Formulation and evaluation of anisamide-targeted amphiphilic cyclodextrin nanoparticles to promote therapeutic gene silencing in a 3D prostate cancer bone metastases model
Evans, James C.; Malhotra, Meenakshi; Fitzgerald, Kathleen A.; Guo, Jianfeng; Cronin, Michael F.; O'Brien, Fergal J.; Curtin, Caroline M.; Darcy, Raphael; O'Driscoll, Caitríona M.
Date:
2016-11-11
Copyright:
© 2016, American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/acs.molpharmaceut.6b00646
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Access to this article is restricted until 12 months after publication by request of the publisher.
Restriction lift date:
2017-11-11
Citation:
Evans, J. C., Malhotra, M., Fitzgerald, K. A., Guo, J., Cronin, M. F., Curtin, C. M., O’Brien, F. J., Darcy, R. and O’Driscoll, C. M. (2016) 'Formulation and evaluation of anisamide-targeted amphiphilic cyclodextrin nanoparticles to promote therapeutic gene silencing in a 3D prostate cancer bone metastases model', Molecular Pharmaceutics, 14(1), pp. 42-52. doi:10.1021/acs.molpharmaceut.6b00646
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 optimized 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
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