Zhang Xiangyu, Wang Qi, Qin Liubing, Fu Hao, Fang Yiwei, Han Baoshan, Duan Yourong
a State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China and.
b Department of General Surgery , School of Medicine, Xinhua Hospital, Shanghai Jiao Tong University , Shanghai , China.
Drug Deliv. 2016 Oct;23(8):2936-2945. doi: 10.3109/10717544.2015.1126769. Epub 2016 Jan 7.
Nanoparticles (NPs) have been widely used as carriers to deliver siRNA and chemotherapeutic agents. Bcl-2 siRNA has been widely used to induce cancer cell apoptosis, and doxorubicin (Dox) can destroy cancer cells by binding with cancer cell DNA.
To investigate the therapeutic effect on lung cancer of simultaneously delivering Dox and Bcl-2-siRNA using epidermal growth factor (EGF) modified monomethoxy (polyethylene glycol)-poly (D, L-lactide-co-glycolide)-poly(L-lysine) (mPEG-PLGA-PLL, PEAL) NPs (EGF-PEAL).
EGF-PEAL NPs were characterized with respect to size, zeta potential and morphology. Cytotoxicity and drug (or siRNA) loading capacity of EGF-PEAL NPs were analyzed. Cellular uptake, drug release profile, cell killing effects of Dox and Bcl-2-siRNA-loaded EGF-PEAL NPs were assessed. Biodistribution and therapeutic effects of Dox and Bcl-2-siRNA EGF-PEAL NPs were evaluated in H1299 tumor-bearing mice.
EGF-PEAL NPs or PEAL NPs had nearly negligible cytotoxicity toward H1299 cells. Dox and Bcl-2-siRNA gradually released from EGF-PEAL NPs and exhibited sustained release patterns. Dox and Bcl-2-siRNA-loaded NPs were taken up by cells and induced the apoptosis of H1299 cells more effectively than using Dox or Bcl-2 siRNA alone. With the intravenous injection of PEAL NPs into H1299 xenografted mice, we found that combination treatment suppressed lung cancer growth and reduced Bcl-2 expression in tumor tissue, and EGF-PEAL NPs concentrated in lung tumor much more than non-targeted PEAL NPs.
We conclude that co-delivery of Dox and Bcl-2-siRNA by tumor-targeted EGF-PEAL NPs could significantly inhibit lung cancer growth.
纳米颗粒（NPs）已被广泛用作递送小干扰RNA（siRNA）和化疗药物的载体。Bcl-2 siRNA已被广泛用于诱导癌细胞凋亡，而阿霉素（Dox）可通过与癌细胞DNA结合来破坏癌细胞。
研究使用表皮生长因子（EGF）修饰的单甲氧基（聚乙二醇）-聚（D，L-丙交酯-共-乙交酯）-聚（L-赖氨酸）（mPEG-PLGA-PLL，PEAL）纳米颗粒（EGF-PEAL）同时递送Dox和Bcl-2-siRNA对肺癌的治疗效果。
对EGF-PEAL纳米颗粒的大小、zeta电位和形态进行表征。分析EGF-PEAL纳米颗粒的细胞毒性和药物（或siRNA）负载能力。评估负载Dox和Bcl-2-siRNA的EGF-PEAL纳米颗粒的细胞摄取、药物释放曲线、细胞杀伤作用。在荷H1299肿瘤小鼠中评估Dox和Bcl-2-siRNA EGF-PEAL纳米颗粒的生物分布和治疗效果。
EGF-PEAL纳米颗粒或PEAL纳米颗粒对H1299细胞的细胞毒性几乎可以忽略不计。Dox和Bcl-2-siRNA从EGF-PEAL纳米颗粒中逐渐释放，并呈现出持续释放模式。负载Dox和Bcl-2-siRNA的纳米颗粒被细胞摄取，并比单独使用Dox或Bcl-2 siRNA更有效地诱导H1299细胞凋亡。通过向H1299异种移植小鼠静脉注射PEAL纳米颗粒，我们发现联合治疗抑制了肺癌生长并降低了肿瘤组织中Bcl-2的表达，并且EGF-PEAL纳米颗粒在肺肿瘤中的聚集比非靶向PEAL纳米颗粒多得多。
我们得出结论，肿瘤靶向的EGF-PEAL纳米颗粒共递送Dox和Bcl-2-siRNA可显著抑制肺癌生长。
