title: 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.affiliation: Department of Internal Medicine II, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Klutz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Willhauck
authors.forename: Christian
authors.initials: C
authors.lastname: Dohmen
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wunderlich
authors.forename: Kerstin
authors.initials: K
authors.lastname: Knoop
authors.forename: Christian
authors.initials: C
authors.lastname: Zach
authors.forename: Reingard
authors.initials: R
authors.lastname: Senekowitsch-Schmidtke
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Gildehaus
authors.forename: Sibylle
authors.initials: S
authors.lastname: Ziegler
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fürst
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.forename: Manfred
authors.initials: M
authors.lastname: Ogris
authors.forename: Christine
authors.initials: C
authors.lastname: Spitzweg
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D016503:Drug Delivery Systems; D005455:Fluorescent Antibody Technique; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007124:Immunoenzyme Techniques; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D064847:Multimodal Imaging; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011094:Polyethyleneimine / Q000008:administration & dosage; D049268:Positron-Emission Tomography; D012333:RNA, Messenger / Q000235:genetics; D011878:Radiotherapy; D060888:Real-Time Polymerase Chain Reaction; D027981:Symporters / Q000235:genetics*; D014057:Tomography, X-Ray Computed; D014407:Tumor Cells, Cultured; D000099209:Sodium-Iodide Symporters
chemical_list: D007457:Iodine Radioisotopes; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D012333:RNA, Messenger; D027981:Symporters; D000099209:Sodium-Iodide Symporters