Evaluation of a novel radiofolate in tumour-bearing mice: promising prospects for folate-based radionuclide therapy

Folate-based radiopharmaceuticals have the potential to be used for imaging and therapy of tumours positive for the folate receptor (FR). We describe the in vitro and in vivo evaluation of a DOTA-folate conjugate. Radiolabelling of the DOTA-folate was carried out via standard procedures using (111)InCl(3) and (177)LuCl(3), respectively. The distribution coefficient (log D) was determined in octanol/PBS (pH 7.4). Tissue distribution was investigated in nude mice bearing KB tumour xenografts at different time points after administration of (111)In-DOTA-folate (radiofolate 1) or (177)Lu-DOTA-folate (radiofolate 2) (1 MBq, 1 nmol per mouse). Pemetrexed (PMX, 400 mu g) was injected 1 h prior to the radiofolate in order to reduce renal uptake. Images were acquired with a SPECT/CT camera 24 h after injection of the radiofolate (40-50 MBq, 3 nmol per mouse). The hydrophilic character of the DOTA-folate was represented by a low log D value (radiofolate 1 -4.21 +/- 0.11). In vivo, maximal tumour uptake was found 4 h after injection (radiofolate 1 5.80 +/- 0.55% ID/g; radiofolate 2 7.51 +/- 1.25% ID/g). In FR-positive kidneys there was considerable accumulation of the radiofolates (radiofolate 1 55.88 +/- 3.91% ID/g; radiofolate 2 57.22 +/- 11.05% ID/g; 4 h after injection). However, renal uptake was reduced by preinjection of PMX (radiofolate 1 9.52 +/- 1.07% ID/g; radiofolate 2 13.43 +/- 0.54% ID/g; 4 h after injection) whereas the tumour uptake was retained (radiofolate 1 6.32 +/- 0.41% ID/g; radiofolate 2 8.99 +/- 0.43% ID/g; 4 h after injection). SPECT/CT images clearly confirmed favourable tissue distribution of the novel radiofolates and the positive effect of PMX. The preliminary requirements for the therapeutic use of the novel DOTA-folate are met by its favourable tissue distribution that can be ascribed to its hydrophilic properties and combined administration with PMX.