Anisamide-targeted PEGylated gold nanoparticles designed to target prostate cancer mediate: enhanced systemic exposure of siRNA, tumour growth suppression and a synergistic therapeutic response in combination with paclitaxel in mice
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Date
2019-02-16
Authors
Luan, Xue
Rahme, Kamil
Cong, Zhongcheng
Wang, Limei
Zou, Yifang
He, Yan
Yang, Hao
Holmes, Justin D.
O'Driscoll, Caitríona M.
Guo, Jianfeng
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier
Published Version
Abstract
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 (Au110-PEI-PEG5000-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.
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Keywords
Non-viral siRNA delivery , Cancer gene therapy , Combination therapy , Prostate cancer
Citation
Luan, X., Rahme, K., Cong, Z., Wang, L., Zou, Y., He, Y., Yang, H., Holmes, J. D., O'Driscoll, C. M. and Guo, J. (2019) 'Anisamide-targeted PEGylated gold nanoparticles designed to target prostate cancer mediate: Enhanced systemic exposure of siRNA, tumour growth suppression and a synergistic therapeutic response in combination with paclitaxel in mice', European Journal of Pharmaceutics and Biopharmaceutics, 137, pp. 56-67. doi: 10.1016/j.ejpb.2019.02.013