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


Imstepf, Sebastian; Pierroz, Vanessa; Raposinho, Paula; Bauwens, Matthias; Felber, Michael; Fox, Thomas; Shapiro, Adam B; Freudenberg, Robert; Fernandes, Célia; Gama, Sofia; Gasser, Gilles; Motthagy, Felix; Santos, Isabel R; Alberto, Roger (2015). Nuclear Targeting with an Auger Electron Emitter Potentiates the Action of a Widely Used Antineoplastic Drug. Bioconjugate Chemistry, 26(12):2397-2407.

Abstract

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.

Abstract

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:16 December 2015
Deposited On:12 Jan 2016 15:50
Last Modified:05 Apr 2016 19:52
Publisher:American Chemical Society (ACS)
ISSN:1043-1802
Publisher DOI:https://doi.org/10.1021/acs.bioconjchem.5b00466

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