Kathrin A Schmohl1, Patrick Dolp1, Christina Schug1, Kerstin Knoop1, Kathrin Klutz1, Nathalie Schwenk1, Peter Bartenstein2, Peter J Nelson1, Manfred Ogris3, Ernst Wagner4, Christine Spitzweg1. 1. 1 Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany . 2. 2 Department of Nuclear Medicine, University Hospital of Munich , LMU Munich, Munich, Germany . 3. 3 Department of Pharmaceutical Chemistry, Laboratory of MacroMolecular Cancer Therapeutics (MMCT), University of Vienna , Vienna, Austria . 4. 4 Department of Pharmaceutical Biotechnology, Department of Pharmacy, Center for System-Based Drug Research and Center for Nanoscience , LMU Munich, Munich, Germany .
Abstract
BACKGROUND: Anaplastic thyroid carcinoma (ATC), the most aggressive form of thyroid cancer, is unresponsive to radioiodine therapy. The current study aimed to extend the diagnostic and therapeutic application of radioiodine beyond the treatment of differentiated thyroid cancer by targeting the functional sodium-iodide symporter (NIS) to ATC. METHODS: The study employed nanoparticle vectors (polyplexes) based on linear polyethylenimine (LPEI), shielded by polyethylene glycol (PEG) and coupled to the synthetic peptide GE11 as an epidermal growth factor receptor (EGFR)-specific ligand in order to target a NIS-expressing plasmid (LPEI-PEG-GE11/NIS) to EGFR overexpressing human thyroid carcinoma cell lines. Using ATC xenograft mouse models, transfection efficiency by 123I scintigraphy and potential for systemic radioiodine therapy after systemic polyplex application were evaluated. RESULTS: In vitro iodide uptake studies in SW1736 and Hth74 ATC cells, and, for comparison, in more differentiated follicular (FTC-133) and papillary (BCPAP) thyroid carcinoma cells demonstrated high transfection efficiency and EGFR-specificity of LPEI-PEG-GE11/NIS that correlated well with EGFR expression levels. After systemic polyplex injection, in vivo 123I gamma camera imaging revealed significant tumor-specific accumulation of radioiodine in an SW1736 and an Hth74 xenograft mouse model. Radioiodine accumulation was found to be higher in SW1736 tumors, reflecting in vitro results, EGFR expression levels, and results from ex vivo analysis of NIS staining. Administration of 131I in LPEI-PEG-GE11/NIS-treated SW1736 xenograft mice resulted in significantly reduced tumor growth associated with prolonged survival compared to control animals. CONCLUSIONS: The data open the exciting prospect of NIS-mediated radionuclide imaging and therapy of ATC after non-viral reintroduction of the NIS gene. The high tumor specificity after systemic application makes the strategy an attractive alternative for the treatment of highly metastatic ATC.
BACKGROUND:Anaplastic thyroid carcinoma (ATC), the most aggressive form of thyroid cancer, is unresponsive to radioiodine therapy. The current study aimed to extend the diagnostic and therapeutic application of radioiodine beyond the treatment of differentiated thyroid cancer by targeting the functional sodium-iodide symporter (NIS) to ATC. METHODS: The study employed nanoparticle vectors (polyplexes) based on linear polyethylenimine (LPEI), shielded by polyethylene glycol (PEG) and coupled to the synthetic peptide GE11 as an epidermal growth factor receptor (EGFR)-specific ligand in order to target a NIS-expressing plasmid (LPEI-PEG-GE11/NIS) to EGFR overexpressing humanthyroid carcinoma cell lines. Using ATC xenograft mouse models, transfection efficiency by 123I scintigraphy and potential for systemic radioiodine therapy after systemic polyplex application were evaluated. RESULTS: In vitro iodide uptake studies in SW1736 and Hth74 ATC cells, and, for comparison, in more differentiated follicular (FTC-133) and papillary (BCPAP) thyroid carcinoma cells demonstrated high transfection efficiency and EGFR-specificity of LPEI-PEG-GE11/NIS that correlated well with EGFR expression levels. After systemic polyplex injection, in vivo 123I gamma camera imaging revealed significant tumor-specific accumulation of radioiodine in an SW1736 and an Hth74 xenograft mouse model. Radioiodine accumulation was found to be higher in SW1736 tumors, reflecting in vitro results, EGFR expression levels, and results from ex vivo analysis of NIS staining. Administration of 131I in LPEI-PEG-GE11/NIS-treated SW1736 xenograft mice resulted in significantly reduced tumor growth associated with prolonged survival compared to control animals. CONCLUSIONS: The data open the exciting prospect of NIS-mediated radionuclide imaging and therapy of ATC after non-viral reintroduction of the NIS gene. The high tumor specificity after systemic application makes the strategy an attractive alternative for the treatment of highly metastatic ATC.
Authors: Sabine Wächter; Alexander I Damanakis; Moritz Elxnat; Silvia Roth; Annette Wunderlich; Frederik A Verburg; Sebastian A Fellinger; Detlef K Bartsch; Pietro Di Fazio Journal: J Clin Med Date: 2018-03-21 Impact factor: 4.241
Authors: Carolin Kitzberger; Rebekka Spellerberg; Volker Morath; Nathalie Schwenk; Kathrin A Schmohl; Christina Schug; Sarah Urnauer; Mariella Tutter; Matthias Eiber; Franz Schilling; Wolfgang A Weber; Sibylle Ziegler; Peter Bartenstein; Ernst Wagner; Peter J Nelson; Christine Spitzweg Journal: EJNMMI Res Date: 2022-05-03 Impact factor: 3.434
Authors: Mariella Tutter; Christina Schug; Kathrin A Schmohl; Sarah Urnauer; Nathalie Schwenk; Matteo Petrini; Wouter J M Lokerse; Christian Zach; Sibylle Ziegler; Peter Bartenstein; Wolfgang A Weber; Ernst Wagner; Lars H Lindner; Peter J Nelson; Christine Spitzweg Journal: Theranostics Date: 2020-03-15 Impact factor: 11.556