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Formulation and evaluation of anisamide-targeted amphiphilic cyclodextrin nanoparticles to promote therapeutic gene silencing in a 3D prostate cancer bone metastases model James C Evans, Meenakshi Malhotra, Kathleen A Fitzgerald, Jianfeng Guo, Michael F Cronin, Caroline M Curtin, Fergal J O'Brien, Raphael Darcy, and Caitriona M O'Driscoll Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.6b00646 • Publication Date (Web): 11 Nov 2016 Downloaded from http://pubs.acs.org on November 17, 2016
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Molecular Pharmaceutics
Formulation and evaluation of anisamide-targeted amphiphilic cyclodextrin nanoparticles to promote therapeutic gene silencing in a 3D prostate cancer bone metastases model Authors James C. Evans1 Meenakshi Malhotra1 Kathleen A. Fitzgerald1 Jianfeng Guo1 Michael F. Cronin1 Caroline M. Curtin2 Fergal J O’Brien2 Raphael Darcy1 Caitriona M O’Driscoll1 ¹Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland. Tissue Engineering Research Group, Anatomy Department, Royal College of Surgeons in Ireland, Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College, Dublin, Ireland; Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI & TCD, Ireland. 2
All correspondence relating to this paper should be addressed to: Professor Caitriona O’Driscoll, School of Pharmacy, University College Cork, Ireland. Tel: +353-21-4901396 Fax: +353-21-4901656 E-mail:
[email protected] ACS Paragon Plus Environment
Molecular Pharmaceutics
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Abstract In recent years, RNA interference (RNAi) has emerged as a potential therapeutic offering the opportunity to treat a wide range of diseases, including prostate cancer. Modified cyclodextrins have emerged as effective gene delivery vectors in a range of disease models. The main objective of the current study was to formulate anisamide-targeted cyclodextrin nanoparticles to interact with the sigma receptor (overexpressed on the surface of prostate cancer cells). The inclusion of octaarginine in the nanoparticle optimised uptake and endosomal release of siRNA in two different prostate cancer cell lines (PC3 and DU145 cells). Resulting nanoparticles were less than 200 nm in size with a cationic surface charge (~ +20 mV). In sigma receptor-positive cell lines, the uptake of anisamide-targeted nanoparticles was reduced in the presence of the sigma receptor competitive ligand, haloperidol. When cells were transfected in 2D, the levels of PLK1 mRNA knockdown elicited by targeted versus untargeted nanoparticles tended to be greater but the differences were not statistically different. In contrast, when cells were grown on 3D scaffolds, recapitulating bone metastasis, targeted formulations showed significantly higher levels of PLK1 mRNA knockdown (46 % for PC3 and 37 % for DU145, p
