Rational Design of Multifunctional Polymeric Nanoparticles Based on Poly(l-histidine) and d-α-Vitamin E Succinate for Reversing Tumor Multidrug Resistance
Zhen Li, Qixian Chen, Yan Qi, Zhihao Liu, Tangna Hao, Xiaoxin Sun, Mingxi Qiao, Xiaodong Ma, Ting Xu, Xiuli Zhao, Chunrong Yang, Dawei Chen
Index: 10.1021/acs.biomac.8b00213
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Abstract
A multifunctional nanoparticulate system composed of methoxy poly(ethylene glycol)-poly(l-histidine)-d-α-vitamin E succinate (MPEG-PLH-VES) copolymers for encapsulation of doxorubicin (DOX) was elaborated with the aim of circumventing the multidrug resistance (MDR) in breast cancer treatment. The MPEG-PLH-VES nanoparticles (NPs) were subsequently functionalized with biotin motif for targeted drug delivery. The MPEG-PLH-VES copolymer exerts no obvious effect on the P-gp expression level of MCF-7/ADR but exhibited a significant influence on the loss of mitochondrial membrane potential, the reduction of intracellular ATP level, and the inhibition of P-gp ATPase activity of MCF-7/ADR cells. The constructed MPEG-PLH-VES NPs exhibited an acidic pH-induced increase on particle size in aqueous solution. The DOX-encapsulated MPEG-PLH-VES/biotin-PEG-VES (MPEG-PLH-VES/B) NPs were characterized to possess high drug encapsulation efficiency of approximate 90%, an average particle size of approximately 130 nm, and a pH-responsive drug release profile in acidic milieu. Confocal laser scanning microscopy (CLSM) investigations revealed that the DOX-loaded NPs resulted in an effective delivery of DOX into MCF-/ADR cells and a notable carrier-facilitated escape from endolysosomal entrapment. Pertaining to the in vitro cytotoxicity evaluation, the DOX-loaded MPEG-PLH-VES/B NPs resulted in more pronounced cytotoxicity to MCF-/ADR cells compared with DOX-loaded MPEG-PLH-VES NPs and free DOX solution. In vivo imaging study in MCF-7/ADR tumor-engrafted mice exhibited that the MPEG-PLH-VES/B NPs accumulated at the tumor site more effectively than MPEG-PLH-VES NPs due to the biotin-mediated active targeting effect. In accordance with the in vitro results, DOX-loaded MPEG-PLH-VES/B NPs showed the strongest inhibitory effect against the MCF-7/ADR xenografted tumors with negligible systemic toxicity, as evidenced by the histological analysis and change of body weight. The multifunctional MPEG-PLH-VES/B nanoparticulate system has been demonstrated to provide a promising strategy for efficient delivery of DOX into MCF-7/ADR cancerous cells and reversing MDR.