Intracellular Doxorubicin Delivery of a Core Cross-linked, Redox-responsive Polymeric Micelles

• Published in: International journal of pharmaceutics 2016-02, Vol.498 (1-2), p.195-204
• Main Authors: Lili, Yu, Ruihua, Mu, Li, Li, Fei, Liang, Lin, Yao, Li, Su
• Format: Article
• Language: English
• Subjects: Animals; Cell Survival - drug effects; Cell Survival - physiology; Core cross-linked; Disulfide bonds; Doxorubicin - administration & dosage; Doxorubicin - chemistry; Doxorubicin - metabolism; Drug Carriers; Drug Delivery Systems - methods; HeLa Cells; Humans; Intracellular drug delivery; Intracellular Fluid - drug effects; Intracellular Fluid - metabolism; Macrophages - drug effects; Macrophages - metabolism; Mice; Micelles; Oxidation-Reduction - drug effects; Polymers - administration & dosage; Polymers - chemistry; Polymers - metabolism; Redox-responsive
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2015.12.042

[Display omitted] 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 (85–151nm), appropriate zeta potential (−24.8mV), and desirable critical micelle concentration (CMC) (0.18mg/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 50μg/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.