Article: article from journal or magazin.
Thrombin-sensitive photodynamic agents: a novel strategy for selective synovectomy in rheumatoid arthritis.
Journal of Controlled Release
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, Arthritis, Rheumatoid/drug therapy, Cells, Cultured, Drug Delivery Systems/methods, Fibroblasts/cytology, Humans, Male, Mice, Photochemotherapy, Photosensitizing Agents/metabolism, Photosensitizing Agents/pharmacokinetics, Prodrugs/metabolism, Prodrugs/pharmacokinetics, Synovial Fluid/cytology, Thrombin/metabolism
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