title: Image-guided, tumor stroma-targeted 131I therapy of hepatocellular cancer after systemic mesenchymal stem cell-mediated NIS gene delivery.
abstract: Due to its dual role as reporter and therapy gene, the sodium iodide symporter (NIS) allows noninvasive imaging of functional NIS expression by (123)I-scintigraphy or (124)I-PET imaging before the application of a therapeutic dose of (131)I. NIS expression provides a novel mechanism for the evaluation of mesenchymal stem cells (MSCs) as gene delivery vehicles for tumor therapy. In the current study, we stably transfected bone marrow-derived CD34(-) MSCs with NIS cDNA (NIS-MSC), which revealed high levels of functional NIS protein expression. In mixed populations of NIS-MSCs and hepatocellular cancer (HCC) cells, clonogenic assays showed a 55% reduction of HCC cell survival after (131)I application. We then investigated body distribution of NIS-MSCs by (123)I-scintigraphy and (124)I-PET imaging following intravenous (i.v.) injection of NIS-MSCs in a HCC xenograft mouse model demonstrating active MSC recruitment into the tumor stroma which was confirmed by immunohistochemistry and ex vivo γ-counter analysis. Three cycles of systemic MSC-mediated NIS gene delivery followed by (131)I application resulted in a significant delay in tumor growth. Our results demonstrate tumor-specific accumulation and therapeutic efficacy of radioiodine after MSC-mediated NIS gene delivery in HCC tumors, opening the prospect of NIS-mediated radionuclide therapy of metastatic cancer using MSCs as gene delivery vehicles.
authors.affiliation: Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Knoop
authors.forename: Marie
authors.initials: M
authors.lastname: Kolokythas
authors.forename: Kathrin
authors.initials: K
authors.lastname: Klutz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Willhauck
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wunderlich
authors.forename: Dan
authors.initials: D
authors.lastname: Draganovici
authors.forename: Christian
authors.initials: C
authors.lastname: Zach
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Gildehaus
authors.forename: Guido
authors.initials: G
authors.lastname: Böning
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Nelson
authors.forename: Christine
authors.initials: C
authors.lastname: Spitzweg
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000532:radiotherapy*; D002470:Cell Survival; D005260:Female; D005455:Fluorescent Antibody Technique; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D056945:Hep G2 Cells; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008113:Liver Neoplasms / Q000235:genetics / Q000532:radiotherapy*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D014162:Transfection / Q000379:methods; D000099209:Sodium-Iodide Symporters
chemical_list: D000952:Antigens, Polyomavirus Transforming; D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D027981:Symporters; D000099209:Sodium-Iodide Symporters