title: Thrombin-sensitive dual fluorescence imaging and therapeutic agent for detection and treatment of synovial inflammation in murine rheumatoid arthritis.
abstract: We have developed a thrombin-sensitive polymeric photosensitizer prodrug (T-PS) to selectively image and eradicate inflammatory lesions in rheumatoid arthritis (RA). Thrombin is a serine protease up-regulated in synovial tissues of rheumatoid arthritis (RA) patients. T-PS consists of a polymeric backbone, to which multiple photosensitizer (PS) units are tethered via short thrombin-cleavable peptide linkers. Fluorescence emission and phototoxicity of the prodrug are efficiently quenched due to the interaction of neighboring photosensitizer units. The prodrug is passively delivered to the inflammation site via the enhanced permeability and retention (EPR) effect. Subsequent site-selective proteolytic cleavage of the peptide linkers restores its photoactivity by increasing the mutual distance between PS. Whole animal imaging in murine collagen-induced arthritis, an experimental model of RA revealed a dose-dependent fluorescence increase in arthritic paws after systemic prodrug injection. In addition, administration of T-PS resulted in much higher fluorescence selectivity for arthritic joints as compared to the free PS. Irradiation of the arthritic joints induced light dose dependent phototoxic effects such as apoptosis, vascular damage and local hemorrhage. Long-term observations showed complete regression of the latter. Irradiated non-arthritic tissues or non-irradiated arthritic tissues showed no histological effects after photodynamic therapy with T-PS. This illustrates that T-PS can localize inflammatory lesions with excellent selectivity and induce apoptosis and vascular shut down after 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. dgabriel@mit.edu
authors.forename: Doris
authors.initials: D
authors.lastname: Gabriel
authors.forename: Norbert
authors.initials: N
authors.lastname: Lange
authors.forename: Veronique
authors.initials: V
authors.lastname: Chobaz-Peclat
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: Zuluaga
authors.forename: Robert
authors.initials: R
authors.lastname: Gurny
authors.forename: Hubert
authors.initials: H
authors.lastname: van den Bergh
authors.forename: Nathalie
authors.initials: N
authors.lastname: Busso
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D061848:Optical Imaging; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D011355:Prodrugs / Q000627:therapeutic use*; D013917:Thrombin
chemical_list: D017319:Photosensitizing Agents; D011355:Prodrugs; D013917:Thrombin