PEG-derivatized birinapant as a nanomicellar carrier of paclitaxel delivery for cancer therapy

Abstract A novel triblock amphiphilic copolymer (PAL-PEG-Birinapant) was designed and synthesized as a dual-functional micellar carrier utilizing birinapant (an inhibitor of inhibitor-of-apoptosis proteins) as a pH-sensitive segment and inhibitor-of-apoptosis proteins-targeting ligand. The mixed micelles comprised of PAL-PEG-Birinapant (PPB) and mPEG2k-PDLLA2k (MPP), named as PPB/MPP (2/1,w/w) micelles were developed for enhanced solubility and antitumor potency of hydrophobic drugs as paclitaxel (PTX). In vitro cell viability and cytotoxicity studies revealed that the PTX–loaded PPB/MPP micelles were more potent than the commercial PTX formulation (Taxol ® ), as well as the in vitro cell apoptosis study. Clear differences in the intracellular uptake of free coumarin-6 (C6) solution and C6-loaded PPB/MPP micelles were observed and indicated that the PPB/MPP micelles could efficiently deliver chemical compound into tumor cells. PPB copolymer and PTX–loaded PPB/MPP micelles demonstrated an excellent safety profile with a maximum tolerated dose (MTD) of above 1.2 g copolymer/kg and above 100 mg PTX/kg in mice respectively in contrast to 20˜24 mg/kg of Taxol®. The near infrared (NIR) fluorescence imaging showed that PPB/MPP micelles persisted for a relatively long time in the circulation and accumulated preferentially in tumor tissue. Moreover, PTX loaded PPB/MPP micelles significantly inhibited the tumor growth both in MDA-MB-231 and Ramos cancer xenograft mice models without obvious toxicity. Collectively, our study presents a new dual-functional micelles that improve the therapeutic efficacy of PTX in vitro and in vivo.