title: Nuclear Targeting with an Auger Electron Emitter Potentiates the Action of a Widely Used Antineoplastic Drug.
abstract: We present the combination of the clinically well-proven chemotherapeutic agent, Doxorubicin, and (99m)Tc, an Auger and internal conversion electron emitter, into a dual-action agent for therapy. Chemical conjugation of Doxorubicin to (99m)Tc 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 (99m)Tc-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.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Imstepf
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pierroz
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa , Estrada Nacional 10 km 139.7, PT-2695-066 Bobadela LRS, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Raposinho
authors.affiliation: Department of Nuclear Medicine, MUMC+ , P. Debeyelaan 25, NL-6229 Maastricht, Netherlands.
authors.forename: Matthias
authors.initials: M
authors.lastname: Bauwens
authors.forename: Michael
authors.initials: M
authors.lastname: Felber
authors.forename: Thomas
authors.initials: T
authors.lastname: Fox
authors.affiliation: Bioscience Department, Infection Innovative Medicines, AstraZeneca R&D Boston , Waltham, Massachusetts 02451, United States.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Shapiro
authors.affiliation: Universitätsklinikum Carl Gustav Carus Dresden , Fetscherstrasse 74, D-01307 Dresden, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Freudenberg
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa , Estrada Nacional 10 km 139.7, PT-2695-066 Bobadela LRS, Portugal.
authors.forename: Célia
authors.initials: C
authors.lastname: Fernandes
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa , Estrada Nacional 10 km 139.7, PT-2695-066 Bobadela LRS, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Gama
authors.forename: Gilles
authors.initials: G
authors.lastname: Gasser
authors.affiliation: Department of Nuclear Medicine, MUMC+ , P. Debeyelaan 25, NL-6229 Maastricht, Netherlands.
authors.forename: Felix
authors.initials: F
authors.lastname: Motthagy
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa , Estrada Nacional 10 km 139.7, PT-2695-066 Bobadela LRS, Portugal.
authors.forename: Isabel R
authors.initials: IR
authors.lastname: Santos
authors.forename: Roger
authors.initials: R
authors.lastname: Alberto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004317:Doxorubicin / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D013667:Technetium / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; D013667:Technetium; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II