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

Busso, Nathalie
So, Alexander
van den Bergh, Hubert
Published in Journal of Controlled Release. 2009, vol. 138, no. 3, p. 225-34
Abstract 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.
Keywords AnimalsArthritis, Rheumatoid/chemically induced/drug therapyCells, CulturedDrug Delivery Systems/methodsFibroblasts/cytologyHumansMaleMicePhotochemotherapyPhotosensitizing Agents/metabolism/pharmacokinetics/therapeutic useProdrugs/metabolism/pharmacokinetics/therapeutic useSynovial Fluid/cytologyThrombin/metabolism
PMID: 19445983
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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. 225-34. doi: 10.1016/j.jconrel.2009.05.012 https://archive-ouverte.unige.ch/unige:4091

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Deposited on : 2009-11-23

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