Multi‐Stimuli‐Responsive Polymeric Prodrug for Enhanced Cancer Treatment

Abstract

Abstract 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.