EGFR-specific PEGylated immunoliposomes for active siRNA delivery in hepatocellular carcinoma
EGFR-specific PEGylated immunoliposomes for active siRNA delivery in hepatocellular carcinoma
复制标题
用于肝细胞癌活性 siRNA 递送的 EGFR 特异性聚乙二醇化免疫脂质体。
DOI：
10.1016/j.biomaterials.2011.09.035
复制
发表时间：
2012-01-01
期刊：
影响因子：
14
通讯作者：
Guo, Yajun
中科院分区：
文献类型：
--
作者：
Gao, Jie;Yu, Yongsheng;Guo, Yajun
开发用于全身siRNA（小干扰RNA）递送的免疫脂质体是非常需要的。我们之前报道了靶向LPD（脂质体多阳离子DNA复合体）结合抗表皮生长因子受体Fab' （TLPD-FCC）用于siRNA递送的发展，其在egfr过表达的乳腺癌中显示出优越的基因沉默活性。然而，TLPD-FCC在egfr过表达的肝细胞癌（HCC）中并没有达到令人满意的基因沉默活性。本研究对TLPD-FCC进行了一些修饰，包括提高抗体偶联效率和降低PEGylation程度，以增加HCC中的基因沉默活性。所得到的优化脂质体称为TLPD-FP75，可有效结合并递送至egfr过表达的HCC，与非靶向LPD （NTLPD-FP75）相比，其基因沉默活性增强。体内组织分布显示，TLPD-FP75在小鼠原位肝癌模型中的积累量高于NTLPD-FP75。共聚焦显微镜证实了肝癌细胞对TLPD-FP75的摄取促进。为了研究体内基因沉默活性，我们将TLPD-FP75静脉注射到原位肝癌小鼠体内。结果显示，TLPD-FP75能有效抑制荧光素酶的表达，而NTLPD-FP75几乎没有沉默。TLPD-FP75被证明在HCC中具有强大的基因沉默活性，并可能增加HCC基因治疗的可行性。(C) 2011 Elsevier Ltd.版权所有。
The development of immunoliposomes for systemic siRNA (small interfering RNA) delivery is highly desired. We reported previously the development of targeted LPD (liposome polycation DNA complex) conjugated with anti-EGFR (epidermal growth factor receptor) Fab' (TLPD-FCC) for siRNA delivery, which showed superior gene silencing activity in EGFR-overexpressing breast cancers. However, TLPD-FCC did not achieve satisfactory gene silencing activity in EGFR-overexpressing hepatocellular carcinoma (HCC). In this study, some modifications including increased antibody conjugation efficiency and reduced PEGylation degree were made to TLPD-FCC to increase gene silencing activity in HCC. The resultant optimized liposomes denoted as TLPD-FP75 efficiently bound and delivered to EGFR-overexpressing HCC, resulting in enhanced gene silencing activity compared to untargeted LPD (NTLPD-FP75). Tissue distribution in vivo revealed that the accumulation of TLPD-FP75 was higher than NTLPD-FP75 in orthotopic HCC model of mice. The promoted uptake of TLPD-FP75 in HCC cells was confirmed by confocal microscopy. To investigate the in vivo gene silencing activity, we administered TLPD-FP75 by intravenous injections into mice bearing orthotopic HCC. The results showed TLPD-FP75 potently suppressed luciferase expression, while little silencing was observed in NTLPD-FP75. TLPD-FP75 was demonstrated to possess potent gene silencing activity in HCC and will potentially increase the feasibility of HCC gene therapy. (C) 2011 Elsevier Ltd. All rights reserved.