Scientific article

Tailoring protease-sensitive photodynamic agents to specific disease-associated enzymes

Published inBioconjugate chemistry, vol. 18, no. 4, p. 1070-1077
Publication date2007

We have developed novel polymeric photosensitizer prodrugs (PPPs) for improved photodynamic therapy. In PPPs, multiple photosensitizer units are covalently coupled to a polymeric backbone via protease-cleavable peptide linkers. These initially non-photoactive compounds become fluorescent and phototoxic after specific enzymatic cleavage of the peptide linkers and subsequent release of the photosensitizer moieties. Tethering the photosensitizer via a short and easily modified amino acid sequence to the polymeric backbone allows for the targeting of a wide variety of proteases. Model compounds, sensitive to trypsin-mediated cleavage, with different pheophorbide a-peptide loading ratios and backbone net charges were evaluated with respect to their solubility, "self-quenching" capacity of fluorescence emission, and reactive oxygen species (ROS) generation. In addition, linker sequence impaired selectivity toward enzymatic cleavage was demonstrated either by incubating PPPs with different enzymes having trypsin-like activity or by introducing a single d-arginine mutant in the peptide sequence. In vitro cell culture tests confirmed dose-dependent higher phototoxicity of enzymatically activated PPPs compared to the nonactivated conjugate after irradiation with white light. These data suggest that similar compounds adapted to disease-associated proteases can be used for selective photodynamic therapy.

  • Cell Line, Tumor
  • Cell Survival/drug effects
  • Chlorophyll/analogs & derivatives/chemistry/pharmacology
  • Humans
  • Peptides/chemistry
  • Photochemotherapy
  • Photosensitizing Agents/chemistry/pharmacology
  • Polylysine/chemistry
  • Prodrugs/chemical synthesis/pharmacology
  • Reactive Oxygen Species/metabolism
  • Trypsin/chemistry
Citation (ISO format)
GABRIEL, Doris et al. Tailoring protease-sensitive photodynamic agents to specific disease-associated enzymes. In: Bioconjugate chemistry, 2007, vol. 18, n° 4, p. 1070–1077. doi: 10.1021/bc060321l
Main files (1)
Article (Published version)
ISSN of the journal1043-1802

Technical informations

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