Photodynamic Therapy Beacons as a "Whole Joint" Treatment of Osteoarthritis
Walsh, Connor (1,2); Chen, Juan(2); Zheng, Gang(1,2)
Institute of Biomaterials and Biomedical Engineering, University of Toronto
Princess Margaret Cancer Centre, University Health Network
Osteoarthritis (OA) remains the leading degenerative joint disease worldwide. With current treatments limited to inadequate symptom alleviation, there is a strong clinical need for disease-modifying treatments that alleviate the patient burden of OA. A recent paradigm shift to view OA as a “whole joint disease” rather than strictly joint cartilage degradation has generated more opportunities for therapeutic innovations. Photodynamic therapy (PDT), a clinically-approved treatment which combines a photosensitizing drug (PS) with light irradiation, holds great potential as a whole joint approach for OA. However, targeting selective PS activation to the diseased joint space without damaging adjacent healthy tissue, notably muscle and ligaments, remains a major challenge in achieving successful OA PDT. To this end, activatable PDT via photodynamic therapy beacons is of great interest. Consisting of a PS, a peptide linker sequence, and a quencher molecule, PDT beacons remain inactive until a site-specific enzyme cleaves the linker, yielding highly selective PDT. Herein, we report the synthesis and characterization of a new PDT beacon (PPMMP13B) designed for activation by matrix metalloproteinase 13 (MMP-13), a potent catabolic protease involved in OA pathogenesis. PPMMP13B exhibits effective fluorescence and singlet oxygen quenching in its intact state. Upon MMP-13-mediated cleavage and activation, PPMMP13B displays a near 12-fold increase in fluorescence signal along with light dose dependent singlet oxygen generation. By mediating OA using a novel MMP-13-specific PDT beacon, this project addresses limitations of current PDT paradigms while taking advantage of the enormous potential as a curative treatment for OA.