Tumor targeting using 67Ga-DOTA-Bz-folate — investigations of methods to improve the tissue distribution of radiofolates

• Published in: Nuclear medicine and biology 2011-07, Vol.38 (5), p.715-723
• Main Authors: Müller, Cristina, Vlahov, Iontcho R., Santhapuram, Hari Krishna R., Leamon, Christopher P., Schibli, Roger
• Format: Article
• Language: English
• Subjects: 67/68Ga; Animals; Biological Transport - drug effects; DOTA-Bz-folate; Female; Folate receptor; Folic Acid - chemistry; Folic Acid - metabolism; Folic Acid - pharmacokinetics; Folic Acid Antagonists - administration & dosage; Folic Acid Antagonists - pharmacology; Gallium Radioisotopes; Glutamates - administration & dosage; Glutamates - pharmacology; Guanine - administration & dosage; Guanine - analogs & derivatives; Guanine - pharmacology; Half-Life; Heterocyclic Compounds - chemistry; Humans; Hydrogen-Ion Concentration; Injections; Isothiocyanates - chemistry; KB Cells; Kidney; Kidney - drug effects; Kidney - metabolism; Mice; Pemetrexed; PET; Radioactive Tracers; SPECT; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Urine - chemistry; Uterine Cervical Neoplasms - diagnostic imaging; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - urine
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2010.12.013

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 [ 67Ga]-gallium. DOTA-Bz-EDA-folate was prepared by conjugation of ethylenediamine-(γ)-folate with 2-( p-isothiocyanobenzyl)-DOTA. Radiolabeling was carried out with 67GaCl 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. 67Ga-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 (