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

Abstract

<b>Purpose</b>: 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 <i>in vivo</i> 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 <i>NIS</i> gene under control of a heat-inducible HSP70B promoter (HSP70B-NIS-MSCs). <b>Experimental Design</b>: 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. <b>Results</b>: The HSP70B promoter showed low basal activity <i>in vitro</i> and was significantly induced in response to heat. <i>In vivo</i>, 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. <b>Conclusions</b>: The heat-inducible HSP70B promoter allows hyperthermia-induced spatial and temporal control of MSC-mediated theranostic <i>NIS</i> gene radiotherapy with efficient tumor-selective and temperature-dependent accumulation of radioiodine in heat-treated tumors.