Proapoptotic miltefosine nanovesicles show synergism with paclitaxel: Implications for glioblastoma multiforme therapy

Hexadecylphosphocholine (HePC) or miltefosine based proapoptotic lipid nanovesicles encapsulating paclitaxel for synergistic anticancer effect of paclitaxel and miltefosine in chemoresistant human glioblastoma multiforme (U-87 MG) overexpressing multidrug resistance 1 (MDR1) gene product P-glycoprotein (P-gp), were developed in this study. The nanovesicles had 100–200 nm size and a negative zeta potential (∼−25 mV) and optimized for miltefosine content based on their physiochemical properties. With a high encapsulation efficiency of 94%, the nanovesicles showed sustained release of paclitaxel in nasal fluid and triggered release in the cerebrospinal fluid. Synergistic action of paclitaxel and miltefosine was observed with a low IC50 of 162 ± 5 nM. The nanovesicle also overcame drug resistance and showed ATP dependent uptake via clathrin mediated pathway in glioblastoma cells. An improved therapeutic efficacy in comparison to Taxol®, the current clinical formulation of paclitaxel was observed. Efficient brain uptake of the nanovesicles upon intranasal administration was observed in vivo and the nanovesicles were also found to be able to cross blood brain barrier. These studies therefore suggest the therapeutic potential of proapoptotic lipid nanovesicles and their feasibility for intranasal administration in the treatment of chemoresistant glioblastoma.

• Miltefosine based proapoptotic lipid nanovesicles encapsulate paclitaxel with high efficiency.
• Nanovesicles while exhibiting sustained release of paclitaxel in nasal fluid, show triggered release profile in cerebrospinal fluid.
• Nanovesicles result in synergistic cytotoxic effect of paclitaxel and miltefosine and overcome drug resistance in glioblastoma cells, U-87 MG.
• ATP dependent endocytosis of nanovesicles by U-87 MG cells via clathrin mediated pathway.
• Upon intranasal administration, nanovesicles reach brain and are also able to cross blood brain barrier upon intravenous administration.