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输送到快速分裂的细胞中 白血病和实体瘤。药物-B12生物偶联物的合成方法 将各种细胞毒性弹头附着在钴胺或钴原子上 一种结构上相关的鸡冠花。活性细胞毒药物被释放 在未成熟的白血病细胞内自发产生，但没有毒性 预饱和阻断受体介导的内吞作用时的观察 含有维生素B12的受体。在实体肿瘤和所有其他 组织，前体药物是无毒的，直到它被光解激活 通过组织穿透红光，或通过聚焦的超声波分解 超音波。我们的体外结果表明，这种“特洛伊木马”策略 靶向给药是一种非常有效的提高药物敏感性的方法 现有抗癌药物的治疗指数。对于眼前的情况 预算期间，我们将制备7种细胞毒性抗癌生物结合物 药物，包括我们已经拥有的百菌清生物结合物 合成的。正宗B12(钴胺)的生物结合物，以及 与B12相似，具有更有利的吸收光谱 将使用红色区域。这些生物偶联物的稳定性也 因为它们在光解和声解条件下的分解 及其对NCI人癌细胞株的毒性作用 将对体外试验进行评估。显示良好活性的生物偶联物 在体外，将对小鼠的肿瘤进行测试。荧光类似物 钴胺将用于研究细胞靶向和 钴胺在肿瘤细胞内的转运。具体的 计划的目标是化学合成，其次是体外和体内合成 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.