The overall goal of this project is to develop a radiopharmaceutical for imaging solid tumors by targeting receptors in tumor vasculature. A common feature of solid tumors is the formation of new blood vessels (angiogenesis). Use of a radioligand to target the receptors involved in this process may provide a way of detecting and treating a wide variety of types of cancer. One receptor, the integrin alpha(v)beta(3), is found on the endothelium of tumor blood vessels at higher concentrations than on blood vessels in normal tissues. Disintegrins are a family of polypeptides with high affinity for integrins including alpha(v)beta(3), but the relative affinities for other receptors varies within the family. One disintegrin, bitistatin, has reported affinity for both alpha(IIb)beta(3) and alpha(v)beta(3). Preliminary data raise the question of whether radiolabeled bitistatin can image both integrins in vivo. In this project, bitistatin and other disintegrins will be tested for their ability to target alpha(v)beta(3) in tumor vasculature. The relative affinities of various disintegrins for alpha(v)beta(3), alpha(IIb)beta(3) and alpha(5)beta(1) integrins will be determined in vitro. Disintegrins will be radiolabeled with single-photon and positron-emitting nuclides by various methods. The effect these modifications on the relative affinities for three integrins will be assessed. Studies will determine whether radiolabeled disintegrins are internalized after binding. In vivo biodistribution of radiolabeled disintegrins will be determined in tumor-bearing mice by microPET imaging and tissue sampling. Blocking studies will be done to confirm receptor-mediated targeting. The distribution of various receptors in tumor specimens will be determined using fluorescent probes and confocal microscopy. Additional studies will address whether the best-performing radiolabeled disintegrin can be used to monitor the effectiveness of anti-angiogenic therapy. This study should identify one or more radiolabeled peptides which have potential clinical utility for rapid, direct imaging of tumors. This approach has the potential for imaging a wide variety of solid tumors regardless of the cell line of origin. A future benefit of this approach is the potential for targeted radiotherapy of tumors by labeling the same disintegrin with a therapeutic radionuclide.
| Knight, Linda C; Romano, Jan E; Cosenza, Stephen C et al. (2007) Differences in binding of (99m)Tc-disintegrins to integrin alphavbeta3 on tumor and vascular cells. Nucl Med Biol 34:371-81 |
| Knight, L C (2003) Non-oncologic applications of radiolabeled peptides in nuclear medicine. Q J Nucl Med 47:279-91 |
