The long-term goal of this project is to develop new ways in which chelated metal ions may be used in the detection and treatment of cancer. Bifunctional chelating agents are important to this work; these compounds contain a powerful metal-chelating group and may be attached covalently to biological molecules such as monoclonal antibodies or drugs such as bleomycin. The products form stable chelates with more than 50 chemical elements; these elements have many useful properties -- such as radioactivity, paramagnetism, luminescence, and catalytic activity -- which have current and future applications in medical diagnosis and treatment.
Specific aims are to use newly prepared monoclonal anti-chelate antibodies to strongly enhance the tumor localization of chelate-tagged bleomycin analogs and other chelate radiopharmaceuticals, and to investigate the mechanism(s) by which tumor uptake of chelate-tagged bleomycins is increased (by an order of magnitude) in the presence of anti-chelate antibodies. The versatile chemistry of the new BLEDTA IV synthesis -- which links bleomycin to chelators and other groups via coordination to inert cobalt(III), with no covalent modification of bleomycin -- will be used to prepare tumor-localizing bleomycin analogs bearing side-chains which may have cytotoxic properties or act as photoaffinity labels for mechanistic studies. The use of chelate-tagged antitumor antibodies with metabolically cleavable linkages between antibody and chelate will be explored with the aim of improving tumor imaging by reducing background interference. New bifunctional chelators with macrocyclic structures will be prepared, aimed at preventing any loss of metal from chelate during metabolism and thus minimizing potential toxic side effects of certain procedures. The methodology involves chemical synthesis and purification, chemical modification of proteins (antibodies), trace metal chelation chemistry, and a large number of associated analytical procedures. The proposed studies should provide information relevant to a number of advanced technical methods, including nuclear medicine, radioimmunotherapy, nuclear magnetic resonance imaging, and immunoassay.
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