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Redox-mediated dissociation of PEG-polypeptide-based micelles for on-demand release of anticancer drugs.

Intelligent nanoparticles are capable of prolonged blood circulation without leakage of the payload and fast drug release upon exposure to environmental stimuli, such as redox stimuli, and therefore are highly desirable for cancer therapy. In this study, polymeric micelles were designed and developed with a hydrophilic poly(ethylene glycol) (PEG) shell and a hydrophobic poly-l-phenylalanine (PPhe) core, linked by a redox cleavable bond, i.e. mPEG-SS-PPhe. The mPEG-SS-PPhe micelles were loaded with the anticancer drug doxorubicin (DOX) and shown an on-demand release profile in the presence of redox agents such as glutathione (GSH). Remarkably, the GSH-triggered micellar dissociation accelerated in vitro release of DOX 4.87 fold faster at 10 mM GSH than that without GSH at 12 h. An enhanced inhibitory effect of DOX-loaded mPEG-SS-PPhe micelles was achieved by improving the intracellular GSH levels. Confocal laser scanning microscopy and flow cytometric analyses of HeLa cells further confirmed that DOX accumulation was accelerated by elevating the extracellular GSH concentrations. In addition, mPEG-SS-PPhe micelles showed excellent biocompatibility on L929 and HeLa cell lines. These redox-sensitive polymeric micelles may provide more possibilities as promising carriers for on-demand drug release in a controlled manner.