Gadolinium(III) Complexes as Potential Theranostics

Abstract

Neutron capture therapy and photon activation therapy are binary cancer treatments based on the release of high linear energy transfer particles from specific nuclides following neutron capture or X-ray photon excitation, respectively. Gadolinium is the only element that can be used in both experimental therapeutic applications, in addition to its well-established application as a diagnostic in MRI. Tumour cell mitochondria provide an appropriate intracellular target for theranostic Gd agents due to their central role in metabolism and apoptosis. This study investigates a library of bifunctional Gd(III) complexes that utilise a phosphonium targeting moiety to exploit the enhanced uptake of delocalised lipophilic cations into cancer cell mitochondria. The synthesis, purification, and characterisation of these Gd(III) complexes are reported to evaluate structure-activity relationships in terms of key parameters such as cellular uptake and lipophilicity. Modifications made to the parent Gd(III) complex included alterations to the arylphosphonium centre, the linker group and the macrocycle. Enhanced stability of these complexes was demonstrated when DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) was used in place of DO3A (1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid), a critical development given the inherent toxicity of free Gd3+ ions. Preliminary biological evaluation of the Gd(III) complexes showed low in vitro cytotoxicity with IC50 values generally found to be greater than 1 mM. Uptake and aggregation of the complexes into the T98G glioblastoma cell line was evaluated by means of ICP-MS and was found to be significantly selective over the SVG p12 glial line, with levels up to 9.22 μg of Gd uptake per mg of protein achieved for the tumour cell line, the highest such levels reported to date. Some of the Gd(III) complexes presented herein afforded tumour cell uptake levels that exceeded the archetypal clinical theranostic Motexafin-Gd.