Development of PIK-75 nanosuspension formulation with enhanced delivery efficiency and cytotoxicity for targeted anti-cancer therapy.

PIK-75 is a phosphatidylinositol 3-kinase (PI3K) inhibitor that shows selectivity toward p110-α over the other PI3K class Ia isoforms p110-β and p110-δ, but it lacks solubility, stability and other kinase selectivity. The purpose of this study was to develop folate-targeted PIK-75 nanosuspension for tumor targeted delivery and to improve therapeutic efficacy in human ovarian cancer model. High pressure homogenization was used to prepare the non-targeted and targeted PIK-75 nanosuspensions which were characterized for size, zeta potential, entrapment efficiency, morphology, saturation solubility and dissolution velocity. In vitro analysis of drug uptake, cell viability and cell survival was conducted in SKOV-3 cells. Drug pharmacokinetics and pAkt expression were determined in SKOV-3 tumor bearing mice. PIK-75 nanosuspensions showed an improvement in dissolution velocity and an 11-fold increase in saturation solubility over pre-milled PIK-75. In vitro studies in SKOV-3 cells indicated a 2-fold improvement in drug uptake and 0.4-fold decrease in IC50 value of PIK-75 following treatment with targeted nanosuspension compared to non-targeted nanosuspension. The improvement in cytotoxicity was attributed to an increase in caspase 3/7 and hROS activity. In vivo studies indicated a 5-10-fold increased PIK-75 accumulation in the tumor with both the nanosuspension formulations compared to PIK-75 suspension. The targeted nanosuspension showed an enhanced downregulation of pAkt compared to non-targeted formulation system. These results illustrate the opportunity to formulate PIK-75 as a targeted nanosuspension to enhance uptake and cytotoxicity of the drug in tumor.