Image-guided tumor-selective radioiodine therapy of liver cancer after systemic nonviral delivery of the sodium iodide symporter gene.

Abstract

We reported the induction of tumor-selective iodide uptake and therapeutic efficacy of (131)I in a hepatocellular carcinoma (HCC) xenograft mouse model, using novel polyplexes based on linear polyethylenimine (LPEI), shielded by polyethylene glycol (PEG), and coupled with the epidermal growth factor receptor-specific peptide GE11 (LPEI-PEG-GE11). The aim of the current study in the same HCC model was to evaluate the potential of biodegradable nanoparticle vectors based on pseudodendritic oligoamines (G2-HD-OEI) for systemic sodium iodide symporter (NIS) gene delivery and to compare efficiency and tumor specificity with LPEI-PEG-GE11. Transfection of HCC cells with NIS cDNA, using G2-HD-OEI, resulted in a 44-fold increase in iodide uptake in vitro as compared with a 22-fold increase using LPEI-PEG-GE11. After intravenous application of G2-HD-OEI/NIS HCC tumors accumulated 6-11% ID/g (123)I (percentage of the injected dose per gram tumor tissue) with an effective half-life of 10 hr (tumor-absorbed dose, 281 mGy/MBq) as measured by (123)I scintigraphic gamma camera or single-photon emission computed tomography computed tomography (SPECT CT) imaging, as compared with 6.5-9% ID/g with an effective half-life of only 6 hr (tumor-absorbed dose, 47 mGy/MBq) for LPEI-PEG-GE11. After only two cycles of G2-HD-OEI/NIS/(131)I application, a significant delay in tumor growth was observed with markedly improved survival. A similar degree of therapeutic efficacy had been observed after four cycles of LPEI-PEG-GE11/(131)I. These results clearly demonstrate that biodegradable nanoparticles based on OEI-grafted oligoamines show increased efficiency for systemic NIS gene transfer in an HCC model with similar tumor selectivity as compared with LPEI-PEG-GE11, and therefore represent a promising strategy for NIS-mediated radioiodine therapy of HCC.

• Authors: Kathrin Klutz, Michael J Willhauck, Christian Dohmen, Nathalie Wunderlich, Kerstin Knoop, Christian Zach, Reingard Senekowitsch-Schmidtke, Franz-Josef Gildehaus, Sibylle Ziegler, Sebastian Fürst, Burkhard Göke, Ernst Wagner, Manfred Ogris, Christine Spitzweg
• Journal: Human gene therapy (Hum Gene Ther) Vol. 22 Issue 12 Pg. 1563-74 (Dec 2011) ISSN: 1557-7422 [Electronic] United States
• PMID: 21851208 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Iodine Radioisotopes
• RNA, Messenger
• Symporters
• Polyethylene Glycols
• sodium-iodide symporter
• Polyethyleneimine

Topics

• Animals
• Blotting, Western
• Carcinoma, Hepatocellular (genetics, pathology, therapy)
• Cell Proliferation
• Combined Modality Therapy
• Drug Delivery Systems
• Fluorescent Antibody Technique
• Gene Transfer Techniques
• Genetic Therapy
• Genetic Vectors (administration & dosage)
• Humans
• Image Processing, Computer-Assisted
• Immunoenzyme Techniques
• Iodine Radioisotopes (pharmacokinetics, therapeutic use)
• Liver Neoplasms (genetics, pathology, therapy)
• Mice
• Mice, Nude
• Multimodal Imaging
• Polyethylene Glycols (administration & dosage)
• Polyethyleneimine (administration & dosage)
• Positron-Emission Tomography
• RNA, Messenger (genetics)
• Radiotherapy
• Real-Time Polymerase Chain Reaction
• Symporters (genetics)
• Tomography, X-Ray Computed
• Tumor Cells, Cultured