Multi-Stimuli-Responsive Polymeric Prodrug for Enhanced Cancer Treatment

Accomplishing efficient delivery of a nanomedicine to the tumor site will encounter two contradictions as follows: 1) a contradiction between prolonged circulation time and endocytosis by cancer cells; 2) a dilemma between the stability of nanomedicine during blood circulation and intracellular drug release. While developing a nanomedicine which can solve the above two contradictions simultaneously is still a challenge, here, a multi-stimuli-responsive polymeric prodrug (PLys-co-(PLys-DA)-co-(PLys-SS-PTX))-b-PLGLAG-mPEG (P-PEP-SS-PTX-DA) is synthesized which is multi-sensitive to overexpressed matrix metalloproteinase-2 (MMP-2), low pH, and high concentration of glutathione in tumors. The P-PEP-SS-PTX-DA can be dePEGylated and reversed from negative at normal physiological pH to positive charge at tumor extracellular microenvironment; in this way, it can solve the contradiction between prolonged circulation time and endocytosis by cancer cells. Owing to the high reductive conditions in cancer cells, P-PEP-SS-PTX-DA is ruptured to release paclitaxel (PTX) intracellular efficiently; therefore, it can resolve the dilemma between the stability of nanomedicine during blood circulation and intracellular drug release. These indicate that the multi-stimuli-responsive polymeric prodrug has potential application prospects in drug delivery and cancer therapy.