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.

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.

• Authors: Xue Luan, Kamil Rahme, Zhongcheng Cong, Limei Wang, Yifang Zou, Yan He, Hao Yang, Justin D Holmes, Caitriona M O'Driscoll, Jianfeng Guo
• Journal: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (Eur J Pharm Biopharm) Vol. 137 Pg. 56-67 (Apr 2019) ISSN: 1873-3441 [Electronic] Netherlands
• PMID: 30779980 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Benzamides
• NF-kappa B
• RNA, Small Interfering
• Polyethylene Glycols
• Gold
• Polyethyleneimine
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents, Phytogenic (administration & dosage)
• Benzamides (chemistry)
• Cell Line, Tumor
• Combined Modality Therapy
• Gene Knockdown Techniques
• Gene Transfer Techniques
• Gold (chemistry)
• Humans
• Male
• Metal Nanoparticles
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• NF-kappa B (genetics)
• Paclitaxel (administration & dosage)
• Polyethylene Glycols (chemistry)
• Polyethyleneimine (chemistry)
• Prostatic Neoplasms (genetics, therapy)
• RNA, Small Interfering (administration & dosage)
• Treatment Outcome
• Xenograft Model Antitumor Assays