Development of novel peptide ligands for alpha 3-integrin of human ovarian cancer using xenograft models for optical and PET imaging

"One-bead one-compound" combinatorial chemistry technology was used to create random peptide libraries containing millions of beads, each with its own distinctive amino acid sequence. Using the "whole cell binding assay" random and focused peptide libraries were screened with human ovarian adenocarcinoma as well as other cell lines and beads with a unique ligand that bind with high affinity to the cell surface receptors were rapidly coated by layers of cells. These beads were isolated, rescreened, and the amino acid chain was determined by microsequencing. Novel peptides were taken through structure activity relationship (SAR), specificity, high-resolution NMR, and ligand optimization studies. Blocking study with a panel of anti-integrin antibodies revealed that a-3 integrin present on these ovarian adenocarcinoma cells was the target receptor for the "OA02" peptide. "OA02" labeled with near infra red probes, after intravenous injection in ovarian and lymphoma xenograft bearing mice was detected selectively in the ovarian tumor. Peptide "OA02" was also attached via a linker to DOTA which was then used to chelate 64Cu. Positron emission tomography studies using the DOTA-peptide was performed with a MicroPET imaging system on nude mice bearing subcutaneous ovarian and lymphoma xenografts. These studies have validated this peptide as a potentially useful target for ovarian tumor imaging.