title: Folate-targeted amphiphilic cyclodextrin.siRNA nanoparticles for prostate cancer therapy exhibit PSMA mediated uptake, therapeutic gene silencing in vitro and prolonged circulation in vivo.
abstract: In this study, a folate targeted cyclodextrin (CD) nanoparticle was prepared by co-formulating CD.siRNA complexes with DSPE-PEG5000-folate to target the prostate specific membrane antigen (PSMA). Targeted formulations showed increased uptake, relative to untargeted controls, in two prostate cancer cell lines expressing PSMA (VCaP and LNCaP). Competitive uptake studies, using excess folate, significantly reduced uptake of targeted nanoparticles in PSMA positive cell lines (P<0.001). Relative to untreated controls, folate-targeted nanoparticles significantly reduced the levels of RelA mRNA in VCaP and LNCaP cells by 44% and 22% respectively (P<0.001). In contrast there was no significant reduction in RelA mRNA in these cell lines by untargeted complexes. Pharmacokinetic (PK) data indicated that the incorporation of PEG into the formulation increased the circulation time of siRNA 8-fold. This study highlights the ability of incorporating a folate ligand into CD.siRNA nanoparticles to allow for targeted delivery of siRNA to prostate cancer cells via the PSMA.
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: Jianfeng
authors.initials: J
authors.lastname: Guo
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: O'Shea
authors.affiliation: UCD Conway Institute of Biomolecular and Biomedical Research, UCD School of Medicine, University College Dublin, Dublin, Ireland.
authors.forename: Karen
authors.initials: K
authors.lastname: Hanrahan
authors.affiliation: UCD Conway Institute of Biomolecular and Biomedical Research, UCD School of Medicine, University College Dublin, Dublin, Ireland.
authors.forename: Amanda
authors.initials: A
authors.lastname: O'Neill
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: William D
authors.initials: WD
authors.lastname: Landry
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Griffin
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Raphael
authors.initials: R
authors.lastname: Darcy
authors.affiliation: UCD Conway Institute of Biomolecular and Biomedical Research, UCD School of Medicine, University College Dublin, Dublin, Ireland.
authors.forename: R William
authors.initials: RW
authors.lastname: Watson
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland. Electronic address: caitriona.odriscoll@ucc.ie.
authors.forename: Caitriona M
authors.initials: CM
authors.lastname: O'Driscoll
mesh_terms: D045744:Cell Line, Tumor; D003505:Cyclodextrins; D005492:Folic Acid; D020868:Gene Silencing; D006801:Humans; D008297:Male; D053758:Nanoparticles; D011471:Prostatic Neoplasms / Q000628:therapy*; D034741:RNA, Small Interfering
chemical_list: D003505:Cyclodextrins; D034741:RNA, Small Interfering; D005492:Folic Acid
keywords: Gene therapy; PSMA; Prostate cancer; RNAi