Nuclear Targeting with an Auger Electron Emitter Potentiates the Action of a Widely Used Antineoplastic Drug

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• 作者：Sebastian Imstepf ; Vanessa Pierroz ; Paula Raposinho ; Matthias Bauwens ; Michael Felber ; Thomas Fox ; Adam B. Shapiro ; Robert Freudenberg ; C茅lia Fernandes ; Sofia Gama ; Gilles Gasser ; Felix Motthagy ; Isabel R. Santos ; Roger Alberto
• 刊名：Bioconjugate Chemistry
• 出版年：2015
• 出版时间：December 16, 2015
• 年：2015
• 卷：26
• 期：12
• 页码：2397-2407
• 全文大小：576K
• ISSN：1520-4812

文摘

We present the combination of the clinically well-proven chemotherapeutic agent, Doxorubicin, and ^99mTc, an Auger and internal conversion electron emitter, into a dual-action agent for therapy. Chemical conjugation of Doxorubicin to ^99mTc afforded a construct which autonomously ferries a radioactive payload into the cell nucleus. At this site, damage is exerted by dose deposition from Auger radiation. The ^99mTc-conjugate exhibited a dose-dependent inhibition of survival in a selected panel of cancer cells and an in vivo study in healthy mice evidenced a biodistribution which is comparable to that of the parent drug. The homologous Rhenium conjugate was found to effectively bind to DNA, inhibited human Topoisomerase II, and exhibited cytotoxicity in vitro. The collective in vitro and in vivo data demonstrate that the presented metallo-conjugates closely mimic native Doxorubicin.