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.
Written by:
Zuluaga MF, Gabriel D, Lange N Are you the author?
Department of Pharmaceutics and Biopharmaceutics, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 30 Quai Ernest-Ansermet, 1211 Geneva 4, Switzerland
Reference: Mol Pharm. 2012 Jun 4;9(6):1570-9
doi: 10.1021/mp2005774
PubMed Abstract
PMID: 22548315