In Vivo Imaging of MMP-13 Activity Using a Specific Polymer-FRET Peptide Conjugate Detects Early Osteoarthritis and Inhibitor Efficacy

被引：30

作者：

Duro-Castano, Aroa ^{[1
]}

Lim, Ngee Han ^{[2
]}

Tranchant, Isabelle ^{[3
]}

Amoura, Mehdi ^{[3
]}

Beau, Fabrice ^{[3
]}

Wieland, Heike ^{[4
]}

Kingler, Otmar ^{[4
]}

Herrmann, Matthias ^{[4
]}

Nazare, Marc ^{[4
,5
]}

Plettenburg, Oliver ^{[4
,6
,7
]}

Dive, Vincent ^{[3
]}

Vicent, Maria J. ^{[1
]}

Nagase, Hideaki ^{[2
]}

机构：

[1] Ctr Invest Principe Felipe, Polymer Therapeut Lab, Av Eduardo Primo Yufera 3, Valencia 46012, Spain

[2] Univ Oxford, NDORMS, Kennedy Inst Rheumatol, Matrix Biol, Roosevelt Dr, Oxford OX3 7FY, England

[3] Univ Paris Saclay, Labex LERMIT, CEA, Serv Ingn Mol Proteines SIMOPRO, F-91191 Gif Sur Yvette, France

[4] Sanofi Aventis Germany GmbH, Immunol & Inflammat TA, Ind Pk, D-65926 Frankfurt, Germany

[5] FMP, Med Chem Leibniz, Campus Berlin Buch,Robert Roessle Str 10, D-13125 Berlin, Germany

[6] Helmholtz Zentrum Munchen, Deutsch Forschungszentrum Gesundheit & Umwelt Gmb, Inst Med Chem, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany

[7] Leibniz Univ Hannover, Schneiderberg 1B, D-30167 Hannover, Germany

来源：

ADVANCED FUNCTIONAL MATERIALS | 2018年 / 28卷 / 37期

关键词：

early detection; live imaging; MMP-13; nanoprobes; osteoarthritis; polymer therapeutics; MATRIX-METALLOPROTEINASE; CARTILAGE DEGRADATION; SELECTIVE-INHIBITION; ARTICULAR-CARTILAGE; MOUSE MODEL; PROBES; DISCOVERY; PROTEASES; COLLAGEN; THERAPY;

D O I：

10.1002/adfm.201802738

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Imaging early molecular changes in osteoarthritic (OA) joints is instrumental for the development of disease-modifying drugs. To this end, a fluorescent resonance energy transfer-based peptide probe that is cleavable by matrix metalloproteinase 13 (MMP-13) has been developed. This protease degrades type II collagen, a major matrix component of cartilage. The probe exhibits high catalytic efficiency (k(cat)/K-M = 6.5 x 10(5) m(-1) s(-1)) and high selectivity for MMP-13 over a set of nine MMPs. To achieve optimal in vivo pharmacokinetics and tissue penetration, the probe has been further conjugated to a linear l-polyglutamate chain of 30 kDa. The conjugate detects early biochemical events that occur in a surgically induced murine model of OA before major histological changes. The nanometric probe is suitable for the monitoring of in vivo efficacy of an orally bioavailable MMP-13 inhibitor, which effectively blocks cartilage degradation during the development of OA. This new polymer-probe can therefore be a useful tool in detecting early OA, disease progression, and in developing MMP-13-based disease-modifying drugs for OA.

引用

页数：9