Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230027, P. R. China.
Adv Healthc Mater. 2014 Nov;3(11):1792-803. doi: 10.1002/adhm.201400037. Epub 2014 Jun 20.
Patients with Her2-overexpressing (Her2(+)) breast cancers generally have a poorer prognosis due to the high aggressiveness and chemoresistance of the disease. Small interfering RNA (siRNA) targeting the gene encoding polo-like kinase 1 (Plk1; siPlk1) has emerged as an efficient therapeutic agent for Her2(+) breast cancers. Poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-PLA)-based nanoparticles for siRNA delivery were previously developed and optimized. In this study, for targeted delivery of siPlk1 to Her2(+) breast cancer, anti-Her2 single-chain variable fragment antibody (ScFv(Her2))-decorated PEG-PLA-based nanoparticles with si Plk1 encapsulation (ScFv(Her2)-NP(si) Plk1) are developed. With the rationally designed conjugation site, ScFv(Her2)-NP(siRNA) can specifically bind to the Her2 antigen overexpressed on the surface of Her2(+) breast cancer cells. Therefore, ScFv(Her2)-NP(si) Plk1 exhibits improved cellular uptake, promoted Plk1 silencing efficiency, and induced enhanced tumor cell apoptosis in Her2(+) breast cancer cells, when compared with nontargeted NP(si) Plk1. More importantly, ScFv(Her2)-NP(siRNA) markedly enhances the accumulation of siRNA in Her2(+) breast tumor tissue, and remarkably improves the efficacy of tumor suppression. Dose-dependent anti-tumor efficacy further demonstrates that ScFvHer2 -decorated PEG-PLA-based nanoparticles with siPlk1 encapsulation can significantly enhance the inhibition of Her2(+) breast tumor growth and reduce the dose of injected siRNA. These results suggest that ScFvHer2 -decorated PEG-PLA-based nanoparticles show great potential for targeted RNA interference therapy of Her2(+) breast tumor.
患有人表皮生长因子受体 2（HER2）过表达（HER2(+)）的乳腺癌患者预后通常较差，这是由于疾病的高度侵袭性和化疗耐药性。针对编码丝氨酸/苏氨酸激酶 polo 样激酶 1（Plk1；siPlk1）的基因的小干扰 RNA（siRNA）已成为治疗 HER2(+)乳腺癌的有效治疗剂。先前已经开发和优化了用于 siRNA 递送的聚乙二醇-嵌段-聚（D，L-丙交酯）（PEG-PLA）为基础的纳米粒子。在这项研究中，为了将 siPlk1 靶向递送至 HER2(+)乳腺癌，开发了包封 siPlk1 的抗 HER2 单链可变片段抗体（ScFv(Her2)）修饰的 PEG-PLA 为基础的纳米粒子（ScFv(Her2)-NP(si) Plk1）。通过合理设计的缀合位点，ScFv(Her2)-NP(siRNA)可以特异性结合到 HER2(+)乳腺癌细胞表面过表达的 HER2 抗原上。因此，与非靶向 NP(si) Plk1 相比，ScFv(Her2)-NP(si) Plk1 表现出增强的细胞摄取、促进 Plk1 沉默效率，并诱导 HER2(+)乳腺癌细胞中增强的肿瘤细胞凋亡。更重要的是，ScFv(Her2)-NP(siRNA)显著增加了 HER2(+)乳腺癌肿瘤组织中 siRNA 的积累，并显著提高了肿瘤抑制的疗效。剂量依赖性的抗肿瘤疗效进一步证明，用 siPlk1 包封的 ScFvHer2 修饰的 PEG-PLA 为基础的纳米粒子可以显著增强对 HER2(+)乳腺癌肿瘤生长的抑制作用，并减少注射的 siRNA 剂量。这些结果表明，ScFvHer2 修饰的 PEG-PLA 为基础的纳米粒子具有靶向 RNA 干扰治疗 HER2(+)乳腺癌的巨大潜力。
