title: Formulation and Evaluation of Anisamide-Targeted Amphiphilic Cyclodextrin Nanoparticles To Promote Therapeutic Gene Silencing in a 3D Prostate Cancer Bone Metastases Model.
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 < 0.05). To our knowledge, this is the first time that a targeted cyclodextrin has been used to transfect prostate cancer cells in a 3D model of bone metastasis.
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork , Cork, Ireland.
authors.forename: James C
authors.initials: JC
authors.lastname: Evans
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork , Cork, Ireland.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Malhotra
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork , Cork, Ireland.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork , Cork, Ireland.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Guo
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork , Cork, Ireland.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Cronin
authors.affiliation: 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 , Dublin, Ireland.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Curtin
authors.affiliation: 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 , Dublin, Ireland.
authors.forename: Fergal J
authors.initials: FJ
authors.lastname: O'Brien
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork , Cork, Ireland.
authors.forename: Raphael
authors.initials: R
authors.lastname: Darcy
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork , Cork, Ireland.
authors.forename: Caitriona M
authors.initials: CM
authors.lastname: O'Driscoll
mesh_terms: D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002412:Cations / Q000378:metabolism; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003505:Cyclodextrins / Q000737:chemistry* / Q000494:pharmacology*; D020868:Gene Silencing / Q000187:drug effects*; D018014:Gene Transfer Techniques; D006220:Haloperidol / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology; D010316:Particle Size; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D002412:Cations; D003505:Cyclodextrins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017480:Receptors, sigma; D006220:Haloperidol
keywords: RNAi; bone microenvironment; collagen scaffolds; prostate cancer metastasis; siRNA delivery; sigma receptor