title: Radioiodinated folic acid conjugates: evaluation of a valuable concept to improve tumor-to-background contrast.
abstract: Folic acid radioconjugates can be used for targeting folate receptor positive (FR(+)) tumors. However, the high renal uptake of radiofolates is a drawback of this strategy, particularly with respect to a therapeutic application due to the risk of damage to the kidneys by particle radiation. The goal of this study was to develop and evaluate radioiodinated folate conjugates as a novel class of folate-based radiopharmaceuticals potentially suitable for therapeutic application. Two different folic acid conjugates, tyrosine-folate (1) and tyrosine-click-folate (3), were synthesized and radioiodinated using the Iodogen method resulting in [(125)I]-2 and [(125/131)I]-4. Both radiofolates were highly stable in mouse and human plasma. Determination of FR binding affinities using (3)H-folic acid and FR(+) KB tumor cells revealed affinities in the nanomolar range for 2 and 4. The cell uptake of [(125)I]-2 and [(125/131)I]-4 proved to be FR specific as it was blocked by the coincubation of folic acid. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) in vitro assays were employed for the determination of tumor cell viability upon exposure to [(131)I]-4. Compared to untreated control cells, significantly reduced cell viability was observed for FR(+) cancer cells (KB, IGROV-1, SKOV-3), while FR(-) cells (PC-3) were not affected. Biodistribution studies performed in tumor bearing nude mice showed the specific accumulation of both radiofolates in KB tumor xenografts ([(125)I]-2: 3.43 ± 0.28% ID/g; [(125)I]-4: 2.28 ± 0.46% ID/g, 4 h p.i.) and increasing tumor-to-kidney ratios over time. The further improvement of the tumor-to-background contrast was achieved by preinjection of the mice with pemetrexed allowing excellent imaging via single-photon emission computed tomography (SPECT/CT). These findings confirmed the hypothesis that the application of radioiodinated folate conjugates may be a valuable concept to improve tumor-to-background contrast. The inhibitory effect of [(131)I]-4 on FR(+) cancer cells in vitro indicates the potential of this class of radiofolates for therapeutic application.
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, Villigen-PSI, Switzerland.
authors.forename: Josefine
authors.initials: J
authors.lastname: Reber
authors.forename: Harriet
authors.initials: H
authors.lastname: Struthers
authors.forename: Thomas
authors.initials: T
authors.lastname: Betzel
authors.forename: Alexander
authors.initials: A
authors.lastname: Hohn
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: Cristina
authors.initials: C
authors.lastname: Müller
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D005492:Folic Acid / Q000737:chemistry*; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000627:therapeutic use; D015899:Tomography, Emission-Computed, Single-Photon; D014443:Tyrosine / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D014443:Tyrosine; D005492:Folic Acid