Department of Internal Medicine II, Ludwig-Maximilians-University, 81377 Munich, Germany.
Hum Gene Ther. 2011 Dec;22(12):1563-74. doi: 10.1089/hum.2011.041. Epub 2011 Oct 11.
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.
我们报道了新型基于线性聚乙烯亚胺（LPEI）的多聚物的诱导肿瘤选择性碘摄取和治疗效果，这些多聚物被聚乙二醇（PEG）屏蔽，并与表皮生长因子受体特异性肽 GE11（LPEI-PEG-GE11）结合。在相同的肝细胞癌（HCC）模型中，本研究的目的是评估基于伪树枝状低聚胺（G2-HD-OEI）的可生物降解纳米载体对系统性钠碘同向转运体（NIS）基因传递的潜力，并与 LPEI-PEG-GE11 进行效率和肿瘤特异性比较。用 G2-HD-OEI 转染 HCC 细胞后，与 LPEI-PEG-GE11 相比，碘摄取增加了 44 倍。静脉应用 G2-HD-OEI/NIS HCC 肿瘤后，通过（123）I 闪烁照相γ相机或单光子发射计算机断层扫描（SPECT CT）成像测量，肿瘤组织吸收剂量为 6-11% ID/g（每克肿瘤组织注射剂量的百分比），有效半衰期为 10 小时（肿瘤吸收剂量为 281 mGy/MBq），而 LPEI-PEG-GE11 的肿瘤组织吸收剂量为 6.5-9% ID/g，有效半衰期仅为 6 小时（肿瘤吸收剂量为 47 mGy/MBq）。仅进行两次 G2-HD-OEI/NIS/（131）I 应用周期后，观察到肿瘤生长明显延迟，生存率显著提高。用 LPEI-PEG-GE11/（131）I 进行四个周期后也观察到类似程度的治疗效果。这些结果清楚地表明，与 LPEI-PEG-GE11 相比，基于 OEI 接枝低聚胺的可生物降解纳米粒子在 HCC 模型中对系统性 NIS 基因转移的效率更高，具有相似的肿瘤选择性，因此代表了 NIS 介导的 HCC 放射性碘治疗的一种有前途的策略。
