Overcoming multidrug resistance using liposomal epirubicin and antisense oligonucleotides targeting pump and nonpump resistances in vitro and in vivo

摘要

Multidrug resistance (MDR) is a serious obstacle in cancer treatment. In this study, epirubicin (Epi), an anthracycline antineoplastic agent, and/or antisense oligonucleotides (ASOs) targeting MDR1, MDR-associated protein (MRP)1, MRP2, and BCL-2/BCL-xL were incorporated into polyethylene glycol-coated (PEGylated) liposomes to develop a suitable anticancer drug delivery system. We evaluated in vitro cytotoxicity, intracellular accumulation and cell cycle analysis of these formulations. We also assessed in vivo pharmacokinetics and antitumor efficacy of these formulations in Sprague-Dawley (SD) rats and mouse colon adenocarcinoma CT26-bearing Balb/c mice. ASOs in PEGylated liposomes significantly enhanced the cytotoxicity and the intracellular accumulation of Epi in CT26 cells. This combination also intensified Epi-induced apoptosis in CT26 cells. An in vivo pharmacokinetic study using SD rats showed that after intravenous administration of PEGylated liposomal Epi and ASOs, Epi had greater area under the curve and longer half-life than in an Epi solution. The treatment of PEGylated liposomal Epi and ASOs also demonstrated significant improvements in tumor growth inhibition and survival percentage in CT26-bearing Balb/c mice in vivo. The PEGylated liposomal formulation of Epi and ASOs against MDR1, MRP1, MRP2, and BCL-2/BCL-xL exhibited the most pronounced effect among all the formulations used in this study. This study pioneered in demonstrating that PEGylated liposomal ASOs targeting both pump and nonpump resistances increase antitumor efficacy in vivo through the simultaneous inhibition of MDR transporters and apoptosis induction. This approach provides a potential strategy to overcome MDR in cancer chemotherapy.