Targeting drug delivery to radiation-induced neoantigens in tumor microvasculature.
2001
Abstract Radiation can be used to guide drugs to specific sites such as neoplasms or aberrant blood vessels. When blood vessels are treated with ionizing radiation, they respond by expressing a number of cell adhesion molecules and receptors that participate in homeostasis. Examples of radiation-induced molecules in blood vessels include ICAM-1, E-selectin, P-selectin and the β 3 integrin. We have observed that the endothelium and blood components respond to oxidative stress in a similar, if not identical manner in all tumor models. Although we have identified several other radiation-induced molecules within tumor blood vessels, the β 3 target for drug delivery achieves the greatest site-specific peptide binding within irradiated tumor blood vessels. We have focused on peptides and antibodies that bind to integrin β 3 . β 3 -binding proteins have been conjugated to fluorochromes and radionuclides to study the site specificity and microscopic distribution. We have found immunofluorescent and immunohistochemical staining of β 3 within the lumen of blood vessels immediately following irradiation. To determine whether it is feasible to guide drug delivery to irradiated tumors, we studied ligands to α 2b β 3 (fibrinogen). Peptides within fibrinogen that bind to α 2b β 3 includes the dodecapeptide, HHLGGAKQAGDV and the RGD peptide. We utilized 131 I conjugation to these ligands to study the biodistribution in tumor bearing mice. Our clinical trial consists of the RGD peptidomimetic, biapcitide, labeled with 99m Tc. This study shows that it is feasible to guide drugs to human neoplasms by use of radiation-guided peptides. These studies have shown that peptides that bind to these integrins bind to tumors following exposure to ionizing radiation.
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