Novel glucosylceramide synthase inhibitor based prodrug copolymer micelles for delivery of anticancer agents.

Abstract In order to improve the efficacy of chemotherapy for cancers, we have developed a novel prodrug micellar formulation to co-deliver ceramide-generating anticancer agents and ceramide degradation inhibitor (PPMP). The prodrug nanocarrier is based on a well-defined POEG- b -PPPMP diblock copolymer. The hydrophilic block of POEG- b -PPPMP is POEG, and the hydrophobic block is composed of a number of PPMP units, which could work synergistically with loaded anticancer drugs. POEG- b -PPPMP was readily synthesized via a one-step reversible addition-fragment transfer (RAFT) polymerization from a PPMP monomer. The newly synthesized polymers were self-assembled into micelles and served as a carrier for several hydrophobic anticancer drugs including DOX, PTX and C6-ceramide. POEG- b -PPPMP prodrug polymer exhibited intrinsic antitumor activity in vitro and in vivo. In addition, POEG- b -PPPMP prodrug polymer was comparable to free PPMP in selectively enhancing the production of pro-apoptotic ceramide species as well as down-regulating the mRNA expression of GCS. DOX-loaded POEG- b -PPPMP micelles exhibited an excellent stability of 42 days at 4 °C. Moreover, DOX loaded in POEG- b -PPPMP micelles showed higher levels of cytotoxicity than DOX loaded in a pharmacologically inert polymer (POEG- b -POM) and Doxil formulation in several tumor cell lines. Consistently, in a 4T1.2 murine breast cancer model, the tumor inhibition followed the order of DOX/POEG- b -PPPMP > DOX/POEG- b -POM ≥ Doxil > POEG- b -PPPMP > POEG- b -POM. Our data suggest that POEG- b -PPPMP micelles are a promising dual-functional carrier that warrants more studies in the future. Graphical abstract Unlabelled Image Highlights • We developed a new copolymer with built-in blocks of ceramide degradation inhibitor. • Our polymer formed micelles that are suitable for codelivery of other anticancer drug. • Our codelivery strategy led to selective induction of proapoptotic ceramide species. • We demonstrated significantly improved antitumor activity in vivo with the codelivery. [ABSTRACT FROM AUTHOR]