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

Eur J Nucl Med Mol Imaging. 2009 Jun;36(6):938-46. doi: 10.1007/s00259-008-1058-9. Epub 2009 Jan 30.


Purpose: 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.

Methods: 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 microg) 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).

Results: 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.

Conclusion: 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.

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Female
  • Folate Receptors, GPI-Anchored
  • Folic Acid / chemistry*
  • Folic Acid / metabolism
  • Folic Acid / pharmacokinetics
  • Folic Acid / therapeutic use*
  • Heterocyclic Compounds, 1-Ring / chemistry
  • Humans
  • Mice
  • Neoplasms / diagnostic imaging
  • Neoplasms / metabolism
  • Neoplasms / radiotherapy*
  • Radiopharmaceuticals / chemistry*
  • Radiopharmaceuticals / metabolism
  • Radiopharmaceuticals / pharmacokinetics
  • Radiopharmaceuticals / therapeutic use*
  • Receptors, Cell Surface / metabolism
  • Tissue Distribution
  • Tomography, Emission-Computed, Single-Photon
  • Tomography, X-Ray Computed


  • Carrier Proteins
  • Folate Receptors, GPI-Anchored
  • Heterocyclic Compounds, 1-Ring
  • Radiopharmaceuticals
  • Receptors, Cell Surface
  • 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
  • Folic Acid