Zhang Mengjun, Jing Shasha, Zhang Jie, Zhang Jiulong, Zang Xinlong, Qiao Mingxi, Zhao Xiuli, Hu Haiyang, Chen Dawei
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, P. R. China.
J Mater Chem B. 2017 Jun 7;5(21):3970-3981. doi: 10.1039/c7tb00659d. Epub 2017 May 16.
Multidrug resistance (MDR) has been a major obstacle to tumor chemotherapy. Pluronic unimers have been reported to be promising copolymers to reverse MDR, and the intracellular delivery of Pluronic unimers is a problem worth thinking. To exert the excellent reversal effect of Pluronic unimers, DOX-loaded G4.0 PAMAM was modified with PluronicL64 via cis-aconitic acid as a pH-sensitive linkage (PCPAMAM/DOX), which could release DOX and Pluronic unimers into cytoplasm. The Pluronic-modified PAMAM (PCPAMAM) exhibited favorable biocompatibility and pH-sensitivity. PCPAMAM/DOX showed a nano-scale size and a sustained in vitro release profile. Compared with a control formulation, PCPAMAM/DOX showed a higher reversal effect on MCF-7/ADR cells and enhanced intracellular drug accumulation. The results of P-gp activity, subcellular distribution of PluronicL64, the ATP level and mitochondrial transmembrane potential all illustrated that free Pluronic unimers could be released by PCPAMAM functioning as reversal agents. In conclusion, PCPAMAM could be a promising vehicle to enhance DOX accumulation by overcoming MDR in MCF-7/ADR cells. This work also provided an effective method to deliver Pluronic unimers into MDR cells.
多药耐药性（MDR）一直是肿瘤化疗的主要障碍。据报道，普朗尼克单聚物是有望逆转MDR的共聚物，而普朗尼克单聚物的细胞内递送是一个值得思考的问题。为了发挥普朗尼克单聚物出色的逆转作用，以顺乌头酸作为pH敏感连接基，用普朗尼克L64修饰负载阿霉素的G4.0聚酰胺-胺（PCPAMAM/DOX），其可将阿霉素和普朗尼克单聚物释放到细胞质中。普朗尼克修饰的聚酰胺-胺（PCPAMAM）表现出良好的生物相容性和pH敏感性。PCPAMAM/DOX呈现纳米级尺寸和体外缓释特性。与对照制剂相比，PCPAMAM/DOX对MCF-7/ADR细胞显示出更高的逆转作用，并增强了细胞内药物蓄积。P-糖蛋白活性、普朗尼克L64的亚细胞分布、ATP水平和线粒体跨膜电位的结果均表明，PCPAMAM作为逆转剂可释放游离的普朗尼克单聚物。总之，PCPAMAM可能是一种有前景的载体，通过克服MCF-7/ADR细胞中的MDR来增强阿霉素蓄积。这项工作还提供了一种将普朗尼克单聚物递送至MDR细胞的有效方法。
