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Two novel prodrug polymers POEG- b -PSSDas (redox-sensitive) and POEG- b -PCCDas (redox-insensitive), which consist of poly(oligo(ethylene glycol) methacrylate) (POEG) hydrophilic blocks and dasatinib (DAS, an oncogenic tyrosine kinases inhibitor) conjugated hydrophobic blocks, were designed as dual-functional carriers for codelivery with doxorubicin (DOX). Both carriers retained antitumor activity of DAS and could form mixed micelles with DOX. Compared to POEG- b -PCCDas micelles, incorporation of disulfide linkage into POEG- b -PSSDas micelles facilitated efficient cleavage of DAS from prodrug micelles in tumor cells/tissues, leading to a higher level of anti-tumor activity in vitro and in vivo. In addition, DOX-loaded POEG- b -PSSDas micelles exhibited triggered DOX release under a redox environment (10 mM glutathione, GSH), and demonstrated enhanced cytotoxicity against 4T1.2 and PC3 cell lines compared to DOX and DOX-loaded POEG- b -PCCDas micelles. More importantly, DOX-loaded POEG- b -PSSDas micelles were more effective in inhibiting the tumor growth and prolonging the survival rate in an aggressive murine breast cancer model (4T1.2) compared to DOX-loaded POEG- b -PCCDas micelles and a micellar formulation co-loaded with DOX and DAS. This redox-responsive prodrug micellar system provides an attractive strategy for effective combination of tumor targeted therapy and traditional chemotherapy, which warrants further investigation. [ABSTRACT FROM AUTHOR]

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]