title: Evaluation of a novel radiofolate in tumour-bearing mice: promising prospects for folate-based radionuclide therapy.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Radiopharmaceutical Science ETH-PSI-USZ, Paul Scherrer Institute, Villigen PSI, Switzerland. cristina.mueller@psi.ch
authors.forename: Cristina
authors.initials: C
authors.lastname: Müller
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Mindt
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000532:radiotherapy*; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000378:metabolism; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D006573:Heterocyclic Compounds, 1-Ring; D019275:Radiopharmaceuticals; D011956:Receptors, Cell Surface; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D005492:Folic Acid