Inhibition of hepatocellular carcinoma growth using immunoliposomes for co-delivery of adriamycin and ribonucleotide reductase M2 siRNA
Inhibition of hepatocellular carcinoma growth using immunoliposomes for co-delivery of adriamycin and ribonucleotide reductase M2 siRNA
复制标题
使用免疫脂质体共同递送阿霉素和核糖核苷酸还原酶 M2 siRNA 抑制肝细胞癌生长
DOI：
10.1016/j.biomaterials.2013.08.088
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发表时间：
2013-12-01
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;Chen, Huaiwen;Guo, Yajun
化疗与基因治疗相结合已受到高度重视。我们制备了靶向的脂质体-聚阳离子-DNA复合体(LPD)，并将其与抗EGFR(表皮生长因子受体)Fab‘共传递阿霉素(ADR)和核糖核苷酸还原酶M2(RRM2)siRNA(ADR-RRM2-TLPD)偶联，以达到对EGFR高表达的人肝细胞癌(HCC)的联合治疗作用。研究了ADR-RRM2-TLPD的抗肿瘤活性及其机制。结果表明，RRM2在肝癌组织中的表达高于非肝癌组织，且RRM2 siRNA抑制了肝癌细胞的增殖，提示RRM2是治疗肝癌的候选靶点。在体内外，ADR-RRM2-TLPD将ADR和RRM2 siRNA靶向EGFR高表达的肝癌细胞，与单一载药或非靶向对照相比，包括靶向LPD联合传递ADR和阴性对照siRNA(靶向LPD)、RRM2-TLPD(靶向LPD联合传递RRM2 siRNA)和ADR-RRM2-NTLPD(非靶向LPD联合传递ADR和RRM2 siRNA)，产生了更强的治疗效果(细胞毒性、细胞凋亡和衰老活性)。机制研究表明，p21参与了ADR-RRM2-TLPD的联合治疗作用。ADR-RRM2-TLPD治疗组小鼠原位肝癌的平均重量明显轻于其他对照组。因此，ADR-RRM2-TLPD为联合治疗高表达EGFR的肝癌提供了一种潜在的策略。(C)2013爱思唯尔有限公司。保留所有权利。
The chemotherapy combined with gene therapy has received great attention. We developed targeted LPD (liposome-polycation-DNA complex) conjugated with anti-EGFR (epidermal growth factor receptor) Fab' co-delivering adriamycin (ADR) and ribonucleotide reductase M2 (RRM2) siRNA (ADR-RRM2-TLPD), to achieve combined therapeutic effects in human hepatocellular carcinoma (HCC) overexpressing EGFR. The antitumor activity and mechanisms of ADR-RRM2-TLPD were investigated. The results showed that RRM2 expression was higher in HCC than in non-HCC tissue, and RRM2 siRNA inhibited HCC cell proliferation, suggesting that RRM2 is a candidate target for HCC therapy. ADR-RRM2-TLPD delivered ADR and RRM2 siRNA to EGFR overexpressing HCC cells specifically and efficiently both in vitro and in vivo, resulting in enhanced therapeutic effects (cytotoxicity, apoptosis and senescence-inducing activity) compared with single-drug loaded or non-targeted controls, including ADR-NC-TLPD (targeted LPD co-delivering ADR and negative control siRNA), RRM2-TLPD (targeted LPD delivering RRM2 siRNA) and ADR-RRM2-NTLPD (non-targeted LPD co-delivering ADR and RRM2 siRNA). Mechanism studies showed that p21 is involved in the combined therapeutic effect of ADR-RRM2-TLPD. The average weight of the orthotopic HCC in mice treated with ADR-RRM2-TLPD was significantly lighter than that of mice treated with other controls. Thus, ADR-RRM2-TLPD represents a potential strategy for combined therapy of HCC overexpressing EGFR. (C) 2013 Elsevier Ltd. All rights reserved.