title: Protease-activated pore-forming peptides for the treatment and imaging of prostate cancer.
abstract: A common hallmark of cancers with highly aggressive phenotypes is increased proteolysis in the tumor and the surrounding microenvironment. Prostate cancer has a number of proteases uniquely associated with it that may play various important roles in disease progression. In this report, we utilize the peritumoral proteolytic activity of prostate cancer to activate engineered peptide constructs for the treatment and noninvasive imaging of prostate cancer. Using a modular "propeptide" approach, a cationic diastereomeric pore-forming peptide domain was linked to an inactivating acidic peptide domain. The inactivating acidic peptide domain was engineered to be a cleavable substrate for the secreted serine protease prostate-specific antigen (PSA) or the transmembrane metalloprotease prostate-specific membrane antigen (PSMA). The propeptides were then evaluated in a direct comparison study. Both the PSA and PSMA activated propeptides were found to be cytotoxic to prostate cancer cells in vitro. In vivo, however, treatment of LNCaP and CWR22Rv1 xenografts with the PSMA propeptide resulted in a pronounced cytostatic effect when compared with xenografts treated with the PSA propeptide or the cationic diastereomeric peptide alone. The PSMA activated propeptide also proved to be an effective optical imaging probe in vivo when labeled with a near-infrared fluorophore. These data suggest that protease-activated pore-forming peptides could potentially be used for both imaging and treating prostate cancer.
authors.affiliation: Department of Pharmacology, University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota. alebeau@umn.edu.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: LeBeau
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Denmeade
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D045744:Cell Line, Tumor; D003952:Diagnostic Imaging / Q000379:methods; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D000954:Antigens, Surface; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017430:Prostate-Specific Antigen