This project will continue to test the hypothesis that radiolabeled folate conjugates can serve as vehicles for selective radionuclide delivery to tumors, such as ovarian carcinoma, that overexpress a cell membrane receptor for folic acid.
The specific aims of the project involve the synthesis of folate-conjugates designed for labeling with radioisotopes of In, Cu and Y, followed by characterization of their ability to selectively target tumor cells in vitro and in vivo. Novel folate-chelate and folate-peptide conjugates will be synthesized in which the radiolabeled chelate or peptide is covalently linked to the gamma-carboxylate of folic acid or a folate-analog. The affinity of the conjugate for cell uptake via the folate receptor will be determined in vitro through competitive binding assays with cultured human tumor cells. Agents exhibiting folate-receptor-mediated cell uptake in vitro will be further screened to assess their ability to target neoplastic tissue in vivo. The primary animal model for these screening studies will be athymic mice bearing folate-receptor-positive human tumor xenografts. The biodistribution and pharmacokinetics of the radiolabeled folate-conjugates will be directly evaluated in the mouse tumor model following intravenous administration of the radiopharmaceutical. Radiopharmaceuticals that exhibit significant tumor uptake and tumor selectivity will be examined in more detail to: (ii) confirm involvement of the folate-receptor; (ii) evaluate the rate of radiotracer internalization by targeted cells; and (iii) probe the metabolic fate of the radiotracer. These results will provide the basis for deciding whether more intensive pre-clinical development of a specific agent is warranted. Through independent manipulations of the targeting moiety, the radiolabeled fragment, and associated linker chemistry, these the target molecules are also designed to directly probe structure-activity relationships that should assist in rational design of improved folate-receptor-targeted agents. If suitable tumor-specific tracer uptake can be achieved, such radiopharmaceuticals could find widespread clinical use in the non-invasive diagnosis and/or treatment of a variety of primary and metastatic tumors.
|Ke, Chun-Yen; Mathias, Carla J; Green, Mark A (2004) Folate-receptor-targeted radionuclide imaging agents. Adv Drug Deliv Rev 56:1143-60|
|Mathias, Carla J; Lewis, Michael R; Reichert, David E et al. (2003) Preparation of 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate as potential folate-receptor-targeted PET radiopharmaceuticals. Nucl Med Biol 30:725-31|
|Siegel, Barry A; Dehdashti, Farrokh; Mutch, David G et al. (2003) Evaluation of 111In-DTPA-folate as a receptor-targeted diagnostic agent for ovarian cancer: initial clinical results. J Nucl Med 44:700-7|
|Ke, Chun-Yen; Mathias, Carla J; Green, Mark A (2003) The folate receptor as a molecular target for tumor-selective radionuclide delivery. Nucl Med Biol 30:811-7|
|Mathias, C J; Hubers, D; Low, P S et al. (2000) Synthesis of [(99m)Tc]DTPA-folate and its evaluation as a folate-receptor-targeted radiopharmaceutical. Bioconjug Chem 11:253-7|
|Mathias, C J; Wang, S; Low, P S et al. (1999) Receptor-mediated targeting of 67Ga-deferoxamine-folate to folate-receptor-positive human KB tumor xenografts. Nucl Med Biol 26:23-5|
|Mathias, C J; Wang, S; Waters, D J et al. (1998) Indium-111-DTPA-folate as a potential folate-receptor-targeted radiopharmaceutical. J Nucl Med 39:1579-85|
|Wang, S; Luo, J; Lantrip, D A et al. (1997) Design and synthesis of [111In]DTPA-folate for use as a tumor-targeted radiopharmaceutical. Bioconjug Chem 8:673-9|