Vitamin E Oil Incorporated Liposomal Melphalan and Simvastatin: Approach to Obtain Improved Physicochemical Characteristics of Hydrolysable Melphalan and Anticancer Activity in Combination with Simvastatin Against Multiple Myeloma.

The objective of this research was to develop vitamin E oil (VEO)-loaded liposomes for intravenous delivery and to study the VEO effect on melphalan (MLN) loading, release, and stability. Further, the research aim was to determine the in vitro anticancer activity and in vivo systemic toxicity of MLN and simvastatin (SVN) combinations, for repurposing SVN in multiple myeloma. The liposomes were prepared by thin-film hydration technique. The optimized liposomes were surface modified with Pluronic F108, lyophilized, and evaluated for mean particle size, MLN content and release behavior, and in vitro hemolysis, cytotoxicity, and macrophage uptake characteristics. Further, in vivo acute toxicity of plain MLN + SVN combination was determined in comparison to their liposomal combination. The VEO alone and in combination with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) has significantly increased the MLN and SVN loading. The reconstituted liposomes showed the mean particle size below 200 nm (cryo-transmission electron microscope analysis also revealed the liposome formation). In presence of VEO, the liposomes have shown substantially controlled drug release, lower hemolysis, sustained cytotoxicity, lower phagocytosis, and moderately improved chemical stability. Besides, the effect of liposomal combination on mice bodyweight is found substantially lower than the plain drug combination. In conclusion, the VEO could be used along with phospholipids and cholesterol to develop liposomal drugs with improved physicochemical characteristics. Further, the interesting cytotoxicity study results indicated that SVN could be repurposed in combination with anticancer drug MLN against multiple myeloma; liposomal drugs could be preferred to obtain improved efficacy with decreased systemic toxicity.