title: Tumor microenvironment-responsive micelles for pinpointed intracellular release of doxorubicin and enhanced anti-cancer efficiency.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.
authors.forename: Wei-Liang
authors.initials: WL
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.
authors.forename: Shu-di
authors.initials: SD
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.
authors.forename: Ji-Zhao
authors.initials: JZ
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Yuan
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: College of Radiological Medicine and Protection, Soochow University, Suzhou 215123, People's Republic of China; Changshu Hospital of Traditional Chinese Medicine, Changshu 215500, People's Republic of China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhou
authors.affiliation: The Hospital of Suzhou People's Hospital Affiliated to Nanjing Medical University, Suzhou, 215000, People's Republic of China.
authors.forename: Chun
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China. Electronic address: zhangxuenong@163.com.
authors.forename: Xue-Nong
authors.initials: XN
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D048271:Chitosan / Q000031:analogs & derivatives / Q000737:chemistry; D003543:Cysteamine / Q000737:chemistry; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics; D065546:Drug Liberation; D005260:Female; D006639:Histidine / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000378:metabolism; D051379:Mice; D008823:Micelles; D010084:Oxidation-Reduction; D051381:Rats; D014018:Tissue Distribution; D059016:Tumor Microenvironment / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004337:Drug Carriers; D008823:Micelles; C514968:carboxymethyl-chitosan; D006639:Histidine; D003543:Cysteamine; D004317:Doxorubicin; D048271:Chitosan
keywords: Doxorubicin; Intracellular release; Micelles; Tumor microenvironment-responsive; Tumor-targeting therapy