Novel multi-sensitive pseudo-poly(amino acid) for effective intracellular drug delivery

Novel intracellular pH, glutathione (GSH) and reactive oxygen species (ROS)-responsive nanoparticles were obtained using mPEG(2k)-block-redox dual sensitive chain-block-mPEG(2k) (PRDSP) which was prepared by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click polymerization. The disulfide bond, peroxalate ester and triazole units were regularly and repeatedly arranged in the hydrophobic blocks. The disulfide bond was GSH-sensitive and the peroxalate ester structure could be disrupted by acid and hydrogen peroxide. In addition, the triazole units are capable of forming pH-responsive hydrogen bonds. Dynamic Light Scattering (DLS) and transmission electron microscopy (TEM) were used to investigate the pH, GSH and ROS sensitivity of the PRDSP nanoparticles (NPs). The results indicated that the average diameter, size distribution and morphology greatly changed upon adding GSH/H2O2 or modulating the pH. As the preloaded model anticancer drug, doxorubicin (DOX) was quickly released from DOX-loaded PRDSP (PRDSP@DOX) NPs by addition of 10 mM glutathione (GSH), or 10 mM H2O2 or under acidic conditions rather than under physiological conditions. Confocal laser scanning microscopy (CLSM) and flow cytometric analyses revealed that PRDSP@DOX could effectively deliver DOX into the cytoplasm and nucleus of cells. Therefore, PRDSP NPs may be a promising redox heterogeneity-sensitive carrier for efficient and controlled anticancer drug release.