Core-Shell Distinct Nanodrug Showing On-Demand Sequential Drug Release To Act on Multiple Cell Types for Synergistic Anticancer Therapy.

Abstract

Among various inflammatory factors/mediators, autocrine and paracrine prostaglandin 2 (PGE₂), which are abundant in various tumors, promote the proliferation and chemoresistance of cancer cells. Thus, eliminating the cytoprotective effect of PGE₂ may strengthen the antitumor effect of chemotherapy. Chemo/anti-inflammatory combination therapy requires the programmed activities of two different kinds of drugs that critically depend on their spatiotemporal manipulation inside the tumor. Here, a micellar polymeric nanosphere, encapsulating chemotherapeutic paclitaxel (PTX) in the core and conjugating anti-inflammatory celecoxib (CXB) to the shell through a peptide linker (PLGLAG), was developed. The PLGLAG linker was cleavable by the enzyme matrix metalloproteinase-2 (MMP-2) in the tumor tissue, causing CXB release and turning the negatively charged nanosphere into a positively charged one to facilitate PTX delivery into cancer cells. The released CXB not only acted on cyclooxygenase-2 (COX-2) to suppress the production of pro-inflammatory PGE₂ in multiple cell types but also suppressed the expression of the anti-apoptotic Bcl-2 gene to sensitize cancer cells to chemotherapy, thus resulting in a synergistic anticancer effect of PTX and CXB. This study represents an example of using a surface charge-switchable nanosphere with on-demand drug release properties to act on multiple cell types for highly effective chemo/anti-inflammatory combination therapy of cancer.