Abstract 1763: The discovery of novel non-RGD-containing αvβ3 ligands for molecular imaging

Abstract Metastasis is the cause of 90% of cancer deaths. The detection of neoplasms before they metastasize using non-invasive molecular imaging approaches can have a significant impact on patient survival. For many years it has been known that αvβ3 integrin, which is over-expressed on angiogenic endothelium and many tumours, associates with the extracellular matrix through an RGD tripeptide motif. RGD-mediated targeting has been utilized for a wide variety of peptide and nanoparticle molecular imaging agents that are in various stages of development and in clinical trials. As RGD peptide decreases cell adhesion, concerns regarding its utilization as a molecular imaging agent have been raised (Kiessling et. al., 2009 Radiology). RGD peptides exert an anti-angiogenic effect through their inhibition of αvβ3 integrin, raising the concern given recent studies (Ebos et. al., 2009 Cancer Cell v15; Paez-Ribes et. al., 2009 Cancer Cell v15) that this anti-angiogenic activity may result in increased tumour invasion and metastasis. We sought, therefore, to discover novel αvβ3 integrin-targeted peptides that do not contain RGD for the development of new molecular imaging agents. Using a recently developed “beads on a bead” approach, we screened a linear octapeptide one bead one compound library using purified αvβ3 integrin. Over one hundred peptides were isolated and sequenced “on bead” using a novel MALDI-TOF/MS technique and a number of non-RGD containing peptides were identified. Two of these peptides had a higher binding affinity for purified αvβ3 integrin than the linear RGD peptide (LCE62, KD = 4.7 nM and LCE64, KD = 16.3 nM) as determined by surface plasmon resonance. In contrast to peptides containing RGD, these peptides did not impact the morphology and adhesion of αvβ3 integrin-expressing MDA-435 cells, nor did they inhibit angiogenesis. The uptake of both fluorescein-labeled LCE62 and LCE64 by αvβ3 integrin-expressing breast cancer cells were significantly higher compared with a control AGD peptide. We have also demonstrated that this uptake was effectively blocked by an excess of free unlabeled peptide. These novel αvβ3 integrin-binding peptides could provide a basis for a new and potentially safer generation of molecular imaging agents for the early diagnosis of cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1763. doi:10.1158/1538-7445.AM2011-1763