Abstract 2907: Novel liposomal compositions of PharmaGap's lead peptide: Effect on ovarian cancer cell proliferation and signaling pathways

Abstract

Background: Liposomes, vesicular structures in the nano - micrometer range, have been widely studied as drug delivery vehicles. Liposomes can self-assemble in aqueous solutions and are normally comprised of lipids organized in concentric bilayers that enclose an internal aqueous volume, unique in their ability to accommodate a wide variety of therapeutic or diagnostic compounds. Novel liposomal compositions of peptide GAP-107B8, have recently been developed and their inhibitory effect on cell proliferation in cancer cell lines has been studied. Protein kinase B, Akt, has been implicated in certain cancer functions, including cell motility and invasion, hormone independence, chemotherapy and radiation resistance. Abnormalities in Akt are associated with certain breast, pancreatic, colorectal, gastric and ovarian cancers. The present work shows that an important mechanism of action for GAP-107B8 peptide formulations is through modification of protein kinase pathways. Objectives: 1) To optimize GAP-107B8 liposomal formulations, 2) To evaluate the efficacy of GAP-107B8 liposomal formulations towards inhibiting proliferation in ovarian cancer cell lines and 3) To gather information on the inhibitory mechanism of action in ovarian cancer cells. Methods: Optimization of the lipid components in the liposomes including lipid identity and ratio in relation to extent of peptide-liposome association was determined by IEC, liposome size and charge. Cell proliferation was measured in A2780cp and OCC-1 ovarian cancer cell lines with liposomal peptide formulations (24 and 72 hrs). Immunoblotting experiments were executed on cancer cell line lysates treated with peptide to explore inhibitory effects on signaling targets. Results: Peptide association ranged from 80-100% for liposomal formulations prepared with two lipid components in varying ratios (formulation 2A and 2B) as opposed to a single lipid component (formulation 1 - 30%). Treatment of ovarian cancer cells with liposomal formulations 2A, 2B and 3 showed significant inhibition on cell proliferation when compared to control groups. Densitometry results showed a 50% reduction in pAkt levels (relative to Akt levels) when ovarian cells were treated with peptide for 1 hour (similar inhibitory effect found after peptide treatment for 4, 8, 14 and 30 hours). Conclusions: A lipid based delivery system for GAP-107B8 peptide was developed in which lipid ratio played an important role for an enhanced peptide-associated liposomal formulation. Proliferation results indicate that administration of peptides in liposome formulations generally results in improved potency in a time dependent manner. All formulations exhibited greater potency after 72 hrs in comparison to earlier time points. GAP-107B8 was found to be a peptide-based inhibitor of protein kinase B (Akt) with a strong potential for anti-cancer properties. 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 2907. doi:1538-7445.AM2012-2907