Chemistry of Materials
Chemistry of Materials
5 years ago

Dual-Targeted Cascade-Responsive Prodrug Micelle System for Tumor Therapy in Vivo

Dual-Targeted Cascade-Responsive Prodrug Micelle System for Tumor Therapy in Vivo
Xinkun Shen, Ruisi Cai, Kaiyong Cai, Zhong Luo, Weizhen Chen, Yonglin Yu, Menghuan Li, Liangliang Dai, Yuxia Pei, Xiaojing Zhao
This study reports a cascade-responsive disassemble micellar drug delivery system with dual-targeting potential (cell and mitochondria targeting), which optimizes the distribution of antitumor drugs on systemic, local, and subcellular levels to enhance antitumor efficacy. A new cationic porphyrin derivative 5-(3-hydroxy-p-(4-trimethylammonium)butoxyphenyl)-10,15,20-triphenylporphyrin chlorine (MTPP) is synthesized as a mitochondria-targeting photosensitizer. After accumulating at a tumor site, the micellar nanosystem is endocytosed by tumor cells facilitated by the folate receptor-mediated pathway. Then, the hydrophobic PDEA block would be protonated in intracellular acidic endo-/lysosomes and promote the escape of prodrug micelles from endo-/lysosome to cytoplasm, resulting in the first-stage destabilization of micelles. Subsequently, the CPT is released in response to high concentration of GSH in cytoplasm, which would greatly increase the hydrophilicity of the BOH block and initiate the complete disassembly of the polymer micelles owing to the damage of the hydrophilic–hydrophobic balance. Additionally, the released MTPP is selectively accumulated in mitochondria and activates mitochondria apoptotic pathway upon light irradiation as a result of ROS generation. Both in vitro and in vivo studies indicate that the polymeric micelle not only effectively improves the targeted delivery efficiency but also dramatically enhances the combinational antitumor efficacy while reducing the side effects associated with the laser irradiation and mitochondria-targeted tumor therapy.

Publisher URL: http://dx.doi.org/10.1021/acs.chemmater.7b02513

DOI: 10.1021/acs.chemmater.7b02513

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