Thrombin-sensitive photodynamic agents: A novel strategy for selective synovectomy in rheumatoid arthritis
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. (c) 2009 Elsevier B.V. All rights reserved.
Keywords: Protease-sensitive prodrugs ; Photodynamic therapy ; Synovectomy ; Rheumatoid arthritis ; Thrombin ; Antigen-Induced Arthritis ; Collagen-Induced Arthritis ; Synovial Fibroblasts ; Joint Destruction ; Matrix-Metalloproteinase ; Plasminogen-Activator ; Drug-Therapy ; Cathepsin-B ; Osmic Acid ; Model
Record created on 2010-11-30, modified on 2016-08-09