Evidence that 99mTc-(V)-DMSA uptake is mediated by NaPi cotransporter type III in tumour cell lines

In vivo studies have demonstrated that pentavalent technetium-99m dimercaptosuccinic acid [Tc-99m-(V)-DMSA] may be a useful tumour imaging agent. Several studies have suggested that Tc-99m-(V)-DMSA uptake may be related to the structural similarity between the Tc-99m-(V)-DMSA core and the PO43- anion. As phosphate ions enter cells via NaPi cotransporters, we investigated whether Tc-99m-(V)-DMSA uptake is mediated by NaPi cotransporters. Tc-99m-(V)-DMSA and phosphate uptake kinetics were compared in three cancer cell lines (MCF-7, G152 and MG-63) under several conditions (with and without sodium and NaPi cotransporter inhibitor and at different pH). Determination of molecular NaPi cotransporter mRNA expression was performed by reverse-transcriptase polymerase chain reaction (Rt-PCR) assay. Results obtained in the presence of NaPi inhibitor, in sodium-free medium and at alkaline pH showed that Tc-99m-(V)-DMSA accumulation is linked to NaPi cotransporter functionality. MCF-7 and G152 exhibited the same tracer uptake, whereas MG-63 showed the highest phosphate accumulation and the lowest Tc-99m-(V)-DMSA uptake. These results were in accordance with mRNA NaPi expression, i.e. all cell lines expressed NaPi type III but MG-63 also co-expressed NaPi type I. The total level of NaPi cotransporter was highly correlated with phosphate accumulation, while the level of type III was related to Tc-99m-(V)-DMSA uptake. We have demonstrated that Tc-99m-(V)-DMSA uptake is specifically mediated by NaPi type III in cancer cells.