title: Thrombin-sensitive photodynamic agents: a novel strategy for selective synovectomy in rheumatoid arthritis.
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.
authors.affiliation: Laboratory of Pharmaceutics and Biopharmaceutics, Section of Pharmaceutical Sciences, University of Lausanne, University of Geneva, 30 Quai Ernest-Ansermet, CH-1211, Geneva, Switzerland.
authors.forename: Doris
authors.initials: D
authors.lastname: Gabriel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Busso
authors.forename: Alexander
authors.initials: A
authors.lastname: So
authors.forename: Hubert
authors.initials: H
authors.lastname: van den Bergh
authors.forename: Robert
authors.initials: R
authors.lastname: Gurny
authors.forename: Norbert
authors.initials: N
authors.lastname: Lange
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy*; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D008297:Male; D051379:Mice; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013582:Synovial Fluid / Q000166:cytology; D013917:Thrombin / Q000378:metabolism*
chemical_list: D017319:Photosensitizing Agents; D011355:Prodrugs; D013917:Thrombin