Tumor microenvironment-responsive micelles for pinpointed intracellular release of doxorubicin and enhanced anti-cancer efficiency

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• 作者：Wei-liang Chen^a ; ¹ ; Shu-di Yang^a ; ¹ ; Fang Li^a ; ¹ ; Ji-zhao Li^a ; Zhi-qiang Yuan^a ; Wen-jing Zhu^a ; Yang Liu^a ; Xiao-feng Zhou^b ; ^c ; Chun Liu^d ; Xue-nong Zhang^a ; ^{zhangxuenong@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：DOX ; doxorubicin ; CS ; chitosan ; EPR ; enhanced permeability and retention ; GSH ; glutathione ; CMCH ; carboxymethyl chitosan ; NAHis ; N-acetyl-l-histidine ; CMCH-SS-NA ; carboxymethyl chitosan-cysteamine-N-acetyl histidine ; CMCH-LA ; CMCH-lauramine ; DOX/CMCH-SS-NA ; DOX loaded CMCH-SS-NA micelles ; DOX/CMCH-LA ; DOX loaded CMCH-LA micelles ; DOX· ; HCl ; doxorubicin hydrochloride ; NPs ; nanoparticles ; EDC· ; HCl ; 1-(3-Dimethylaminopropyl)-3-ethyl carbon carbodiimide hydrochloride ; NHS ; N-hydroxysuccin
• 刊名：International Journal of Pharmaceutics
• 出版年：2016
• 出版时间：25 September 2016
• 年：2016
• 卷：511
• 期：2
• 页码：728-740
• 全文大小：3923 K

文摘

Internal stimuli, such as intracellular lysosomal pH, enzyme, redox and reduction, can be applied to improve biological specificity of chemotherapeutic drugs for cancer therapy. Thus, functionalized copolymers based on their response to specific microenvironment of tumor regions have been designed as smart drug vesicles for enhanced anti-cancer efficiency and reduced side effects. Herein, we reported dually pH/reduction-responsive novel micelles based on self-assembly of carboxymethyl chitosan-cysteamine-N-acetyl histidine (CMCH-SS-NA) and doxorubicin (DOX). The tailor-made dually responsive micelles demonstrated favorable stability in normal physiological environment and triggered rapid drug release in acidic and/or reduction environment. Additionally, the nanocarriers responded to the intracellular environment in an ultra-fast manner within several minutes, which led to the pinpointed release of DOX in tumor cells effectively and ensured higher DOX concentrations within tumor areas with the aid of targeted delivery, thereby leading to enhanced tumor ablation. Thus, this approach with sharp drug release behavior represented a versatile strategy to provide a promising paradigm for cancer therapy.