Stimuli-Responsive Micelles with Detachable Poly(2-ethyl-2-oxazoline) Shell Based on Amphiphilic Polyurethane for Improved Intracellular Delivery of Doxorubicin

Abstract

Polyurethanes (PUs) have various biomedical applications including controlled drug delivery. However, the incompletely release of drug at tumor sites limits the efficiency of these drug loaded polyurethane micelles. Here we report a novel polymer poly(2-ethyl-2-oxazoline)-SS-polyurethane-SS-poly(2-ethyl-2-oxazoline) triblock polyurethane (PEtOz-PU(PTMCSS)-PEtOz). The hydrophilic pH-responsive poly(2-ethyl-2-oxazoline) was used as an end-block to introduce pH responsiveness, and the hydrophobic PU middle-block was easily synthesized by the reaction of poly (trimethylene carbonate) diol containing disulfide bonds (PTMC-SS-PTMC diol) and bis (2-isocyanatoethyl) disulfide (CDI). PEtOz-PU(PTMCSS)-PEtOz could self-assemble to form micelles (176 nm). The drug release profile of PEtOz-PU(PTMCSS)-PEtOz micelles loaded with Doxorubicin (DOX) was studied in the presence of acetate buffer (10 mM, pH 5.0) and 10 mM dithiothreitol (DTT). The results showed that under this environment, DOX-loaded polyurethane micelles could release DOX faster and more thoroughly, about 97% of the DOX was released from the DOX-loaded PEtOz-PU(PTMCSS)-PEtOz micelle. In addition, fluorescent microscopy and cell viability assays validated that the DOX-loaded polyurethane micelle strongly inhibits the growth of C6 cells, suggesting their potential as a new nanomedicine against cancer.