title: Tumor targeting using 67Ga-DOTA-Bz-folate--investigations of methods to improve the tissue distribution of radiofolates.
abstract: BACKGROUND
  Use of folic acid radioconjugates for folate receptor (FR) targeting is a promising strategy for imaging purposes as well as for potential therapy of cancer and inflammatory diseases due to the frequent FR overexpression found on cancer cells and activated macrophages. Herein, we report on preclinical results using a novel DOTA-Bz-EDA-folate conjugate radiolabeled with [(67)Ga]-gallium.
  
  
  METHODS
  DOTA-Bz-EDA-folate was prepared by conjugation of ethylenediamine-(γ)-folate with 2-(p-isothiocyanobenzyl)-DOTA. Radiolabeling was carried out with (67)GaCl(3) according to standard procedures. Biodistribution studies of the tracer were performed in mice bearing FR-positive KB tumor xenografts. The effects on radiofolate biodistribution with coadministered renal uptake-blocking amino acids, diuretic agents, antifolates as well as different routes of administration were likewise investigated. Supportive imaging studies were performed using a small-animal single photon emission computed tomography (SPECT)/CT scanner.
  
  
  RESULTS
  (67)Ga-DOTA-Bz-EDA-folate showed a high and specific accumulation in tumors (6.30%±0.75% ID/g, 1 h pi and 6.08%±0.89% ID/g, 4 h pi). Nonspecific radioactivity uptake in nontargeted tissues was negligible, but significant accumulation was found in FR-positive kidneys, which resulted in unfavorably low tumor-to-kidney ratios (<0.1). Coadministered amino acids or diuretics did not effectively reduce renal accumulation; in contrast, predosed pemetrexed did significantly reduce kidney uptake (<29% of control values). The SPECT/CT studies confirmed the excellent tumor-to-background contrast of (67)Ga-radiofolate and the favorable reduction in kidney uptake (with improved imaging quality) resulting from pemetrexed administration.
  
  
  CONCLUSIONS
  Conventional methods to reduce kidney uptake of radiofolates fail. However, the novel (67)Ga-radiolabeled DOTA-Bz-EDA-folate can effectively be used to image FR-positive cancer and potentially inflammatory diseases. Due to its rapid blood clearance properties, this tracer is also a promising candidate for positron emission tomography imaging if radiolabeled with the short-lived [(68)Ga]-gallium radionuclide.
authors: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland. cristina.mueller@psi.ch
authors: Cristina
authors: C
authors: Müller
authors: Iontcho R
authors: IR
authors: Vlahov
authors: Hari Krishna R
authors: HK
authors: Santhapuram
authors: Christopher P
authors: CP
authors: Leamon
authors: Roger
authors: R
authors: Schibli
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D005260:Female; D005492:Folic Acid / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005710:Gallium Radioisotopes; D005971:Glutamates / Q000008:administration & dosage / Q000494:pharmacology; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D006207:Half-Life; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007267:Injections; D017879:Isothiocyanates / Q000737:chemistry*; D007624:KB Cells; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D000068437:Pemetrexed; D011849:Radioactive Tracers; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed; D014556:Urine / Q000737:chemistry; D002583:Uterine Cervical Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000652:urine
chemical_list: C087160:2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid; D005493:Folic Acid Antagonists; D005710:Gallium Radioisotopes; D005971:Glutamates; D006571:Heterocyclic Compounds; D017879:Isothiocyanates; D011849:Radioactive Tracers; D000068437:Pemetrexed; D006147:Guanine; D005492:Folic Acid