The platinum agent cisplatin is the pillar of ovarian cancer chemotherapy, but its clinical utility is limited by the onset of resistance. Reduced platinum accumulation in tumours has been proposed as a hallmark for platinum resistance. In turn, a correlation between copper trafficking and cisplatin accumulation in cancer has been repeatedly reported based on in vitro cell studies. In this study, we set out to use radionuclide imaging as a tool to untangle the link between platinum resistance and cisplatin and copper trafficking in vivo, in ovarian cancer models with different sensitivity to cisplatin. 195mPt-cisplatin was first utilised in vivo to quantify accumulation in cisplatin-sensitive A2780 ovarian cancer xenografts in comparison to its cisplatin-resistant counterpart A2780cisR. SPECT imaging and ex vivo biodistribution showed rapid renal excretion and very sparse tissue accumulation of 195mPt-cisplatin, but confirmed that at 2 h post injection cisplatin-sensitive A2780 xenografts accumulate significantly more 195mPt-cisplatin (%ID/g=1.6±0.1) than A2780cisR (%ID/g=0.7±0.1). Dynamic PET studies were then performed on the same models and time points using 64Cu as a proxy for endogenous copper. In cisplatin-naïve mice, significantly higher 64Cu accumulation was observed in sensitive A2780 tumours (%ID/g=7.0±0.7) compared to A2780cisR (%ID/g=3.0±0.3), suggesting that copper mirrors cisplatin behaviour in vivo. Most interestingly, when the same animals were imaged again two days later with a second dose of 64Cu, immediately after cisplatin treatment (4 mg/kg), no difference in 64Cu tumour accumulation was observed for the two models with copper uptake in A2780 tumours falling to the same level of A2780cisR, indicating inhibition of 64Cu uptake by cisplatin treatment in the cisplatin sensitive model. Ex vivo analysis of the same tumour tissues by laser-ablation ICP-MS confirmed that, similar to what was found for 195mPt-cisplatin imaging, cisplatin resistant A2780cisR xenografts accumulated less cisplatin in vivo. Overall, this work shows that cisplatin and copper accumulation in the A2780/A2780cisR models are deeply interconnected, and suggests that cisplatin may compete for the same entry machinery as copper in cisplatin-sensitive A2780 xenografts. This work also show-cases the power of radionuclide imaging as a tool to investigate the pharmacology of new and established drugs in an in vivo setting.

Harnessing radionuclide imaging to investigate the in vivo behaviour of metal-based drugs

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