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.

Systemic Image-Guided Liver Cancer Radiovirotherapy Using Dendrimer-Coated Adenovirus Encoding the Sodium Iodide Symporter as Theranostic Gene

“…**P # 0.01. application of radioiodine (13). Our previous work convincingly demonstrated the proof of principle of the NIS gene therapy concept (3,8,9,11,12,14,15). The next step toward clinical application has to be the development of gene-transfer vehicles that are able to promote targeted and efficient systemic NIS gene transfer with the potential to reach tumor metastases.…”

“…The enhanced permeability and retention effect is a phenomenon that describes the passive accumulation of macromolecules within the tumor stroma due to leaky tumor vasculature combined with inadequate lymphatic drainage (15) and is the basis for the observed passive tumor-targeting of dendrimer-coated adenovirus vectors after systemic delivery. Our dual-targeting strategy was further enhanced by an active transcriptional tumor-targeting using the alpha feroprotein promoter for tumor-selective replication and NIS expression.…”

Establishment of an Effective Radioiodide Thyroid Ablation Protocol in Mice

“…We and others have shown the potential of NIS as a reporter gene for molecular imaging with a broad range of possible applications [13,14,15,16,17,18,19,20,21,22,23,24]. In our previous work, the role of NIS as a reporter gene allowed noninvasive multimodal imaging of functional NIS expression by 99m Tc or 123 I scintigraphy as well as SPECT and 124 I PET imaging that correlated well with the results of ex vivo gamma counter measurements as well as NIS mRNA and protein analysis.…”

PolyIC GE11 polyplex inhibits EGFR‐overexpressing tumors

“…Conjugation of GE11 to polyethyleneimine-polyethyleneglycol (PEI-PEG-GE11, PPGE11) enabled the targeting of EGFR over-expressing tumors in vitro and in vivo (9,10). We have recently shown that local and systemic application of EGFR-targeted poly Inosine/Cytosine (PolyIC) by PEI-PEG-EGF (PP-EGF) eradicates several pre-established EGFR-over-expressing tumor models (2,3).…”