title: A novel, anisamide-targeted cyclodextrin nanoformulation for siRNA delivery to prostate cancer cells expressing the sigma-1 receptor.
abstract: Prostate cancer is a leading cause of cancer-related death in men and RNA interference (RNAi) has emerged as a potential therapeutic option. However, the absence of a safe and specific delivery vector remains a major obstacle to the clinical application of RNAi. Cyclodextrin derivatives are known to be efficient delivery systems with low toxicity in a variety of cell types. In this study, a cationic cyclodextrin derivative was synthesized to complex siRNA. The nanoparticle was then further modified by exploiting the ability of the β-cyclodextrin cavity to form an inclusion complex with the hydrophobic molecule adamantane. PEGylated adamantane derivatives were synthesized with and without the anisamide-targeting ligand on the terminal end of the PEG chain. Anisamide is known to bind specifically to the sigma receptor which is overexpressed on the surface of prostate cancer cells. The resulting nanocomplexes were slightly cationic and less than 300 nm in size. They successfully protected siRNA from serum-induced nuclease degradation and were non-toxic to prostate cancer cells. In addition, the targeted nanoparticles mediated high levels of siRNA cellular uptake and corresponding PLK1 gene knockdown in prostate cancer cells in vitro. To our knowledge, this is the first time that the ability of cyclodextrins to form inclusion complexes with adamantane derivatives has been exploited for the targeted delivery of siRNA to prostate cancer cells via the sigma receptor.
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Ireland.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Ireland.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Malhotra
authors.affiliation: Centre for Synthesis and Chemical Biology, University College Dublin, Ireland.
authors.forename: Matt
authors.initials: M
authors.lastname: Gooding
authors.affiliation: Centre for Synthesis and Chemical Biology, University College Dublin, Ireland.
authors.forename: Florence
authors.initials: F
authors.lastname: Sallas
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Ireland.
authors.forename: James C
authors.initials: JC
authors.lastname: Evans
authors.affiliation: Centre for Synthesis and Chemical Biology, University College Dublin, Ireland; School of Chemistry, University College Dublin, Ireland.
authors.forename: Raphael
authors.initials: R
authors.lastname: Darcy
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Ireland. Electronic address: caitriona.odriscoll@ucc.ie.
authors.forename: Caitriona M
authors.initials: CM
authors.lastname: O'Driscoll
mesh_terms: D000218:Adamantane / Q000737:chemistry; D002412:Cations; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D018014:Gene Transfer Techniques; D006801:Humans; D008297:Male; D053758:Nanoparticles; D010316:Particle Size; D011471:Prostatic Neoplasms / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D017480:Receptors, sigma / Q000235:genetics*; D047392:beta-Cyclodextrins / Q000737:chemistry; D000097605:Sigma-1 Receptor; D000097869:Polo-Like Kinase 1
chemical_list: D000218:Adamantane; D002412:Cations; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D017480:Receptors, sigma; D047392:beta-Cyclodextrins; D000097605:Sigma-1 Receptor; D000097869:Polo-Like Kinase 1; C031215:betadex
keywords: Anisamide targeted cyclodextrin; Gene delivery; Inclusion complex formation; Prostate cancer; Sigma receptor; Targeted nanoparticle