Tumor cell uptake and selectivity of gadolinium(III)-phosphonium complexes: The role of delocalisation at the phosphonium centre

Abstract

The synthesis of a series of bifunctional Gd(III) complexes 1-3 covalently bound to arylphosphonium cations possessing a varying degree of delocalisation at the phosphonium centre is presented. The influence of the degree of delocalisation was investigated with regards to in vitro cytotoxicity, cellular uptake of Gd, tumor-cell selectivity and intracellular localisation of Gd within human glioblastoma (T98G) and human glial (SVG p12) cells. Cellular uptake and selectivity studies for the Gd(III) complexes indicate that a reduced delocalisation at the phosphonium centre can lead to an enhanced Gd uptake into SVG p12 cells which results in a decrease in the overall tumor cell selectivity. Synchrotron X-ray fluorescence (microbeam XRF) imaging has demonstrated for the first time that uniform uptake of Gd(III) complex 2 within a population of T98G cells increased as a function of increasing Gd incubation times. The Gd maps show dispersed spots of high intensity which are consistent with mitochondrial uptake.

Synthesis and tumour cell uptake studies of gadolinium(III)–phosphonium complexes

“…No significant trends were observed in cell uptake when various phosphonium targeting vectors were used (1-5), in direct contrast to previous studies involving Gd(III)-DO3A-phosphonium complexes where, for example, the DO3A analogue of 2 was found to have very high T98G cell uptake compared to the parent triphenylphosphonium complex but with a much lower tumour cell selectivity [7][8][9] . Similarly, a related trend was also observed for the alkyl and TEG linker complexes 6-10 which were found to have reduced tumour cell selectivities but showed significantly higher Gd uptake than the para-xylyl linker complexes 1-5 in both cell lines but even more so in the T98G tumour line.…”

“…Complexes 1-10 were all found to have low (mM) cytotoxicity at therapeutically-relevant concentrations, with significant in vitro tumour cell uptake and reasonable tumour cell selectivity at lower concentrations. The reduced tumour cell selectivity of the complexes at higher concentrations is consistent with previous findings which proposes a different mechanism for uptake beyond a certain threshold, although it may also be indicative of ΔΨ m depolarisation 9 .…”

“…Ideally, Gd theranostic agents should demonstrate relatively low cytotoxicity to ensure any uptake into healthy tissue causes only minimal damage, as the intended cytotoxic event for Gd-based binary agents results from either the thermal neutron (NCT/NCEPT) or X-ray photon (PAT) irradiation. The IC 50 values for complexes 1-10 were found to lie in the low mM range, in agreement with those previously-reported for related DO3A complexes [7][8][9] . A one-tailed Mann-Whitney U test demonstrated that these complexes were slightly more cytotoxic toward the T98G cells over their healthy SVG p12 cell line, albeit the overall toxicity of the complexes was only marginal (mM).…”

“…Statistical analysis of the data was performed by means of a two-way ANOVA, demonstrating significantly greater uptake of Gd in the T98G glioma cell line compared with the SVG p12 glial cell line for complexes 2 and 6-9 but no statistically significant difference was found between the two cell lines for complexes 1, 3-5 and 10. Indeed, for complexes 1-3, the tumour cell uptake and selectivity results are not as significant as our previous research reporting related DO3A complexes whereby a reduced delocalisation at the phosphonium centre in moving from, for example, R 1 = Ph (1) to Me (2) was strongly correlated with a reduced tumour-cell selectivity and significantly increased Gd uptake 9 . Furthermore, statistical analysis demonstrated that at the lowest treatment dose for each Gd(III) complex (with the exception of complex 3), a significantly higher Gd uptake in the T98G tumour cell line over the SVG p12 cell line was found.…”

Thiourea-Derived Chelating Ligands and Their Organometallic Compounds: Investigations into Their Anticancer Activity

“…The distributions of P, Zn, and Ir in SKOV-3 cells incubated with 4a were mapped at the 2-ID-D beamline at the Advanced Photon Source (Argonne National Laboratory, Lemont, IL) with modifications to the protocol described previously [ 55 , 56 , 57 ]. The beamline used a double multilayer monochromator and a gold “high flux” zone plate setup to focus a monochromatic beam into a spot of 300–400 nm full width at half maximum (FWHM) in diameter.…”