3255. doi: 10.1021/acsabm.0c01612. Epub 2021 Mar 22.
The inefficient targeting and phagocytic clearance of nanodrug delivery systems are two major obstacles in cancer therapy. Here, inspired by the special properties of zwitterionic polymers and folic acid (FA), a partly biodegradable copolymer of FA-modified poly(ε-caprolactone) block poly(2-methacryloxoethyl phosphorylcholine), PCL--PMPC-FA, was synthesized via atom transfer radical polymerization (ATRP) and click reaction. Non-FA-modified copolymer PCL--PMPC was also synthesized as a control. The hydrodynamic diameter of the PCL--PMPC-FA micelles is 158 nm (PDI 0.261), slightly larger than that of the PCL--PMPC micelles (139 nm, PDI 0.242). The drug doxorubicin (DOX) could be entrapped in the micelles, and as the pH decreased from 7.4 to 5.0, DOX release (in vitro) was accelerated. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that both the PCL--PMPC and the PCL--PMPC-FA micelles showed low toxicity to L929, HeLa, and MCF-7 cells. In addition, the DOX-loaded micelles, PCL--PMPC/DOX and PCL--PMPC-FA/DOX micelles, exhibited low toxicity to L929 cells but high toxicity to HeLa and MCF-7 cells, especially the PCL--PMPC-FA/DOX micelles. HeLa and MCF-7 cell uptakes of the PCL--PMPC-FA/DOX micelles were 4.8 and 4.5 times higher than that of the PCL--PMPC/DOX micelles, respectively. Therefore, PCL--PMPC-FA micelles have great potential for developing drug delivery systems with extended circulation times and tumor-targeting properties.
纳米药物递送系统的靶向效率低和吞噬清除率高是癌症治疗的两大障碍。受两性离子聚合物和叶酸（FA）特殊性质的启发，本文通过原子转移自由基聚合（ATRP）和点击反应合成了部分可生物降解的 FA 修饰聚（ε-己内酯）嵌段聚（2-甲氧基乙氧基磷酸胆碱），PCL-PMPC-FA。还合成了非 FA 修饰的共聚物 PCL-PMPC 作为对照。PCL-PMPC-FA 胶束的水动力学直径为 158nm（PDI 为 0.261），略大于 PCL-PMPC 胶束（139nm，PDI 为 0.242）。阿霉素（DOX）可以包埋在胶束中，当 pH 值从 7.4 降低到 5.0 时，DOX 释放（体外）加快。3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）测定表明，PCL-PMPC 和 PCL-PMPC-FA 胶束对 L929、HeLa 和 MCF-7 细胞的毒性均较低。此外，载 DOX 的胶束，PCL-PMPC/DOX 和 PCL-PMPC-FA/DOX 胶束对 L929 细胞的毒性较低，但对 HeLa 和 MCF-7 细胞的毒性较高，尤其是 PCL-PMPC-FA/DOX 胶束。HeLa 和 MCF-7 细胞对 PCL-PMPC-FA/DOX 胶束的摄取量分别是 PCL-PMPC/DOX 胶束的 4.8 倍和 4.5 倍。因此，PCL-PMPC-FA 胶束具有延长循环时间和肿瘤靶向特性的药物递送系统的巨大潜力。
