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

S. Imstepf; V. Pierroz; P. Raposinho; Matthias Bauwens; M. Felber; T. Fox; A.B. Shapiro; R. Freudenberg; C. Fernandes; S. Gama; G. Gasser; Felix Mottaghy; I.R. Santos; R. Alberto

doi:10.1021/acs.bioconjchem.5b00466

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

S. Imstepf, V. Pierroz, P. Raposinho, Matthias Bauwens, M. Felber, T. Fox, A.B. Shapiro, R. Freudenberg, C. Fernandes, S. Gama, G. Gasser, Felix Mottaghy, I.R. Santos, R. Alberto^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	2397-2407
Number of pages	11
Journal	Bioconjugate Chemistry
Volume	26
Issue number	12
DOIs	https://doi.org/10.1021/acs.bioconjchem.5b00466
Publication status	Published - Dec 2015

Keywords

ANISOTROPY-BASED ASSAY
DOUBLE-STRAND BREAKS
CANCER-THERAPY
BIOLOGICAL EFFECTIVENESS
ORTHOPHOSPHATE HYDROGEL
DOXORUBICIN PRODRUG
ANTITUMOR-ACTIVITY
ENERGY DEPOSITION
MAMMALIAN-CELLS
DNA

Access to Document

10.1021/acs.bioconjchem.5b00466

Cite this

Imstepf, S., Pierroz, V., Raposinho, P., Bauwens, M., Felber, M., Fox, T., Shapiro, A. B., Freudenberg, R., Fernandes, C., Gama, S., Gasser, G., Mottaghy, F., Santos, I. R., & Alberto, R. (2015). Nuclear Targeting with an Auger Electron Emitter Potentiates the Action of a Widely Used Antineoplastic Drug. Bioconjugate Chemistry, 26(12), 2397-2407. https://doi.org/10.1021/acs.bioconjchem.5b00466

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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.",

keywords = "ANISOTROPY-BASED ASSAY, DOUBLE-STRAND BREAKS, CANCER-THERAPY, BIOLOGICAL EFFECTIVENESS, ORTHOPHOSPHATE HYDROGEL, DOXORUBICIN PRODRUG, ANTITUMOR-ACTIVITY, ENERGY DEPOSITION, MAMMALIAN-CELLS, DNA",

author = "S. Imstepf and V. Pierroz and P. Raposinho and Matthias Bauwens and M. Felber and T. Fox and A.B. Shapiro and R. Freudenberg and C. Fernandes and S. Gama and G. Gasser and Felix Mottaghy and I.R. Santos and R. Alberto",

year = "2015",

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doi = "10.1021/acs.bioconjchem.5b00466",

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publisher = "American Chemical Society",

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Imstepf, S, Pierroz, V, Raposinho, P, Bauwens, M, Felber, M, Fox, T, Shapiro, AB, Freudenberg, R, Fernandes, C, Gama, S, Gasser, G, Mottaghy, F, Santos, IR & Alberto, R 2015, 'Nuclear Targeting with an Auger Electron Emitter Potentiates the Action of a Widely Used Antineoplastic Drug', Bioconjugate Chemistry, vol. 26, no. 12, pp. 2397-2407. https://doi.org/10.1021/acs.bioconjchem.5b00466

TY - JOUR

T1 - Nuclear Targeting with an Auger Electron Emitter Potentiates the Action of a Widely Used Antineoplastic Drug

AU - Imstepf, S.

AU - Pierroz, V.

AU - Raposinho, P.

AU - Bauwens, Matthias

AU - Felber, M.

AU - Fox, T.

AU - Shapiro, A.B.

AU - Freudenberg, R.

AU - Fernandes, C.

AU - Gama, S.

AU - Gasser, G.

AU - Mottaghy, Felix

AU - Santos, I.R.

AU - Alberto, R.

PY - 2015/12

Y1 - 2015/12

N2 - 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.

AB - 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.

KW - ANISOTROPY-BASED ASSAY

KW - DOUBLE-STRAND BREAKS

KW - CANCER-THERAPY

KW - BIOLOGICAL EFFECTIVENESS

KW - ORTHOPHOSPHATE HYDROGEL

KW - DOXORUBICIN PRODRUG

KW - ANTITUMOR-ACTIVITY

KW - ENERGY DEPOSITION

KW - MAMMALIAN-CELLS

KW - DNA

U2 - 10.1021/acs.bioconjchem.5b00466

DO - 10.1021/acs.bioconjchem.5b00466

M3 - Article

SN - 1043-1802

VL - 26

SP - 2397

EP - 2407

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

IS - 12

ER -