title: Hypoxia-targeted 131I therapy of hepatocellular cancer after systemic mesenchymal stem cell-mediated sodium iodide symporter gene delivery.
abstract: Adoptively transferred mesenchymal stem cells (MSCs) home to solid tumors. Biologic features within the tumor environment can be used to selectively activate transgenes in engineered MSCs after tumor invasion. One of the characteristic features of solid tumors is hypoxia. We evaluated a hypoxia-based imaging and therapy strategy to target expression of the sodium iodide symporter (NIS) gene to experimental hepatocellular carcinoma (HCC) delivered by MSCs.MSCs engineered to express transgenes driven by a hypoxia-responsive promoter showed robust transgene induction under hypoxia as demonstrated by mCherry expression in tumor cell spheroid models, or radioiodide uptake using NIS. Subcutaneous and orthotopic HCC xenograft mouse models revealed significant levels of perchlorate-sensitive NIS-mediated tumoral radioiodide accumulation by tumor-recruited MSCs using 123I-scintigraphy or 124I-positron emission tomography. Functional NIS expression was further confirmed by ex vivo 123I-biodistribution analysis. Administration of a therapeutic dose of 131I in mice treated with NIS-transfected MSCs resulted in delayed tumor growth and reduced tumor perfusion, as shown by contrast-enhanced sonography, and significantly prolonged survival of mice bearing orthotopic HCC tumors. Interestingly, radioiodide uptake into subcutaneous tumors was not sufficient to induce therapeutic effects. Our results demonstrate the potential of using tumor hypoxia-based approaches to drive radioiodide therapy in non-thyroidal tumors.
authors.affiliation: Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Müller
authors.affiliation: Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Kathrin A
authors.initials: KA
authors.lastname: Schmohl
authors.affiliation: Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Knoop
authors.affiliation: Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Schug
authors.affiliation: Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Urnauer
authors.affiliation: Clinical Biochemistry Group, Medizinische Klinik und Poliklinik IV, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Hagenhoff
authors.affiliation: Department of Clinical Radiology, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Dirk-André
authors.initials: DA
authors.lastname: Clevert
authors.affiliation: Department of Clinical Radiology, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ingrisch
authors.affiliation: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Niess
authors.affiliation: Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Janette
authors.initials: J
authors.lastname: Carlsen
authors.affiliation: Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Zach
authors.affiliation: Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.affiliation: Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bartenstein
authors.affiliation: Clinical Biochemistry Group, Medizinische Klinik und Poliklinik IV, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Nelson
authors.affiliation: Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Spitzweg
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D000860:Hypoxia; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008819:Mice, Nude; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000099209:Sodium-Iodide Symporters
chemical_list: D007457:Iodine Radioisotopes; D027981:Symporters; D000099209:Sodium-Iodide Symporters
keywords: gene therapy; hepatocellular carcinoma; hypoxia-targeting; mesenchymal stem cells; sodium iodide symporter