Liposomal Melphalan: Approach to obtain improved plasma stability, pharmacokinetics, and in vitro and in vivo anticancer efficacy in combination with liposomal simvastatin against mouse RPMI-8226 multiple myeloma model

Abstract

Drug resistance and dose-limiting toxicities are the chief hurdles of multiple myeloma (MM) treatment. The targeted nanoparticulate drugs have shown increased specificity and efficacy and decreased toxicities than plain drugs. The present study was aimed to test the anticancer efficacy of Melphalan (MLN) in combination with an antihyperlipidemic drug (Simvastatin; SVN) and improve the treatment using liposomal drugs against mouse RPMI-8226 MM model. The Vitamin E oil (VEO)-composed and MLN- and SVN-loaded liposomes (MLs and SLs) surface coated with Pluronic F108 (PF-108) have shown a mean particle size below 200 nm. The in vitro cytotoxicity study results indicated improved anticancer activity of anticancer drug MLN in combination with SVN against human MM cells (RPMI-8226); whereas, the liposomal drugs showed the sustained anticancer effect. The in vitro plasma chemical stability and pharmacokinetic profiles of liposomal MLN have substantially improved. The liposomal combination (MLs + SLs) treatment has resulted in substantially improved tumor growth inhibition and reduced toxicity in comparison to plain drug combination (MLN + SVN) treatment that showed improved efficacy over standard BTZ treatment. Further, the BAX and Caspase-3 gene expressions are found moderately higher (1.98- and 1.62-fold higher) in tumor tissues treated with the liposomal combination. The above results indicate repurposing potential of SVN in amalgamation with MLN in MM treatment; however, the liposomal drugs could be used over plain drugs to achieve higher efficacy with decreased toxicity.