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

Tutter, Mariella; Schug, Christina; Schmohl, Kathrin A.; Urnauer, Sarah; Schwenk, Nathalie; Petrini, Matteo; Lokerse, Wouter J. M.; Zach, Christian; Ziegler, Sibylle; Bartenstein, Peter; Weber, Wolfgang A.; Wagner, Ernst; Lindner, Lars H.; Nelson, Peter J. und Spitzweg, Christine (2020): 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. In: Theranostics, Bd. 10, Nr. 10: S. 4490-4506

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 I-131. 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 I-125 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 degrees C) was locally applied to the tumor. 0 - 72 h later radioiodine uptake was assessed by I-123-scintigraphy. The most effective uptake regime was then selected for I-131 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 I-131 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1838-7640
• Sprache: Englisch