BIFUNCTIONAL CHELATING AGENTS IN TUMOR LOCALIZATION

该项目的长期目标是开发新的方法， 金属离子可用于癌症的检测和治疗。 双功能螯合剂对这项工作很重要;这些化合物 含有强有力的金属螯合基团，并且可以共价连接到 生物分子如单克隆抗体或药物如 博莱霉素 产品与50多种化学物质形成稳定的螯合物 元素;这些元素有许多有用的属性，例如 放射性、顺磁性、发光和催化活性-- 在医学诊断和治疗中具有当前和未来的应用。 具体目标是使用新制备的单克隆抗螯合抗体 强烈增强螯合物标记的博来霉素的肿瘤定位， 类似物和其他螯合放射性药物，并研究 肿瘤摄取螯合物标记的博来霉素的机制 在抗螯合剂存在下增加（数量级） 抗体的 新的BLEDTA IV合成的多功能化学-- 其通过配位将博来霉素与螯合剂和其它基团连接， 惰性钴（III），没有博来霉素的共价修饰-将被 用于制备带有侧链的肿瘤定位博来霉素类似物 其可具有细胞毒性性质或作为光亲和标记物， 机械研究。 螯合物标记的抗肿瘤抗体与 抗体和螯合物之间的代谢上可裂解的连接将是 目的是通过减少背景来改善肿瘤成像 干扰 具有大环结构的新型双功能螯合剂将 准备，目的是防止任何损失的金属螯合过程中， 代谢，从而最大限度地减少某些药物的潜在毒副作用。 程序. 该方法包括化学合成和纯化， 蛋白质（抗体）的化学修饰，痕量金属螯合 化学和大量相关的分析方法。 的 拟议的研究应提供与若干问题有关的资料， 先进的技术方法，包括核医学、放射免疫治疗， 核磁共振成像和免疫测定。

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.