TUMOR TARGETING VITAMIN B12 DERIVATIVES FOR X-RAY ACTIVATED CHEMOTHERAPY

摘要

A therapeutic agent has an antineoplastic drug bonded with an X-ray-cleavable bond to cobalt of cobalamin. In embodiments, the drug is doxorubicin, paclitaxel, methotrexate, erlotinib, chlorambucil, dasatinib, SN38, colchicine, or gefitinib; and in embodiments a Cy5 fluorophore bonded to ribose of the cobalamin. The agent is formed by reducing hydroxocobalamin with zinc, reacting with 3-bromopropylamine to form aminopropyl cobalamin; and linking the drug to the aminopropyl cobalamin by conjugation through a hydroxyl group by carbamate formation with 1,1'-Carbonyl-di-(1,2,4-triazole). An optional Cy5 handle is added by coupling a 5' hydroxyl group of a ribose first with ethylene diamine and then with N-hydroxysuccinimide of Cy5. The agent treats cancer by administration in a dose expected to induce apoptosis in cells of the cancer when the light-cleavable bond is cleaved, the cancer absorbs the agent; and the cancer is exposed to X-ray or visible light to cleave the X-ray-light-cleavable bond.