Reduced dose-limiting toxicity of intraperitoneal mitoxantrone chemotherapy using cardiolipin-based anionic liposomes

Abstract

Intraperitoneal chemotherapy confers limited clinical benefit as a result of the dose-limiting toxicity of anticancer drugs. We aimed to develop optimized liposomes for mitoxantrone (MTO) administration that provide high encapsulation efficiency and increase the therapeutic index. Cationic MTO was loaded onto anionic liposomes by electrostatic surface complexation. The anticancer activity was evaluated in a peritoneal carcinomatosis model. The retention of MTO at the tumor site was monitored by molecular imaging. MTO loading efficiencies by electrostatic complexation were >95% for all anionic liposomes but <5% for neutral liposomes. Among anionic liposomes, cardiolipin liposomes (CLs) exhibited the strongest binding affinity for MTO, the highest anticancer activity, and the lowest toxicity. MTO delivered by CLs showed prolonged retention at tumor sites. Unlike free MTO showing significant cardiotoxicity, MTO administered in CLs provided negligible cardiotoxicity. CL-mediated delivery may increase the therapeutic index of MTO chemotherapy by prolonged retention and reduced cardiotoxicity.