Enhanced prostate cancer targeting by modified protease sensitive photosensitizer prodrugs

Mol Pharm. 2012 Jun 4;9(6):1570-9. doi: 10.1021/mp2005774. Epub 2012 May 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Photochemotherapy / methods*
  • Photosensitizing Agents / chemical synthesis
  • Photosensitizing Agents / metabolism
  • Photosensitizing Agents / therapeutic use*
  • Polymers / chemical synthesis
  • Polymers / metabolism
  • Polymers / therapeutic use*
  • Prodrugs / chemical synthesis
  • Prodrugs / metabolism
  • Prodrugs / therapeutic use*
  • Prostatic Neoplasms / drug therapy*
  • Urokinase-Type Plasminogen Activator / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Photosensitizing Agents
  • Polymers
  • Prodrugs
  • Urokinase-Type Plasminogen Activator