School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.
Department of Sciences, Faculty of Natural and Applied Science, Notre Dame University (Louaize), Zouk Mosbeh, Lebanon; Department of Chemistry and the Tyndall National Institute, University College Cork, Cork, Ireland.
Eur J Pharm Biopharm. 2019 Apr;137:56-67. doi: 10.1016/j.ejpb.2019.02.013. Epub 2019 Feb 16.
Small interfering RNA (siRNA) has recently illustrated therapeutic potential for malignant disorders. However, the clinical application of siRNA-based therapeutics is significantly retarded by the paucity of successful delivery systems. Recently, multifunctional gold nanoparticles (AuNPs) as non-viral delivery carriers have shown promise for transporting chemotherapeutics, proteins/peptides, and genes. In this study, AuNPs capped with polyethylenimine (PEI) and PEGylated anisamide (a ligand known to target the sigma receptor) have been developed to produce a range of positively charged anisamide-targeted PEGylated AuNPs (namely Au-PEI-PEG-AA). The anisamide-targeted AuNPs effectively complexed siRNA via electrostatic interaction, and the resultant complex (Au-PEI-PEG-AA.siRNA) illustrated favourable physicochemical characteristics, including particle size, surface charge, and stability. In vitro, anisamide-targeted AuNPs selectively bound to human prostate cancer PC-3 cells, inducing efficient endosomal escape of siRNA, and effective downregulation of the RelA gene. In vivo, prolonged systemic exposure of siRNA was achieved by anisamide-targeted AuNPs resulting in significant tumour growth suppression in a PC3 xenograft mouse model without an increase in toxicity. In addition, a combination of siRNA-mediated NF-κB knockdown using anisamide-targeted AuNPs with Paclitaxel produced a synergistic therapeutic response, thus providing a promising therapeutic strategy for the treatment of prostate cancer.
小干扰 RNA（siRNA）最近在恶性疾病的治疗方面显示出了治疗潜力。然而，由于缺乏成功的递送系统，siRNA 基疗法的临床应用受到了严重阻碍。最近，多功能金纳米粒子（AuNPs）作为非病毒递送载体，已显示出在递送化疗药物、蛋白质/肽和基因方面的应用前景。在这项研究中，我们制备了一系列带正电荷的靶向丙酰苯胺的聚乙二醇化金纳米粒子（即 Au-PEI-PEG-AA），该纳米粒子是由带聚乙烯亚胺（PEI）和聚乙二醇化丙酰苯胺（一种已知靶向 sigma 受体的配体）的 AuNPs 制成的。靶向丙酰苯胺的 AuNPs 通过静电相互作用有效地与 siRNA 复合，所得复合物（Au-PEI-PEG-AA.siRNA）具有良好的物理化学特性，包括粒径、表面电荷和稳定性。体外实验表明，靶向丙酰苯胺的 AuNPs 选择性地与人类前列腺癌细胞 PC-3 结合，诱导 siRNA 有效地进入内体逃逸，并有效下调 RelA 基因。在体内，靶向丙酰苯胺的 AuNPs 延长了 siRNA 的系统暴露，从而在 PC3 异种移植小鼠模型中显著抑制肿瘤生长，而没有增加毒性。此外，用靶向丙酰苯胺的 AuNPs 介导的 NF-κB 敲低与紫杉醇联合使用产生了协同治疗反应，从而为前列腺癌的治疗提供了一种有前途的治疗策略。
