Permeable polymersomes from temperature and pH dual stimuli-responsive PVCL-b-PLL block copolymers for enhanced cell internalization and lysosome targeting

Abstract

A series of dual stimuli-responsive block copolymers comprising temperature-responsive poly(N-vinylcaprolactam) (PVCL) and biodegradable pH-responsive poly(l-lysine) (PLL) of varying chain length were synthesized by a combination of free radical polymerization and ring opening polymerization. The block copolymers formed micelles and vesicles (polymersomes) in response to temperature and pH, respectively, in aqueous solution. The nanoassemblies were characterized by transmission electron microscopy and dynamic light scattering techniques. Encapsulation of both hydrophobic and hydrophilic dyes in the polymersomes was shown. Doxorubicin (DOX) was loaded in the polymersomes and its controlled release in response to the two stimuli, independently and jointly, was studied. The drug was found to be released due to stimuli-induced increased permeability without disassembly of the polymersomes. A significant increase in the cellular uptake of the drug-loaded polymersomes at hyperthermia conditions was demonstrated at 41 °C and release of the drug upon localization in lysosomes was observed. Cellular internalization pathway of the polymersomes was investigated by competitive inhibition assay and a combination of endocytic pathways dominated by caveolae-mediated mechanism was found to be operative.