Improvement of PDT applications by combination with drug treatments or modification of photosensitizer biodistribution and pharmacokinetics

Prodrug designs combining macromolecular delivery systems with site-selective drug release represent a powerful strategy to increase selectivity of cancer treatments. We have employed this strategy to develop a novel polymeric photosensitizer prodrug (uPA-PPP) for photodynamic therapy of organ-confined prostate cancer. In uPA-PPPs multiple molecules of pheophorbide a are attached to a polymeric carrier via peptide linkers that can be cleaved by urokinase-plasminogen-activator, a protease overexpressed in prostate cancer. These prodrugs are non-phototoxic in their native state but become fluorescent and produce singlet oxygen after protease mediated activation. In the present work, we investigated the influence of side-chain modifications, molecular weight, and overall charge on the photoactivity and pharmacokinetics of uPA-PPPs.