Biodegradable multi-blocked polyurethane micelles for intracellular drug delivery: the effect of disulfide location on the drug release profile

Abstract

Biodegradable multi-blocked polyurethane (PU) based micelles with redox responsive properties have been widely used as anticancer drug delivery systems due to their customizable molecular structures. Disulfide bonds can be easily introduced into the hard segment of polyurethanes by conventional two-step polymerization processes, which result in a random distribution of the reduction responsive disulfide linkages on polyurethanes. We speculated that the disassembly and drug release profiles of polyurethane micelles were related to the location of the disulfide linkages on the polymer main chain. To this end, two kinds of redox responsive polyurethane micelles with the same quantity of disulfide bonds but at different locations were prepared: (i) most of the disulfide bonds located at the hydrophobic core of the polyurethane micelles (PU-SS-C) and (ii) disulfide bonds located primarily at the interface between the hydrophobic core and the hydrophilic shell (PU-SS-I). Paclitaxel (PTX) was chosen as the model hydrophobic drug to evaluate the loading and redox-triggered release of the PU micelles. It was demonstrated that the PU-SS-I micelles disassembled simultaneously in response to a 10 mM glutathione (GSH) stimulus and the payloads released more rapidly than that of PU-SS-C nanocarriers. The results show that the release profiles of PU based nanocarriers can be optimized by the location of the disulfide on the polyurethane main chain. The rapid redox-stimulated release properties of the PU-SS-I nanocarriers will be a promising anticancer drug delivery system to ensure sufficient drug concentration to kill the cancer cell and to prevent the emergence of multidrug resistance (MDR). In addition, confocal laser scanning microscopy (CLSM) demonstrated the cellular uptake of doxorubicin-loaded (DOX-loaded) micelles and the GSH-responsive intracellular release of DOX. The in vitro cytotoxicity and cell uptake of the PTX-loaded micelles was also assessed in H460 cells.