International Joint Cancer Institute, The Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China; National Engineering Research Center for Antibody Medicine & Shanghai Key Laboratory of Cell Engineering and Antibody, 399 Libing Road, Shanghai 201203, China.
Biomaterials. 2013 Dec;34(38):10084-98. doi: 10.1016/j.biomaterials.2013.08.088. Epub 2013 Sep 20.
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.
化疗联合基因治疗受到了广泛关注。我们开发了靶向 LPD（脂质体-聚阳离子-DNA 复合物），它与抗表皮生长因子受体（EGFR）Fab'偶联，共递送阿霉素（ADR）和核糖核苷酸还原酶 M2（RRM2）siRNA（ADR-RRM2-TLPD），以实现对 EGFR 过表达的人肝癌（HCC）的联合治疗效果。研究了 ADR-RRM2-TLPD 的抗肿瘤活性和机制。结果表明，RRM2 在 HCC 中的表达高于非 HCC 组织，RRM2 siRNA 抑制 HCC 细胞增殖，表明 RRM2 是 HCC 治疗的候选靶点。ADR-RRM2-TLPD 特异性地将 ADR 和 RRM2 siRNA 递送至 EGFR 过表达的 HCC 细胞，无论是在体外还是体内，都具有高效性，与单药负载或非靶向对照相比，增强了治疗效果（细胞毒性、凋亡和衰老诱导活性），包括 ADR-NC-TLPD（靶向 LPD 共递 ADR 和阴性对照 siRNA）、RRM2-TLPD（靶向 LPD 递送 RRM2 siRNA）和 ADR-RRM2-NTLPD（非靶向 LPD 共递 ADR 和 RRM2 siRNA）。机制研究表明，p21 参与了 ADR-RRM2-TLPD 的联合治疗效果。用 ADR-RRM2-TLPD 治疗的荷瘤小鼠的原位 HCC 的平均重量明显轻于用其他对照治疗的小鼠。因此，ADR-RRM2-TLPD 代表了一种治疗 EGFR 过表达 HCC 的联合治疗策略。
