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

Campo, Marino A.
Published in Bioconjugate chemistry. 2007, vol. 18, no. 4, p. 1070-7
Abstract 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.
Keywords Cell Line, TumorCell Survival/drug effectsChlorophyll/analogs & derivatives/chemistry/pharmacologyHumansPeptides/chemistryPhotochemotherapyPhotosensitizing Agents/chemistry/pharmacologyPolylysine/chemistryProdrugs/chemical synthesis/pharmacologyReactive Oxygen Species/metabolismTrypsin/chemistry
PMID: 17477499
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GABRIEL, Doris et al. Tailoring protease-sensitive photodynamic agents to specific disease-associated enzymes. In: Bioconjugate chemistry, 2007, vol. 18, n° 4, p. 1070-7. doi: 10.1021/bc060321l https://archive-ouverte.unige.ch/unige:14306

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Deposited on : 2011-02-01

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