Theranostics 2020; 10(10):4490-4506. doi:10.7150/thno.41489

Research Paper

Effective control of tumor growth through spatial and temporal control of theranostic sodium iodide symporter (NIS) gene expression using a heat-inducible gene promoter in engineered mesenchymal stem cells

Mariella Tutter1, Christina Schug1, Kathrin A. Schmohl1, Sarah Urnauer1, Nathalie Schwenk1, Matteo Petrini2, Wouter J. M. Lokerse2, Christian Zach3, Sibylle Ziegler3, Peter Bartenstein3, Wolfgang A. Weber4, Ernst Wagner5, Lars H. Lindner2, Peter J. Nelson1, Christine Spitzweg1✉

1. Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
2. Department of Internal Medicine III, University Hospital of Munich, LMU Munich, Munich, Germany
3. Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany
4. Department of Nuclear Medicine, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
5. Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, LMU Munich, Munich, Germany

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Citation:
Tutter M, Schug C, Schmohl KA, Urnauer S, Schwenk N, Petrini M, Lokerse WJM, Zach C, Ziegler S, Bartenstein P, Weber WA, Wagner E, Lindner LH, Nelson PJ, Spitzweg C. Effective control of tumor growth through spatial and temporal control of theranostic sodium iodide symporter (NIS) gene expression using a heat-inducible gene promoter in engineered mesenchymal stem cells. Theranostics 2020; 10(10):4490-4506. doi:10.7150/thno.41489. Available from http://www.thno.org/v10p4490.htm

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Abstract

Purpose: The tumor homing characteristics of mesenchymal stem cells (MSCs) make them attractive vehicles for the tumor-specific delivery of therapeutic agents, such as the sodium iodide symporter (NIS). NIS is a theranostic protein that allows non-invasive monitoring of the in vivo biodistribution of functional NIS expression by radioiodine imaging as well as the therapeutic application of 131I. To gain local and temporal control of transgene expression, and thereby improve tumor selectivity, we engineered MSCs to express the NIS gene under control of a heat-inducible HSP70B promoter (HSP70B-NIS-MSCs).

Experimental Design: NIS induction in heat-treated HSP70B-NIS-MSCs was verified by 125I uptake assay, RT-PCR, Western blot and immunofluorescence staining. HSP70B-NIS-MSCs were then injected i.v. into mice carrying subcutaneous hepatocellular carcinoma HuH7 xenografts, and hyperthermia (1 h at 41°C) was locally applied to the tumor. 0 - 72 h later radioiodine uptake was assessed by 123I-scintigraphy. The most effective uptake regime was then selected for 131I therapy.

Results: The HSP70B promoter showed low basal activity in vitro and was significantly induced in response to heat. In vivo, the highest tumoral iodine accumulation was seen 12 h after application of hyperthermia. HSP70B-NIS-MSC-mediated 131I therapy combined with hyperthermia resulted in a significantly reduced tumor growth with prolonged survival as compared to control groups.

Conclusions: The heat-inducible HSP70B promoter allows hyperthermia-induced spatial and temporal control of MSC-mediated theranostic NIS gene radiotherapy with efficient tumor-selective and temperature-dependent accumulation of radioiodine in heat-treated tumors.

Keywords: sodium iodide symporter, regional hyperthermia, mesenchymal stem cells, gene therapy, theranostics