The goal is to develop novel ava6-targeting peptides that selectively locate to ava6 positive tumors in vivo. Oral squamous cell carcinoma (SCC) accounts for 5.5% of all human malignancies worldwide. Primary treatment is radical often mutilating surgery. Since mortality from oral SCC has remained at greater than 50% for decades, novel strategies to limit its recurrence and invasive-potential are desperately needed. We believe that the cell surface expressed integrin ava6 offers and excellent target for both imaging (early detection) and therapy of oral cancer. Novel ava6-targeting peptides will be identified using the """"""""One-Bead-One-Compound"""""""" random and rational combinatorial cyclic-peptide libraries. 4-[19F]-fluorobenzoyl will be incorporated into the peptide library as an approach to transition the identified sequences into a radiolabeled peptide for imaging using MicroPET II and fluorine-18 chemistry. The peptide libraries will be screened against immobilized integrins as well as cell lines to establish their selectivity and specificity. Peptide radiolabeling will be performed using a solid-phase approach. The peptidyl resin will be radiolabeled using 4-[18F]fluorobenzoic acid. This method is highly flexible, is rapid and amenable to automation. Once successful candidates have been identified as highly selective towards ava6 high resolution screening in mice in vivo using MicroPET II will be performed. By the end of year 2 it is anticipated that several potential ava6-targetingpeptides will be identified. The second part of this proposal we will investigate the ava6-targetingpeptides in vivo in mice using the small animal scanner MicroPET II. Standard immunohistochemistry and phosphor imaging technologies will be used to correlate radiotracer distribution in tumors with integrin expression. In vitro and structural activity experiments will be performed to explain sequence specificity and affinity.
| Hausner, Sven H; Kukis, David L; Gagnon, M Karen J et al. (2009) Evaluation of [64Cu]Cu-DOTA and [64Cu]Cu-CB-TE2A chelates for targeted positron emission tomography with an alphavbeta6-specific peptide. Mol Imaging 8:111-21 |
| Hausner, Sven H; Abbey, Craig K; Bold, Richard J et al. (2009) Targeted in vivo imaging of integrin alphavbeta6 with an improved radiotracer and its relevance in a pancreatic tumor model. Cancer Res 69:5843-50 |
| Gagnon, M Karen J; Hausner, Sven H; Marik, Jan et al. (2009) High-throughput in vivo screening of targeted molecular imaging agents. Proc Natl Acad Sci U S A 106:17904-9 |
| Hausner, Sven H; Marik, Jan; Gagnon, M Karen J et al. (2008) In vivo positron emission tomography (PET) imaging with an alphavbeta6 specific peptide radiolabeled using 18F-""click"" chemistry: evaluation and comparison with the corresponding 4-[18F]fluorobenzoyl- and 2-[18F]fluoropropionyl-peptides. J Med Chem 51:5901-4 |
