Uptake and Distribution of a Platinum(II)-Carborane Complex Within a Tumour Cell Using Synchrotron XRF Imaging

Abstract

Treatment of A549 human lung carcinoma cells with a DNA metallointercalator complex containing a PtII-terpy (terpy = 2,2′:6′,2′′-terpyridine) unit linked to a functionalized closo-carborane cage results in the uptake of the complex within the cells, as determined by synchrotron X-ray fluorescence (XRF) imaging. Although a significant cellular uptake of Pt existed, there was no significant accumulation of the element within the cell nuclei. Other statistically significant changes from the XRF data included an increase in Cl, K, and Cu and a decrease in Fe within the treated cells.

Synchrotron X-ray fluorescence studies of a bromine-labelled cyclic RGD peptide interacting with individual tumor cells

“…imaging agents (Chen et al, 2004a,b;Kaim & Schwederski, 1994), including radiolabels such as 18 F, 64 Cu, 68 Ga, 76 Br and 89 Zr for PET imaging (Chen et al, 2004c,d;Li et al, 2008;Lang et al, 2011;Temming et al, 2006), 99m Tc, 111 In and 125 I for SPECT imaging (Jia et al, 2006;Edwards et al, 2009;Haubner et al, 2001), Gd nanotubes for MRI (Mulder et al, 2005), and near-IR dyes such as cypate (Edwards et al, 2009) for in vivo optical imaging, few studies offer high-resolution images of the uptake of RGD peptides within a single tumor cell. Synchrotron X-ray fluorescence (XRF) is a powerful microanalytical tool which offers multi-element imaging at submicrometre resolution for those elements with Z > 11 (Crossley et al, 2011). XRF can identify changes in elemental content and localization within biological samples, including whole cells (Dillon et al, 2002;Harris et al, 2005Harris et al, , 2008, and it has been successfully used to determine the elemental biodistribution within tumor cells treated with Pt(II) and Gd(III) complexes (Crossley et al, 2010(Crossley et al, , 2011Hall et al, 2003).…”

“…Synchrotron X-ray fluorescence (XRF) is a powerful microanalytical tool which offers multi-element imaging at submicrometre resolution for those elements with Z > 11 (Crossley et al, 2011). XRF can identify changes in elemental content and localization within biological samples, including whole cells (Dillon et al, 2002;Harris et al, 2005Harris et al, , 2008, and it has been successfully used to determine the elemental biodistribution within tumor cells treated with Pt(II) and Gd(III) complexes (Crossley et al, 2010(Crossley et al, , 2011Hall et al, 2003).…”

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

“…[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. [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.…”

“…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).…”

Foreword to the 39th International Conference on Coordination Chemistry Bioinorganic Research Front

“…The present paper shows how the relative proportions of the Pt(II) and Pt(IV) forms of some complexes change over time within cells. Lou Rendina (Sydney), Hugh Harris (Adelaide), and colleagues [6] have used synchrotron X-ray fluorescence (XRF) spectroscopy to identify the cellular location of a DNA-intercalating Pt-terpyridyl complex bearing a carborane thiolate ligand; a potential target in boron neutron capture therapy. Rather than localising within the nucleus, the bifunctional complex is found to be distributed throughout the cell both within and outside the nucleus.…”