Stromal Targeting of Sodium Iodide Symporter Using Mesenchymal Stem Cells Allows Enhanced Imaging and Therapy of Hepatocellular Carcinoma

Overview

Journal Hum Gene Ther

Specialties Genetics
Pharmacology

Date 2013 Feb 14

PMID 23402366

Citations 21

Authors

Kerstin Knoop

Nathalie Schwenk

Patrick Dolp

Michael J Willhauck

Christoph Zischek

Christian Zach

Markus Hacker

Burkhard Goke

Ernst Wagner

Peter J Nelson

Christine Spitzweg

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Interleukin-6-controlled, mesenchymal stem cell-based sodium/iodide symporter gene therapy improves survival of glioblastoma-bearing mice.

Kitzberger C, Shehzad K, Morath V, Spellerberg R, Ranke J, Steiger K Mol Ther Oncolytics. 2023; 30:238-253.

PMID: 37701849 PMC: 10493263. DOI: 10.1016/j.omto.2023.08.004.

Dual EGFR- and TfR-targeted gene transfer for sodium iodide symporter gene therapy of glioblastoma.

Spellerberg R, Benli-Hoppe T, Kitzberger C, Hageneier M, Schwenk N, Ozturk O Mol Ther Oncolytics. 2022; 27:272-287.

PMID: 36458201 PMC: 9709165. DOI: 10.1016/j.omto.2022.10.013.

The sodium iodide symporter (NIS) as theranostic gene: its emerging role in new imaging modalities and non-viral gene therapy.

Kitzberger C, Spellerberg R, Morath V, Schwenk N, Schmohl K, Schug C EJNMMI Res. 2022; 12(1):25.

PMID: 35503582 PMC: 9065223. DOI: 10.1186/s13550-022-00888-w.

Mesenchymal Stem Cells Delivery in Individuals with Different Pathologies: Multimodal Tracking, Safety and Future Applications.

Belmar-Lopez C, Vassaux G, Medel-Martinez A, Burnet J, Quintanilla M, Cajal S Int J Mol Sci. 2022; 23(3).

PMID: 35163605 PMC: 8835939. DOI: 10.3390/ijms23031682.

Selective sodium iodide symporter () genetherapy of glioblastoma mediatedby EGFR-targeted lipopolyplexes.

Spellerberg R, Benli-Hoppe T, Kitzberger C, Berger S, Schmohl K, Schwenk N Mol Ther Oncolytics. 2021; 23:432-446.

PMID: 34853814 PMC: 8604759. DOI: 10.1016/j.omto.2021.10.011.

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