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Mesenchymal stem cell-mediated, tumor stroma-targeted radioiodine therapy of metastatic colon cancer using the sodium iodide symporter as theranostic gene.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine (2015-03-07)
Kerstin Knoop, Nathalie Schwenk, Kathrin Schmohl, Andrea Müller, Christian Zach, Clemens Cyran, Janette Carlsen, Guido Böning, Peter Bartenstein, Burkhard Göke, Ernst Wagner, Peter J Nelson, Christine Spitzweg
ABSTRACT

The tumor-homing property of mesenchymal stem cells (MSCs) allows targeted delivery of therapeutic genes into the tumor microenvironment. The application of sodium iodide symporter (NIS) as a theranostic gene allows noninvasive imaging of MSC biodistribution and transgene expression before therapeutic radioiodine application. We have previously shown that linking therapeutic transgene expression to induction of the chemokine CCL5/RANTES allows a more focused expression within primary tumors, as the adoptively transferred MSC develop carcinoma-associated fibroblast-like characteristics. Although RANTES/CCL5-NIS targeting has shown efficacy in the treatment of primary tumors, it was not clear if it would also be effective in controlling the growth of metastatic disease. To expand the potential range of tumor targets, we investigated the biodistribution and tumor recruitment of MSCs transfected with NIS under control of the RANTES/CCL5 promoter (RANTES-NIS-MSC) in a colon cancer liver metastasis mouse model established by intrasplenic injection of the human colon cancer cell line LS174t. RANTES-NIS-MSCs were injected intravenously, followed by (123)I scintigraphy, (124)I PET imaging, and (131)I therapy. Results show robust MSC recruitment with RANTES/CCL5-promoter activation within the stroma of liver metastases as evidenced by tumor-selective iodide accumulation, immunohistochemistry, and real-time polymerase chain reaction. Therapeutic application of (131)I in RANTES-NIS-MSC-treated mice resulted in a significant delay in tumor growth and improved overall survival. This novel gene therapy approach opens the prospect of NIS-mediated radionuclide therapy of metastatic cancer after MSC-mediated gene delivery.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Sodium iodide, puriss., meets analytical specification of Ph. Eur., BP, USP, 99-100.5% (calc. to the dried substance)
Sigma-Aldrich
Sodium iodide, puriss. p.a., ≥99.0% (AT)
Sigma-Aldrich
Sodium iodide, ACS reagent, ≥99.5%
Sigma-Aldrich
Sodium iodide, ReagentPlus®, ≥99%
Sigma-Aldrich
Sodium iodide, anhydrous, free-flowing, Redi-Dri, ACS reagent, ≥99.5%
Sigma-Aldrich
Sodium iodide, Vetec, reagent grade
Sigma-Aldrich
Sodium iodide, anhydrous, free-flowing, Redi-Dri, ReagentPlus®, ≥99%
Sigma-Aldrich
Phenylacetic acid, ≥99%, FCC, FG
Sigma-Aldrich
Sodium iodide, ≥99.99% trace metals basis
Sigma-Aldrich
Sodium iodide, 99.999% trace metals basis
Sigma-Aldrich
Phenylacetic acid, 99%
Sigma-Aldrich
Sodium iodide, AnhydroBeads, −10 mesh, 99.999% trace metals basis
Sigma-Aldrich
Xylazine, ≥99%