Stepwise pH-sensitive and biodegradable polypeptide hybrid micelles for enhanced cellular internalization and efficient nuclear drug delivery.

The short blood circulation time, reduced cellular uptake, and uncontrollable drug release still hinder the polymer micelle as an efficient drug delivery vehicle in clinical applications. In this study, a series of stepwise pH-sensitive and biodegradable polypeptide hybrid terpolymers, poly (lysine-co-N,N-bis(acryloyl) cystamine-co-dimethylmaleic anhydride) (PLB-DMMA), were designed and synthesized to achieve prolonged circulation time, enhanced cellular uptake and controllable anti-cancer drug release. The synthesized terpolymers can self-assemble into spherical nano-micelles (NMs) with narrow distributions and exhibited stepwise responses to extracellular and intracellular pH condition of the tumor cell. The as prepared NMs showed a negative surface charge under normal physiological conditions exhibiting advantageous stability during blood circulation. By the first-step pH response, the surface charge of the NMs switched from negative to positive to enhance cellular uptake under the slightly acidic tumor extracellular environment. After internalization into tumor cells, the second-step pH response resulted in an endosome escape of the NMs via the "proton-sponge" effect in the acidic endo/lysosome environment. Additionally, a rapid drug release was triggered in response to the intracellular reductive environment of tumor cells via the destruction of disulfide-linked polymer chains to enhance the nucleus delivery of DOX. in vitro cell assays showed that the blank NMs showed negligible systemic toxicity against normal cells while the DOX-loaded NMs significantly inhibited growth of the tumor cells. In general, it was suggested that the as developed stepwise pH-sensitive and biodegradable PLB-DMMA based NMs would be a smart and promising drug delivery candidate for anti-cancer chemotherapy.