BIFUNCTIONAL CHELATING AGENTS IN TUMOR LOCALIZATION

这个项目的长期目标是开发一种新的方法 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 含有强大的金属螯合基团，并可共价连接到 生物分子，如单抗或药物，如 博莱霉素。产品与50多种化学物质形成稳定的络合物。 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-- 在医疗诊断和治疗方面具有当前和未来的应用。 具体目的是使用新制备的抗螯合单抗 加强螯合标记博莱霉素对肿瘤的定位作用 类似物和其他螯合放射性药物，并研究 肿瘤摄取螯合标记博莱霉素的机制(S) 在抗螯合物的存在下增加(一个数量级) 抗体。新的BLEDTA IV合成的通用化学-- 它通过配位将博莱霉素与螯合剂和其他基团连接起来 没有博莱霉素共价修饰的惰性钴(III)-将是 用于制备含侧链的肿瘤定位博莱霉素类似物 其可具有细胞毒性特性或用作光亲和标记 机械学研究。螯合标记抗肿瘤抗体在临床上的应用 抗体和螯合物之间在代谢上可切割的联系将是 探索的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 做好准备，目的是防止金属在 新陈代谢，从而将某些潜在的毒副作用降至最低 程序。方法学包括化学合成和提纯， 蛋白质(抗体)的化学修饰，微量金属络合 化学，以及大量相关的分析程序。这个 拟议的研究应提供与以下方面有关的信息 先进的技术手段，包括核医学，放射免疫疗法， 核磁共振成像和免疫分析。

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.