The
tumor-homing property of mesenchymal stem cells (MSC) has lead to their use as delivery vehicles for therapeutic genes. The application of the
sodium iodide symporter (NIS) as therapy gene allows noninvasive imaging of functional transgene expression by (123)I-scintigraphy or PET-imaging, as well as therapeutic application of (131)I or (188)Re. Based on the critical role of the
chemokine RANTES (regulated on activation, normal T-cell expressed and presumably secreted)/CCL5 secreted by MSCs in the course of
tumor stroma recruitment, use of the
RANTES/CCL5 promoter should allow
tumor stroma-targeted expression of NIS after MSC-mediated delivery. Using a human
hepatocellular cancer (HCC) xenograft mouse model (Huh7), we investigated distribution and
tumor recruitment of
RANTES-NIS-engineered MSCs after systemic injection by
gamma camera imaging. (123)I-scintigraphy revealed active MSC recruitment and CCL5 promoter activation in the
tumor stroma of Huh7 xenografts (6.5% ID/g (123)I,
biological half-life: 3.7 hr,
tumor-absorbed dose: 44.3 mGy/MBq). In comparison, 7% ID/g (188)Re was accumulated in
tumors with a
biological half-life of 4.1 hr (
tumor-absorbed dose: 128.7 mGy/MBq). Administration of a therapeutic dose of (131)I or (188)Re (55.5 MBq) in
RANTES-NIS-MSC-treated mice resulted in a significant delay in
tumor growth and improved survival without significant differences between (131)I and (188)Re. These data demonstrate successful stromal targeting of NIS in HCC
tumors by selective recruitment of NIS-expressing MSCs and by use of the
RANTES/CCL5 promoter. The resulting
tumor-selective
radionuclide accumulation was high enough for a
therapeutic effect of (131)I and (188)Re opening the exciting prospect of NIS-mediated
radionuclide therapy of metastatic
cancer using genetically engineered MSCs as gene delivery vehicles.