pHe- and glutathione-stepwise-responsive polypeptide nanogel for smart and efficient drug delivery

Smart drug delivery system of core–shell-type polypeptide nanogel of poly(Z-l-lysine-co-l-cystine) (PLL-LC) has been synthesized, which showed high drug loading content (DLC 16.5%) of DOX and pHe–glutathione (GSH) stepwise responsive disassembly. Modifying the shell of the nanogel by 2,3-dimethylmaleic anhydride (DMA) makes it quickly respond to the weak acidic tumor microenvironment (pHe 6.8–6.5), inducing the surface charge reversal and promoting the nanogel efficient uptake by cancer cells. Next, the nanogel can release encapsulated DOX in cytoplasm in the presence of high level of GSH therein via reduction and disassembly of the nanogel, resulting in highly selective cytotoxicity. MTT studies reveal the good biocompatibility of the nanogel before charge reversal and an efficient toxicity to cell under pHe microenvironment. In vitro experiments confirm the smart stepwise degradability of the nanogel and efficient therapy ability to cancer cell, indicating the nanogel is a potential drug delivery system.