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
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Publisher
Elsevier
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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