Urnauer Sarah, Klutz Kathrin, Grünwald Geoffrey K, Morys Stephan, Schwenk Nathalie, Zach Christian, Gildehaus Franz-Josef, Rödl Wolfgang, Ogris Manfred, Wagner Ernst, Spitzweg Christine
Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany.
Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology and Center for Nanoscience (CeNS), LMU Munich, Germany.
J Gene Med. 2017 May;19(5). doi: 10.1002/jgm.2957.
Nonviral polymer-based gene transfer represents an adaptable system for tumor-targeted gene therapy because various design strategies of shuttle systems, together with the mechanistic concept of active tumor targeting, lead to improved gene delivery vectors resulting in higher tumor specificity, efficacy and safety.
Using the sodium iodide symporter (NIS) as a theranostic gene, nonviral gene delivery vehicles based on linear polyethylenimine (LPEI), polyethylene glycol (PEG) and coupled to the synthetic peptide B6 (LPEI-PEG-B6), which specifically binds to tumor cells, were investigated in a hepatocellular carcinoma xenograft model for tumor selectivity and transduction efficiency.
In vitro incubation of three different tumor cell lines with LPEI-PEG-B6/NIS resulted in significant increase in iodide uptake activity compared to untargeted and empty vectors. After establishment of subcutaneous HuH7 tumors, NIS-conjugated nanoparticles were injected intravenously followed by analysis of radioiodide biodistribution using I-scintigraphy showing significant perchlorate-sensitive iodide accumulation in tumors of LPEI-PEG-B6/NIS-treated mice (8.0 ± 1.5% ID/g I; biological half-life of 4 h). After four cycles of repetitive polyplex/ I applications, a significant delay of tumor growth was observed, which was associated with markedly improved survival in the therapy group.
These results clearly demonstrate that systemic in vivo NIS gene transfer using nanoparticle vectors coupled to B6 tumor targeting ligand is capable of inducing tumor-specific radioiodide uptake. This promising gene therapy approach opens the exciting prospect of NIS-mediated radionuclide therapy in metastatic cancer, together with the possibility of combining several targeting ligands to enhance selective therapeutic efficacy in a broad field of cancer types with various receptor expression profiles.
基于非病毒聚合物的基因传递代表了一种适用于肿瘤靶向基因治疗的系统，因为穿梭系统的各种设计策略，以及主动肿瘤靶向的机制概念，可产生改进的基因传递载体，从而提高肿瘤特异性、疗效和安全性。
使用碘化钠同向转运体（NIS）作为治疗诊断基因，在肝细胞癌异种移植模型中研究基于线性聚乙烯亚胺（LPEI）、聚乙二醇（PEG）并偶联合成肽B6（LPEI-PEG-B6）的非病毒基因传递载体，该载体可特异性结合肿瘤细胞，以评估其肿瘤选择性和转导效率。
与未靶向和空载体相比，用LPEI-PEG-B6/NIS体外孵育三种不同的肿瘤细胞系导致碘摄取活性显著增加。皮下接种HuH7肿瘤后，静脉注射NIS偶联的纳米颗粒，然后使用I闪烁扫描分析放射性碘生物分布，结果显示LPEI-PEG-B6/NIS处理的小鼠肿瘤中存在显著的高氯酸盐敏感性碘积累（8.0±1.5%ID/g I；生物半衰期为4小时）。在重复进行四轮多聚体/I应用后，观察到肿瘤生长明显延迟，这与治疗组的存活率显著提高相关。
这些结果清楚地表明，使用与B6肿瘤靶向配体偶联的纳米颗粒载体进行体内系统性NIS基因传递能够诱导肿瘤特异性放射性碘摄取。这种有前景的基因治疗方法为转移性癌症中NIS介导的放射性核素治疗开辟了令人兴奋的前景，同时也有可能结合多种靶向配体，以增强在具有各种受体表达谱的广泛癌症类型中的选择性治疗效果。
