title: Theranostic Approach for Metastatic Pigmented Melanoma Using ICF15002, a Multimodal Radiotracer for Both PET Imaging and Targeted Radionuclide Therapy.
abstract: This work reports, in melanoma models, the theranostic potential of ICF15002 as a single fluorinated and iodinated melanin-targeting compound.
  
  
  
  Studies were conducted in the murine syngeneic B16BL6 model and in the A375 and SK-MEL-3 human xenografts. ICF15002 was radiolabeled with fluorine-18 for positron emission tomography (PET) imaging and biodistribution, with iodine-125 for metabolism study, and iodine-131 for targeted radionuclide therapy (TRT). TRT efficacy was assessed by tumor volume measurement, with mechanistics and dosimetry parameters being determined in the B16BL6 model. Intracellular localization of ICF15002 was characterized by secondary ion mass spectrometry (SIMS).
  
  
  
  PET imaging with [18F]ICF15002 evidenced tumoral uptake of 14.33±2.11%ID/g and 4.87±0.93%ID/g in pigmented B16BL6 and SK-MEL-3 models, respectively, at 1 hour post inoculation. No accumulation was observed in the unpigmented A375 melanoma. SIMS demonstrated colocalization of ICF15002 signal with melanin polymers in melanosomes of the B16BL6 tumors. TRT with two doses of 20 MBq [131I]ICF15002 delivered an absorbed dose of 102.3 Gy to B16BL6 tumors, leading to a significant tumor growth inhibition [doubling time (DT) of 2.9±0.5 days in treated vs 1.8±0.3 in controls] and a prolonged median survival (27 days vs 21 in controls). P53S15 phosphorylation and P21 induction were associated with a G2/M blockage, suggesting mitotic catastrophe. In the human SK-MEL-3 model, three doses of 25 MBq led also to a DT increase (26.5±7.8 days vs 11.0±3.8 in controls) and improved median survival (111 days vs 74 in controls).
  
  
  
  Results demonstrate that ICF15002 fulfills suitable properties for bimodal imaging/TRT management of patients with pigmented melanoma.
authors.affiliation: UMR 990 INSERM/Université d'Auvergne, F-63005 Clermont-Ferrand, France; UMR 892 INSERM/6299 CNRS/Université de Nantes, F-44007 Nantes, France.
authors.forename: Latifa
authors.initials: L
authors.lastname: Rbah-Vidal
authors.affiliation: UMR 990 INSERM/Université d'Auvergne, F-63005 Clermont-Ferrand, France; Arronax, CS 10112, F-44817 Saint Herblain Cedex, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Vidal
authors.affiliation: UMR 990 INSERM/Université d'Auvergne, F-63005 Clermont-Ferrand, France.
authors.forename: Emilie M F
authors.initials: EM
authors.lastname: Billaud
authors.affiliation: UMR 990 INSERM/Université d'Auvergne, F-63005 Clermont-Ferrand, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Besse
authors.affiliation: UMR 1107 INSERM/Université d'Auvergne, Equipe Biophysique Neurosensorielle, F-63000 Clermont-Ferrand, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ranchon-Cole
authors.affiliation: Centre Jean Perrin, Laboratoire d'anatomo-pathologie, F-63011 Clermont-Ferrand, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Mishellany
authors.affiliation: CNRS/IN2P3/Université Blaise Pascal, Laboratoire de Physique Corpusculaire, F-63000 Clermont-Ferrand, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Perrot
authors.affiliation: CNRS/IN2P3/Université Blaise Pascal, Laboratoire de Physique Corpusculaire, F-63000 Clermont-Ferrand, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Maigne
authors.affiliation: UMR 990 INSERM/Université d'Auvergne, F-63005 Clermont-Ferrand, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Moins
authors.affiliation: INSERM, U1196, F-91405, Orsay, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Guerquin-Kern
authors.affiliation: UMR 990 INSERM/Université d'Auvergne, F-63005 Clermont-Ferrand, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Degoul
authors.affiliation: UMR 990 INSERM/Université d'Auvergne, F-63005 Clermont-Ferrand, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Chezal
authors.affiliation: UMR 990 INSERM/Université d'Auvergne, F-63005 Clermont-Ferrand, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Auzeloux
authors.affiliation: UMR 990 INSERM/Université d'Auvergne, F-63005 Clermont-Ferrand, France. Electronic address: elisabeth.noirault@udamail.fr.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Miot-Noirault
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000000981:diagnostic imaging* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D008546:Melanoma, Experimental; D051379:Mice; D064847:Multimodal Imaging; D009362:Neoplasm Metastasis; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism; D000068936:Theranostic Nanomedicine / Q000379:methods*; D014018:Tissue Distribution; D000090324:Tumor Protein, Translationally-Controlled 1; D023041:Xenograft Model Antitumor Assays
chemical_list: D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1