Wang Lele, Zhang Jing, Song Meijia, Tian Baocheng, Li Keke, Liang Yan, Han Jingtian, Wu Zimei
School of Pharmacy, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, PR China.
School of Pharmacy, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, PR China.
Colloids Surf B Biointerfaces. 2017 Apr 1;152:1-11. doi: 10.1016/j.colsurfb.2016.12.032. Epub 2016 Dec 21.
Based on targeted amphiphilic block copolymer N-acetyl glucosamine-poly (styrene-alt-maleic anhydride)-b-polystyrene (NAG-P(St-alt-MA)-b-PSt), a pH/redox dual-triggered shell-crosslinked polymeric micelle system was constructed. The shell-crosslinked micelles (CLM) were prepared by post-crosslinking method to regulate drug release kinetics using cystamine as linkers between carboxy groups of the shell. Compared with non-crosslinked micelles (NCLM), CLM showed spherical shapes with little increased mean diameter of 102.40±0.54nm, low polydispersity index (PDI) of 0.19±0.36, enlarged zeta potential value from -41.46±0.99 to -9.31±0.50mV, indicating the successful modification of disulfide bonds in shell. In vitro drug release study clearly exhibited a pH and redox dual-sensitive drug release profile with significantly accelerated drug release under pH 5.0 and 10mM GSH conditions (46.84% in 96h) without burst release. Both CLM and NCLM showed quite different release profiles between physiological (pH 7.4) and tumoral microenvironment (pH 5.0), effectively avoiding the premature drug leakage and realizing on-demand drug release. The MTT assay implied that CLM presented a time- and concentration-dependent manner to inhibit proliferation of A549 and MCF-7 cells and much lower IC values in comparison with that of NCLM after 72h incubation. Both FCM and CLSM results showed that CLM displayed much higher cellular uptake efficiency and anti-tumor activities than NCLM and free DOX. CLM and NCLM could be internalized by energy-dependent endocytosis mechanism due to similar surface properties. Overall, this dual-stimuli triggered micelle system provided a promising tumor-responsive platform for cancer therapy.
基于靶向两亲性嵌段共聚物N-乙酰葡糖胺-聚（苯乙烯-alt-马来酸酐）-b-聚苯乙烯（NAG-P(St-alt-MA)-b-PSt），构建了一种pH/氧化还原双触发的壳交联聚合物胶束系统。通过后交联法制备壳交联胶束（CLM），以胱胺作为壳层羧基之间的连接剂来调节药物释放动力学。与非交联胶束（NCLM）相比，CLM呈球形，平均直径略有增加，为102.40±0.54nm，多分散指数（PDI）较低，为0.19±0.36，zeta电位值从-41.46±0.99增大到-9.31±0.50mV，表明壳层中二硫键修饰成功。体外药物释放研究清楚地显示出pH和氧化还原双敏感的药物释放曲线，在pH 5.0和10mM谷胱甘肽（GSH）条件下药物释放显著加速（96小时内释放46.84%）且无突释。CLM和NCLM在生理（pH 7.4）和肿瘤微环境（pH 5.0）之间均表现出截然不同的释放曲线，有效避免了药物过早泄漏并实现按需药物释放。MTT试验表明，CLM呈现出时间和浓度依赖性方式抑制A549和MCF-7细胞的增殖，与NCLM相比，孵育72小时后IC值低得多。流式细胞术（FCM）和共聚焦激光扫描显微镜（CLSM）结果均表明，CLM比NCLM和游离阿霉素（DOX）表现出更高的细胞摄取效率和抗肿瘤活性。由于表面性质相似，CLM和NCLM可通过能量依赖的内吞机制内化。总体而言，这种双刺激触发的胶束系统为癌症治疗提供了一个有前景的肿瘤响应平台。
