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.

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.

journal_name

Theranostics

journal_title

Theranostics

authors

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

doi

10.7150/thno.41489

subject

Has Abstract

pub_date

2020-03-15 00:00:00

pages

4490-4506

issue

10

issn

1838-7640

pii

thnov10p4490

journal_volume

10

pub_type

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