The overall objective of the proposed research is to study the hypothesis that site-specific drug delivery can be accomplished by targeting delivery systems to radiation-induced proteins in tumor blood vessels. The limitation of other forms of site-specific drug delivery (immunoconjugates and gene therapy) includes specificity for particular tumors, nonspecific delivery to other organs (eg. liver) and inhomogeneity of drug within tumors. We propose that targeting drug delivery to antigens can circumvent each of these limitations and receptors expressed in irradiated tumor blood vessels. We have identified molecular responses that occur in all tumor blood vessels. Our preliminary data show that antibodies and proteins designed to bind to these targets can be linked to radionuclides, liposomes and gene therapy vectors. Our preliminary data show no binding to other organs and only tumor-specific binding. Moreover, the biodistribution of radiation-guided drug delivery is homogeneous throughout the vasculature of tumors. Radiation-induced antigens and receptors in tumor blood vessels include P-selectin, E-selectin and the b3 component of integrin a2bb3. The ligands that bind to the integrin a2bb3 include fibrinogen, fibronectin and vitronectin. To determine whether these ligands can be used to guide drug delivery, we labeled fibrinogen with 131j and studied 131I-fibrinogen biodistribution by gamma camera imaging. We found site-specific delivery to irradiated tumors. In the proposed studies, we will determine the sites of binding of fibrinogen within tumor blood vessels. We will determine whether small peptides and antibodies targeted against these fibrinogen receptors can be used for drug delivery. These peptides and antibodies will be conjugated or inserted within drug delivery systems to study biodistribution and pharmacokinetics of these systems. We will also test the hypothesis that x-ray-guided drug delivery systems are capable of delivering tumoricidal doses of drugs to irradiated tumors. Our future goal is to validate the pharmacokinetics and biodistribution of these x-ray-guided delivery systems in clinical trials.
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