1. The intracellular and nuclear-targeted delivery of an antiandrogen drug by carrier peptides.
- Author
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Hodoniczky J, Sims CG, Best WM, Bentel JM, and Wilce JA
- Subjects
- Androgen Antagonists chemical synthesis, Androgen Antagonists metabolism, Anilides chemical synthesis, Anilides metabolism, Animals, Carrier Proteins metabolism, Cell Line, Tumor, HeLa Cells, Humans, Male, Nitriles chemical synthesis, Nitriles metabolism, Peptides metabolism, Permeability, Rats, Tosyl Compounds chemical synthesis, Tosyl Compounds metabolism, Androgen Antagonists administration & dosage, Anilides administration & dosage, Carrier Proteins administration & dosage, Cell Membrane Permeability physiology, Drug Delivery Systems, Drug Design, Nitriles administration & dosage, Nuclear Envelope metabolism, Peptides administration & dosage, Tosyl Compounds administration & dosage
- 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., ((c) 2008 Wiley Periodicals, Inc.)
- Published
- 2008
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