title: The intracellular and nuclear-targeted delivery of an antiandrogen drug by carrier peptides.
abstract: Cell permeable carrier peptides are currently of interest for their potential to improve the delivery of bioactive molecules into cells and to specific cellular compartments. We have investigated the activity of a derivative of the antiandrogen drug, bicalutamide, attached to the cell-permeable carrier peptide penetratin(R). We have used both disulfide (labile) and thioether (nonlabile) linkages to attach the bicalutamide derivative to the peptide in order to assess whether one type of chemistry has advantages over the other. In addition we have added a nuclear localization sequence (NLS) to the carrier peptide to investigate whether localization of the drug to the nucleus of the cell affects the activity of the drug. Biotin-labeled peptides were used to demonstrate that the carrier peptide is rapidly accumulated inside cultured cells, and that the incorporation of an NLS in the sequence results in its nuclear targeting. The bicalutamide derivative linked to carrier peptides via a disulfide-linkage exerted no greater antiproliferative effect in LNCaP cells, than the bicalutamide derivative alone. The bicalutamide derivative linked to the carrier peptide by a non-labile thioether linkage showed a similar activity profile. When the construct includes a nuclear targeting sequence, however, a markedly increased antiproliferative effect was observed. This study has thus shown that the activity of bicalutamide may be enhanced by the nonlabile attachment of a cell-permeable and nuclear-targeted peptide, which has implications for the development of novel antiandrogens for the treatment of prostate cancer.
authors: Chemistry/Biochemistry and Molecular Biology, School of Biomedical and Chemical Sciences, The University of Western Australia, WA 6009, Australia.
authors: Jason
authors: J
authors: Hodoniczky
authors: Colette G
authors: CG
authors: Sims
authors: Wayne M
authors: WM
authors: Best
authors: Jacqueline M
authors: JM
authors: Bentel
authors: Jacqueline A
authors: JA
authors: Wilce
mesh_terms: D000726:Androgen Antagonists / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism; D000813:Anilides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000008:administration & dosage* / Q000378:metabolism; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000502:physiology; D016503:Drug Delivery Systems; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D008297:Male; D009570:Nitriles / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism; D009685:Nuclear Envelope / Q000378:metabolism*; D010455:Peptides / Q000008:administration & dosage* / Q000378:metabolism; D010539:Permeability; D051381:Rats; D014105:Tosyl Compounds / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D002352:Carrier Proteins; D009570:Nitriles; D010455:Peptides; D014105:Tosyl Compounds; C053541:bicalutamide