BIOCONJUGATE DERIVATIVES OF COENZYMES B-12

研究人员正在使用维生素B12受体来靶向 将细胞毒性抗癌药物递送到快速分裂的细胞， 白血病和实体瘤。 药物-B12生物缀合物通过以下方法合成： 将各种细胞毒性弹头连接到钴胺素的钴原子上， 一种结构上相关的柯啉类化合物。 活性细胞毒性药物被释放 自发地在未成熟的白血病细胞内，但没有毒性。 当受体介导的内吞作用被预饱和阻断时观察到 维生素B12的受体。 在实体瘤和所有其他 前体药物是无毒的，直到它被光解激活 用穿透组织的红光，或用聚焦超声 超声. 我们的体外实验结果表明，这种“特洛伊木马”策略， 靶向给药是一种非常有效的方法， 现有抗癌药物的治疗指数。 立即 在预算期间，我们将制备7种细胞毒性抗癌药物的生物缀合物， 药物，包括苯丁酸氮芥生物结合物，我们已经 合成了真正的B12（钴胺素）的生物缀合物，以及 B12的接近类似物，其具有更有利的吸收光谱， 将使用红色区域。 这些生物复合物的稳定性，以及 因为它们在光解和超声条件下的分解将 研究了它们对NCI人癌细胞系的毒性， 将进行体外评价。显示有利活性的生物缀合物 将在体外针对小鼠中的肿瘤进行测试。 荧光类似物 钴胺素将用于研究细胞靶向， 钴胺素在肿瘤细胞中的细胞内运输。 具体 计划目标是化学合成，其次是体外和体内 生物测试

The investigators are using the vitamin B12 receptor to target the delivery of cytotoxic anticancer drugs to rapidly dividing cells in leukemia and solid tumor. Drug-B12 bioconjugates are synthesized by attaching various cytotoxic warheads to the cobalt atom of cobalamin or a structurally-related corrinoid. The active cytotoxic drug is released spontaneously inside of immature leukemia cells, but no toxicity is observed when receptor-mediated endocytosis is blocked by presaturation of the receptors with vitamin B12. In solid tumors and all other tissues, the pro-drug is non-toxic until it is activated by photolysis with tissue-penetrating red light, or with sonolysis by focused ultrasound. Our results in vitro show this "Trojan Horse" strategy for targeted drug delivery to be a very effective method to increase the therapeutic index of existing anticancer drugs. For the immediate budget period, we will prepare bioconjugates of 7 cytotoxic anticancer drugs, including the chlorambucil bioconjugate that we have already synthesized. Bioconjugates of authentic B12 (cobalamin), as well as a close analog of B12 that has a more favorable absorption spectrum in the red region will be used. The stability of these bioconjugates, as well as their decomposition under photolytic and sonolytic conditions will be studied, and their toxicity against NCI human cancer cell lines in vitro will be evaluated. The bioconjugates that show favorable activity in vitro will be tested against tumors in mice. Fluorescent analogs of cobalamine will be used to study the cellular targeting and intracellular trafficking of cobalamin in tumor cells. The specific program goals are chemical synthesis, followed by in vitro and in vivo biological testing.