Selective Aggregation of a Platinum–Gadolinium Complex Within a Tumor‐Cell Nucleus

Abstract

Per Anhalter in den Zellkern: Ein in DNA intercalierter Metallkomplex kann die selektive Ansammlung eines intakten Wirkstoffs in den Kernen von humanen Lungenkrebszellen (A549) ermöglichen. Mit einem Platinkomplex gelang es nun, auf diesem Weg Gadolinium in Zellkerne zu schleusen. Die Synchrotron‐Röntgenfluoreszenz‐Bildgebung diente zum Nachweis des Prozesses (siehe Bilder).

Synchrotron Radiation Spectroscopic Techniques as Tools for the Medicinal Chemist: Microprobe X-Ray Fluorescence Imaging, X-Ray Absorption Spectroscopy, and Infrared Microspectroscopy

“…Microprobe SRXRF has proven itself as a technique for providing unequalled information regarding the distribution of metal and metalloid-containing drugs in cells and tumours at subtoxic and therapeutic doses. [8,26,[31][32]38,[40][41]56] Targets such as the nucleus, [26,38] including the euchromatin [32] and heterochromatin [8] regions, nucleoli, [32,48,52] membranes, and mitochondria [52] can be identified as sites of localisation following studies of existing and potential therapeutic and diagnostic agents. The technique has been invaluable for confirming theories of drug actions (namely, the coordinative action of cisplatin and its analogues) [38][39] and for confirming concepts associated with the modes of action of designed therapeutics (namely, confirmation of drug penetration to the site of dense DNA).…”

“…The technique has been invaluable for confirming theories of drug actions (namely, the coordinative action of cisplatin and its analogues) [38][39] and for confirming concepts associated with the modes of action of designed therapeutics (namely, confirmation of drug penetration to the site of dense DNA). [8,40] In addition, microprobe SRXRF has been used to determine whether potential therapeutic agents remain intact [40] or dissociate following cell uptake. [41] The additional quantitative analysis of endogenous elements has become significant for probing changes to the homeostasis of the cells as exemplified in the studies of Ca changes associated with As uptake, [32] and intracellular K fluctuations following the uptake of Pt-Gd complexes.…”

“…[41] The additional quantitative analysis of endogenous elements has become significant for probing changes to the homeostasis of the cells as exemplified in the studies of Ca changes associated with As uptake, [32] and intracellular K fluctuations following the uptake of Pt-Gd complexes. [40] Detection of subtle changes in the concentrations and distributions of endogenous cations or anions can provide invaluable information regarding apoptosis and other modes of drug action.…”

“…Secondly, the finding that Gd and Pt accumulated in the nucleus was extremely important since the effectiveness of Gd(III) neutron capture therapy relies on the ability of the complex to localise in close proximity to critical cellular components of the cancer cells. [40] In addition, statistical analysis of the intracellular K concentrations showed K increases of approximately 10× those of the control cells. The authors attributed this to: (i) a possible activation of Na + /K + ATPase; (ii) the direct interaction of the drug with potassium ion channels that effectively trap K + in the cell; or (iii) the down regulation of potassium ion channel expression by targeting chromosomal DNA; although these hypotheses are yet to be confirmed.…”

“…Since 157 Gd possesses the largest effective nuclear cross-section, Gd(III) complexes are ideal agents for thermal neutron capture therapy employed for the destruction of tumour cells. [40] As a mechanism of achieving this, Rendina and coworkers [40] designed and synthesised the Pt-Gd complex that incorporated the DNA intercalating moiety, [Pt II (terpy)] (terpy = 2,2':6'2''-terpyridine).…”