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: Kerstin Knoop, Marie Kolokythas, Kathrin Klutz, Michael J Willhauck, Nathalie Wunderlich, Dan Draganovici, Christian Zach, Franz-Josef Gildehaus, Guido Böning, Burkhard Göke, Ernst Wagner, Peter J Nelson, Christine Spitzweg
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 19 Issue 9 Pg. 1704-13 (Sep 2011) ISSN: 1525-0024 [Electronic] United States
• PMID: 21587211 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Polyomavirus Transforming
• Iodine Radioisotopes
• RNA, Messenger
• Symporters
• sodium-iodide symporter

Topics

• Animals
• Antigens, Polyomavirus Transforming (genetics, metabolism)
• Blotting, Western
• Carcinoma, Hepatocellular (genetics, radiotherapy)
• Cell Survival
• Female
• Fluorescent Antibody Technique
• Gene Transfer Techniques
• Genetic Therapy (methods)
• Hep G2 Cells
• Humans
• Iodine Radioisotopes (pharmacokinetics)
• Liver Neoplasms (genetics, radiotherapy)
• Mesenchymal Stem Cells (metabolism, pathology)
• Mice
• Mice, Nude
• RNA, Messenger (genetics, metabolism)
• Real-Time Polymerase Chain Reaction
• Symporters (genetics, metabolism)
• Transfection (methods)