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Oncotarget. 2016 Aug 23;7(34):54795-54810. doi: 10.18632/oncotarget.10758.

Hypoxia-targeted 131I therapy of hepatocellular cancer after systemic mesenchymal stem cell-mediated sodium iodide symporter gene delivery.

Author information

1
Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
2
Clinical Biochemistry Group, Medizinische Klinik und Poliklinik IV, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
3
Department of Clinical Radiology, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
4
Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
5
Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
6
Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, Ludwig Maximilian University of Munich, Munich, Germany.

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.

KEYWORDS:

gene therapy; hepatocellular carcinoma; hypoxia-targeting; mesenchymal stem cells; sodium iodide symporter

PMID:
27458162
PMCID:
PMC5342382
DOI:
10.18632/oncotarget.10758
[Indexed for MEDLINE]
Free PMC Article

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