title: Intracellular Doxorubicin Delivery of a Core Cross-linked, Redox-responsive Polymeric Micelles.
abstract: Redox-responsive micelles based on amphiphilic polyethylene glycol-polymethyl methacrylate with the introduction of disulfide containing cross-linked agent (mPEG-PMMA-SS) were developed for intracellular drug release. Benefiting from the amphiphilicity, mPEG-PMMA-SS could self-assembled into core cross-linked micelles in aqueous medium with tunable sizes (85-151 nm), appropriate zeta potential (-24.8 mV), and desirable critical micelle concentration (CMC) (0.18 mg/mL). Doxorubicin (DOX) could efficiently load into the micelles with satisfactory entrapment efficiency. As expected, the in vitro release studies displayed that DOX release from mPEG-PMMA-SS micelles was about 75% within 10h under tumor-relevant reductive condition, whereas only about 25% DOX was released in non-reductive medium. SRB assays indicated that these mPEG-PMMA-SS micelles were biocompatible and nontoxic up to a concentration of 50 μg/mL. The cytotoxicity studies and the intracellular drug delivery demonstrated that the drug release behavior in cells was related to the concentration of GSH in cytoplasm. Furthermore, the cell experiments using fluorescence microscopy showed clearly that DOX was delivered by micelles to the cytoplasm, released in cytoplasm under reductive environment, and then accumulated in cell nucleus. These results suggest that such redox-responsive micelles may develop into an efficient cytoplasmic delivery for hydrophobic anticancer drugs.
authors.affiliation: Department of Pharmacy, Xi'an Medical University, Xi'an, shaanxi, 710021 China; Stake Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China. Electronic address: yulili0218@163.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lili
authors.affiliation: College of Environmental and Chemical Engineering, Xian Polytechnic University, Xian 710048, China.
authors.forename: Mu
authors.initials: M
authors.lastname: Ruihua
authors.affiliation: Department of Pharmacy, Xi'an Medical University, Xi'an, shaanxi, 710021 China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Xi'an Medical University, Xi'an, shaanxi, 710021 China.
authors.forename: Liang
authors.initials: L
authors.lastname: Fei
authors.affiliation: Department of Pharmacy, Xi'an Medical University, Xi'an, shaanxi, 710021 China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Pharmacy, Xi'an Medical University, Xi'an, shaanxi, 710021 China.
authors.forename: Su
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry* / Q000378:metabolism; D004337:Drug Carriers; D016503:Drug Delivery Systems / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008823:Micelles; D010084:Oxidation-Reduction / Q000187:drug effects; D011108:Polymers / Q000008:administration & dosage* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D004317:Doxorubicin
keywords: Core cross-linked; Disulfide bonds; Intracellular drug delivery; Micelles; Redox-responsive