Klutz Kathrin, Russ Verena, Willhauck Michael J, Wunderlich Nathalie, Zach Christian, Gildehaus Franz Josef, Göke Burkhard, Wagner Ernst, Ogris Manfred, Spitzweg Christine
Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany.
Clin Cancer Res. 2009 Oct 1;15(19):6079-86. doi: 10.1158/1078-0432.CCR-09-0851. Epub 2009 Sep 29.
We recently reported the significant therapeutic efficacy of radioiodine therapy in various tumor mouse models following transcriptionally targeted sodium iodide symporter (NIS) gene transfer. These studies showed the high potential of NIS as a novel diagnostic and therapeutic gene for the treatment of extrathyroidal tumors. As a next crucial step towards clinical application of NIS-mediated radionuclide therapy we aim at systemic delivery of the NIS gene to target extrathyroidal tumors even in the metastatic stage.
In the current study, we used synthetic polymeric vectors based on pseudodendritic oligoamines with high intrinsic tumor affinity (G2-HD-OEI) to target a NIS-expressing plasmid (CMV-NIS-pcDNA3) to neuroblastoma (Neuro2A) cells.
Incubation with NIS-containing polyplexes (G2-HD-OEI/NIS) resulted in a 51-fold increase in perchlorate-sensitive iodide uptake activity in Neuro2A cells in vitro. Through (123)I-scintigraphy and ex vivo gamma counting Neuro2A tumors in syngeneic A/J mice were shown to accumulate 8% to 13% ID/g (123)I with a biological half-life of 13 hours, resulting in a tumor-absorbed dose of 247 mGy/MBq (131)I after i.v. application of G2-HD-OEI/NIS. Nontarget organs, including liver, lung, kidneys, and spleen revealed no significant iodide uptake. Moreover, two cycles of systemic NIS gene transfer followed by (131)I application (55.5 MBq) resulted in a significant delay in tumor growth associated with markedly improved survival.
In conclusion, our data clearly show the high potential of novel pseudodendritic polymers for tumor-specific NIS gene delivery after systemic application, opening the prospect of targeted NIS-mediated radionuclide therapy of nonthyroidal tumors even in metastatic disease.
我们最近报道了转录靶向碘化钠转运体（NIS）基因转移后，放射性碘疗法在各种肿瘤小鼠模型中的显著治疗效果。这些研究表明，NIS作为一种用于治疗甲状腺外肿瘤的新型诊断和治疗基因具有很高的潜力。作为迈向NIS介导的放射性核素疗法临床应用的下一个关键步骤，我们旨在将NIS基因全身递送至即使处于转移阶段的甲状腺外肿瘤靶点。
在当前研究中，我们使用基于具有高内在肿瘤亲和力的假树枝状低聚胺的合成聚合物载体（G2-HD-OEI），将表达NIS的质粒（CMV-NIS-pcDNA3）靶向至神经母细胞瘤（Neuro2A）细胞。
与含NIS的多聚体（G2-HD-OEI/NIS）孵育后，Neuro2A细胞在体外对高氯酸盐敏感的碘摄取活性增加了51倍。通过（123）I闪烁扫描和体外γ计数，同基因A/J小鼠体内的Neuro2A肿瘤显示出每克摄取8%至13%注射剂量（ID/g）的（123）I，生物半衰期为13小时，静脉注射G2-HD-OEI/NIS后，肿瘤吸收剂量为247 mGy/MBq（131）I。包括肝脏、肺、肾脏和脾脏在内的非靶器官未显示出明显的碘摄取。此外，两个周期的全身NIS基因转移后再应用（131）I（55.5 MBq）导致肿瘤生长显著延迟，同时生存率明显提高。
总之，我们的数据清楚地表明，新型假树枝状聚合物在全身应用后具有将NIS基因特异性递送至肿瘤的高潜力，为即使在转移性疾病中对非甲状腺肿瘤进行靶向NIS介导的放射性核素治疗开辟了前景。
