Abstract A50: Targeting nanotherapeutics for breast, ovarian, and prostate cancer

Abstract

Abstract African Americans have the highest incidence and mortality rates from cancer despite representing a minority of the population of the United States. In particular, breast and prostate cancer significantly contribute to these disproportionate rates in African American women and men respectively compared to other ethnic groups. We have developed a series of novel self-folding combinatorial libraries composed of cholic acid or cholesterol functional groups with single and branched hexamer peptide arms. Fixed hydrophobic amino acids near the N-terminus (position 5) of the peptide arms interact with the hydrophobic face of the planar cholic acid or cholesterol molecule to form 3-Dimensional compact molecules offering a variety of unique peptide sequence presentations. Receptors overexpressed on cancerous cells serve as the targets for these synthetic molecules. Screening of One-Bead One-Compound (OBOC) combinatorial libraries under stringent conditions provides a powerful approach to test hundreds of thousands to millions of compounds in one batch. Novel cholic-peptide hybrid molecules containing RGD motifs binding to vβ3 integrin were discovered against MDA-MB-231 breast cancer. An NGR motif known to target receptors up regulated in the tumor vasculature and perivascular cells were found in cholesterol-peptide protein conformation mimetics binding to A2780 chemo-resistant ovarian cancer. Targeting ligands to PC3N and LnCap prostate cancers from both cholesterol and cholic acid library sets were discovered. Based on these findings, focused libraries were constructed and screened for enhanced affinity and specificity. Candidate peptidomimetics are equipped on our novel cholic acid nanocarriers enhancing nanotherapeutic targeting, efficacy, and limiting toxicity. The reduced toxicity stemming from tumor targeting and increased efficacy from the combination of nanocarrier EPR effects and targeting ligands result in longer, more tolerable therapeutic cycles that might significantly extend the life expectancy and quality of life of breast and prostate cancer in patients, for which current treatment options are ineffective. Developing novel treatment strategies which include the selective delivery of cytotoxic agents for the treatment of cancers disproportionately afflicting minority populations may be translated for clinical development as a promising diagnostic and therapeutic tools. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A50.