title: Ex Vivo and In Vivo Imaging and Biodistribution of Aptamers Targeting the Human Matrix MetalloProtease-9 in Melanomas.
abstract: The human Matrix MetalloProtease-9 (hMMP-9) is overexpressed in tumors where it promotes the release of cancer cells thus contributing to tumor metastasis. We raised aptamers against hMMP-9, which constitutes a validated marker of malignant tumors, in order to design probes for imaging tumors in human beings. A chemically modified RNA aptamer (F3B), fully resistant to nucleases was previously described. This compound was subsequently used for the preparation of F3B-Cy5, F3B-S-acetylmercaptoacetyltriglycine (MAG) and F3B-DOTA. The binding properties of these derivatives were determined by surface plasmon resonance and electrophoretic mobility shift assay. Optical fluorescence imaging confirmed the binding to hMMP-9 in A375 melanoma bearing mice. Quantitative biodistribution studies were performed at 30 min, 1h and 2 h post injection of 99mTc-MAG-aptamer and 111In-DOTA-F3B. 99mTc radiolabeled aptamer specifically detected hMMP-9 in A375 melanoma tumors but accumulation in digestive tract was very high. Following i.v. injection of 111In-DOTA-F3B, high level of radioactivity was observed in kidneys and bladder but digestive tract uptake was very limited. Tumor uptake was significantly (student t test, p<0.05) higher for 111In-DOTA-F3B with 2.0%ID/g than for the 111In-DOTA-control oligonucleotide (0.7%ID/g) with tumor to muscle ratio of 4.0. Such difference in tumor accumulation has been confirmed by ex vivo scintigraphic images performed at 1h post injection and by autoradiography, which revealed the overexpression of hMMP-9 in sections of human melanomas. These results demonstrate that F3B aptamer is of interest for detecting hMMP-9 in melanoma tumor.
authors.affiliation: UNIV Lyon, Université Claude Bernard Lyon 1, LAGEP UMR 5007 CNRS, Villeurbanne, France.|Hospices Civils de Lyon, Imthernat plateform, Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Kryza
authors.affiliation: Université de Bordeaux, CNRS, INCIA, UMR 5287, Bordeaux, France.|Service de Médecine Nucléaire, CHU de Bordeaux, Bordeaux, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Debordeaux
authors.affiliation: Inserm U1212, Bordeaux, France.|CNRS UMR5320, Pessac, France.|University of Bordeaux, ARNA Laboratory, Bordeaux, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Azéma
authors.affiliation: Inserm U1212, Bordeaux, France.|CNRS UMR5320, Pessac, France.|University of Bordeaux, ARNA Laboratory, Bordeaux, France.
authors.forename: Aref
authors.initials: A
authors.lastname: Hassan
authors.affiliation: Inserm U1212, Bordeaux, France.|CNRS UMR5320, Pessac, France.|University of Bordeaux, ARNA Laboratory, Bordeaux, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Paurelle
authors.affiliation: Université de Bordeaux, CNRS, INCIA, UMR 5287, Bordeaux, France.|Service de Médecine Nucléaire, CHU de Bordeaux, Bordeaux, France.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schulz
authors.affiliation: Université de Bordeaux, CNRS, INCIA, UMR 5287, Bordeaux, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Savona-Baron
authors.affiliation: Hospices Civils de Lyon, Imthernat plateform, Lyon, France.
authors.forename: Elsa
authors.initials: E
authors.lastname: Charignon
authors.affiliation: Hospices Civils de Lyon, Imthernat plateform, Lyon, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Bonazza
authors.affiliation: UNIV Lyon, Université Claude Bernard Lyon 1, LAGEP UMR 5007 CNRS, Villeurbanne, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Taleb
authors.affiliation: Université de Bordeaux, CNRS, INCIA, UMR 5287, Bordeaux, France.|Service de Médecine Nucléaire, CHU de Bordeaux, Bordeaux, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Fernandez
authors.affiliation: UNIV Lyon, Université Claude Bernard Lyon 1, LAGEP UMR 5007 CNRS, Villeurbanne, France.|Hospices Civils de Lyon, Imthernat plateform, Lyon, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Janier
authors.affiliation: Inserm U1212, Bordeaux, France.|CNRS UMR5320, Pessac, France.|University of Bordeaux, ARNA Laboratory, Bordeaux, France.
authors.forename: Jean Jacques
authors.initials: JJ
authors.lastname: Toulmé
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005456:Fluorescent Dyes / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D061848:Optical Imaging; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D052157:Aptamers, Nucleotide; D005456:Fluorescent Dyes; D009363:Neoplasm Proteins; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9