Scientific article

Thrombin-sensitive photodynamic agents: a novel strategy for selective synovectomy in rheumatoid arthritis

Published inJournal of controlled release, vol. 138, no. 3, p. 225-234
Publication date2009

Protease-sensitive macromolecular prodrugs have attracted interest for bio-responsive drug delivery to sites with up-regulated proteolytic activities such as inflammatory or cancerous lesions. Here we report the development of a novel polymeric photosensitizer prodrug (T-PS) to target thrombin, a protease up-regulated in synovial tissues of rheumatoid arthritis (RA) patients, for minimally invasive photodynamic synovectomy. In T-PS, multiple photosensitizer units are tethered to a polymeric backbone via short, thrombin-cleavable peptide linkers. Photoactivity of the prodrug is efficiently impaired due to energy transfer between neighbouring photosensitizer units. T-PS activation by exogenous and endogenous thrombin induced an increase in fluorescence emission by a factor of 16 after in vitro digestion and a selective fluorescence enhancement in arthritic lesions in vivo, in a collagen-induced arthritis mouse model. In vitro studies on primary human synoviocytes showed a phototoxic effect only after enzymatic digestion of the prodrug and light irradiation, thus demonstrating the functionality of T-PS induced PDT. The developed photosensitizer prodrugs combine the passive targeting capacity of macromolecular drug delivery systems with site-selective photosensitizer release and activation. They illuminate lesions with pathologically enhanced proteolytic activity and induce cell death, subsequent to irradiation.

  • Animals
  • Arthritis, Rheumatoid/chemically induced/drug therapy
  • Cells, Cultured
  • Drug Delivery Systems/methods
  • Fibroblasts/cytology
  • Humans
  • Male
  • Mice
  • Photochemotherapy
  • Photosensitizing Agents/metabolism/pharmacokinetics/therapeutic use
  • Prodrugs/metabolism/pharmacokinetics/therapeutic use
  • Synovial Fluid/cytology
  • Thrombin/metabolism
Citation (ISO format)
GABRIEL, Doris et al. Thrombin-sensitive photodynamic agents: a novel strategy for selective synovectomy in rheumatoid arthritis. In: Journal of controlled release, 2009, vol. 138, n° 3, p. 225–234. doi: 10.1016/j.jconrel.2009.05.012
Main files (1)
Article (Published version)
ISSN of the journal0168-3659

Technical informations

Creation11/10/2009 10:20:00 AM
First validation11/10/2009 10:20:00 AM
Update time03/14/2023 3:17:37 PM
Status update03/14/2023 3:17:37 PM
Last indexation01/15/2024 7:12:51 PM
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