title: Enhanced prostate cancer targeting by modified protease sensitive photosensitizer prodrugs.
abstract: Prodrugs combining macromolecular delivery systems with site-selective drug release represent a powerful strategy to increase selectivity of anticancer agents. We have adapted this strategy to develop new polymeric photosensitizer prodrugs (PPP) sensitive to urokinase-like plasminogen activator (uPA). In these compounds (to be referred to as uPA-PPPs) multiple copies of pheophorbide a are attached to a polymeric carrier via peptide linkers that can be cleaved by uPA, a protease overexpressed in prostate cancer (PCa). uPA-PPPs are non-phototoxic in their native state but become fluorescent and produce singlet oxygen after uPA-mediated activation. In the present work, we studied the influence of side-chain modifications, molecular weight, and overall charge on the photoactivity and pharmacokinetics of uPA-PPPs. An in vitro promising candidate with convertible phototoxicity was then further investigated in vivo. Systemic administration resulted in a selective accumulation and activation of the prodrug in luciferase transfected PC-3 xenografts, resulting in a 4-fold increase in fluorescence emission over time. Irradiation of fluorescent tumors induced immediate tumor cell eradication as shown by whole animal bioluminescence imaging. PDT with uPA-PPP could therefore provide a more selective treatment of localized PCa and reduce side effects associated with current radical treatments.
authors.affiliation: Department of Pharmaceutics and Biopharmaceutics, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 30 Quai Ernest-Ansermet, 1211 Geneva 4, Switzerland.
authors.forename: Maria-Fernanda
authors.initials: MF
authors.lastname: Zuluaga
authors.forename: Doris
authors.initials: D
authors.lastname: Gabriel
authors.forename: Norbert
authors.initials: N
authors.lastname: Lange
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D011108:Polymers / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D017319:Photosensitizing Agents; D011108:Polymers; D011355:Prodrugs; D014568:Urokinase-Type Plasminogen Activator