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.

Organometallic Rhenium Complexes Divert Doxorubicin to the Mitochondria

“…However,we attribute this effect to nearly quantitative quenching of DNA-intercalated conjugates.W eh ave recently made similar observations for more bulky rhenium conjugates of Dox, where fluorescence microscopy suggested perinuclear and cytosolic uptake,b ut quantification by ICP-MS clearly evidenced am ajor uptake into the nucleus and only to avery limited extent into mitochondria (1-2 %). [16] With Cp-Dox and Cp-N-Dox, we observed for the first time,n oteworthy uptake of aD ox derivative into mitochondria. Even though earlier reports have presented mitochondrial accumulation of Dox derivatives,t hey all rely on fluorescence microscopy or flow cytometry.B oth methods are at least questionable to make afirm statement about the intracellular distribution of Dox derivatives,since the apparent uptake into mitochondria may be over-interpreted by the unknown amount of Dox in the nucleus,w hich is invisible owing to quenching upon intercalation into DNA.…”

Subcellular Targeting of Theranostic Radionuclides

“…These studies provided valuable knowledge that illuminated the inverse relationship between AE-emitter distance to the DNA and DNA damage and cell kill ( Kortylewicz et al, 2012 ). Since then, several small molecule DNA intercalators have been proposed as nuclear-targeting agents for AE-emitting radionuclides, such as radiolabeled derivatives of acridine orange ( Pereira et al, 2017 ), pyrene ( Häfliger et al, 2005 ; Reissig et al, 2016 ), doxorubicin ( Imstepf et al, 2015 ), and daunorubicin ( Fondell et al, 2011 ). Acridine orange is a cell-permeable molecule with anticancer drug and radiosensitizing properties.…”

A Multifunctional Radiotheranostic Agent for Dual Targeting of Breast Cancer Cells

“…However, nuclear localization of these radionuclides is a prerequisite for inducing DNA damage. Introducing a peptidic nuclear localizing sequence (NLS) or a small molecule that acts as DNA intercalator such as acridine orange (AO) or doxorubicin have been strategies applied in AET agents for achieving close proximity of the radionuclide to the DNA.…”