Bhaskar Roy, Poulomi Sengupta, S. Soni
Apr 15, 2012
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Journal
Cancer Research
Abstract
The phosphoinositide 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) pathway plays a pivotal role in the growth and survival of various cancers. Small molecule inhibitors targeting PI3K/AKT/mTOR pathway (eg. Wortmannin, LY294002, PI-103, PI828) are promising anti cancer agents. Major drawbacks of these drugs are their poor water solubility and off-target toxicity. Nanoscale drug delivery systems have been harnessed as drug carriers to target tumours through enhanced permeation and retention effect. In this study, we developed a nanoformulation of PI103, a potent dual PI3K/mTOR inhibitor, to improve delivery and reduce side effects. PI103 was encapsulated in a homogeneous self-assembled mixture of phosphatidylcholine and cholesterol. DSPE-PEG protective shell was introduced to increase its circulation time. Thin-film-hydration technique followed by extrusion through 200 nm porous membranes developed nanoparticles of 110-150 nm size with 0.15-0.20 mM drug loading. Release kinetics study confirmed the stability of this formulation in PBS for several days as well as a sustained release property in in-vitro Cell Lysate system. In-vitro cell proliferation assay demonstrated improved cytotoxicity of nanoformulated PI103 in murine breast cancer cell line 4T1 and K-ras upregulated and PTEN suppressed ovarian cancer model cells. Fluorescent Activated Cell Sorting (FACS) analysis with FITC tagged Annexin-V, an early apoptosis marker, showed increased apoptosis with the nanoformulation than the free drug. Western blot analysis expressed more potent inhibition of PI3 kinase/Akt pathway by the nanoformulated PI103. These results indicate that nanoformulation can enhance the potential of PI103. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2892. doi:1538-7445.AM2012-2892