Micellar form of novel poorly soluble pro-apoptotic agent, N-([(2-hydroxy-5-nitrophenyl) amino] carbonothioyl}-3, 5-dimethylbenzamide (PIT) for effective targeting to solid tumors

Keywords:
PEG-PE micelles, novel pro-apoptotic agent, antitumor activity

Abstract:
PIT is a first-in-class small molecule non-lipid inhibitor of PIP3/PH domain interaction, which displays preferential targeting of PTEN-deficient cancer cells and dramatic sensitizing effect on TRAIL toxicity in vitro. However, poor solubility of PIT requires the development of the potential dosage form allowing its better solubilization, such as polymeric micelle. In this study, we developed a parenteral micellar formulation of PIT, using the polymeric micelles made of poly(ethylene-glycol)-phosphoethanolamine (PEG-PE) and evaluated the anticancer activity of PEG-PE micelle-formulated PIT against murine 4T1 metastatic breast cancer in vivo. PIT was active against 4T1 cancer model both in aqueous solution and micellar form by the i.v route of administration. Free and micellar PIT inhibited tumor growth by 58 and 95%, respectively, compared to control. The action of PIT proceeds via the induction of apoptosis in cancer cells as confirmed by TUNEL staining.

Nanotech 2008 Conference Program Abstract