Acid/reduction dual-sensitive amphiphilic graft polyurethane with folic acid and detachable poly(ethylene glycol) as anticancer drug delivery carrier

Abstract

In order to not only improve the stability of nanomicelles in blood circulation but also promote the cellular uptake in tumors and rapidly release the encapsulated drugs in tumor cells, a kind of acid/reduction dual-sensitive amphiphilic graft polyurethane with folic acid and detachable poly(ethylene glycol) (FA-PUSS-gimi-mPEG) was synthesized by grafting folic acid and monomethoxy poly(ethylene glycol) to the polyurethane side chain. FA-PUSS-gimi-mPEG could self-assemble in aqueous solution to form negatively charged nanomicelles, which endowed them good stability under normal physiological condition. Using ultraviolet-visible spectrometer (UV–vis) and dynamic light scattering (DLS), it was found that the hydrophilic poly(ethylene glycol) layer of FA-PUSS-gimi-mPEG micelles could be detached due to the cleavage of benzoic-imine bond under slightly acidic condition, which resulted in reversing the charge of the micellar surface and exposing folic acid to the micellar surface. FA-PUSS-gimi-mPEG micelles could load doxorubicin (DOX), moreover the drug release rate was faster at pH 5.0 and 10 mM glutathione (GSH) than that under normal physiological condition. The results of cell experiments further demonstrated that FA-PUSS-gimi-mPEG micelles had acid/reduction dual-sensitive property. The changes in the structure of FA-PUSS-gimi-mPEG micelles could enhance the cellular uptake under acid condition and the micelles could accelerate the drug release in tumor cells due to the presence of disulfide bonds in the polymer. Therefore, FA-PUSS-gimi-mPEG micelles could efficiently deliver anticancer drug into tumor cells and enhance the inhibition of cellular proliferation through multi-effect synergy.