Details
| Original language | English |
|---|---|
| Article number | 1802738 |
| Journal | Advanced functional materials |
| Volume | 28 |
| Issue number | 37 |
| Publication status | Published - 10 Sept 2018 |
Abstract
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 (kcat/KM = 6.5 × 105m−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.
Keywords
- early detection, live imaging, MMP-13 nanoprobes, osteoarthritis, polymer therapeutics
ASJC Scopus subject areas
- Chemistry(all)
- General Chemistry
- Materials Science(all)
- General Materials Science
- Physics and Astronomy(all)
- Condensed Matter Physics
Cite this
- Standard
- Harvard
- Apa
- Vancouver
- BibTeX
- RIS
In: Advanced functional materials, Vol. 28, No. 37, 1802738, 10.09.2018.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - In Vivo Imaging of MMP-13 Activity Using a Specific Polymer-FRET Peptide Conjugate Detects Early Osteoarthritis and Inhibitor Efficacy
AU - Duro-Castano, Aroa
AU - Lim, Ngee Han
AU - Tranchant, Isabelle
AU - Amoura, Mehdi
AU - Beau, Fabrice
AU - Wieland, Heike
AU - Kingler, Otmar
AU - Herrmann, Matthias
AU - Nazaré, Marc
AU - Plettenburg, Oliver
AU - Dive, Vincent
AU - Vicent, María J.
AU - Nagase, Hideaki
N1 - Funding information: A.D.-C., N.H.L., I.T. contributed equally to this work. The authors thank Bryony Stott for providing the histology and for the blind scoring of the sections. The work was funded through the EU FP7 grant LIVIMODE awarded to a consortium including V.D., H.N., M.J.V., and Sanofi-Aventis, Spanish Ministry grant SAF2016-80427-R to M.J.V. and NIH grant AR40994 to H.N. Partly cofunded by FEDER (PO FEDER Valencian Community-2014–2020). A.D.-C. and M.J.V. synthesized and characterized PGA, PGA-Cy5.5, PGAcoEG(6)N3, and PGA-P-18. I.T. and V.D. designed, developed, and characterized P-18 and screened PGA-P-18 as MMP substrates. N.H.L. and H.N. conducted in vivo imaging and inhibitor study in the mouse OA model. H.W., O.K., M.H., M.N., and O.P. synthesized and characterized MMP-13 inhibitor A-4727. V.D., A.D.-C., M.J.V., N.H.L., and H.N. drafted the manuscript. All authors read and approved the final version of the manuscript. There is no financial interest of any of the authors and therefore there is no conflict of interest. H.W., O.K., and M.H. are employees of Sanofi-Aventis Deutschland GmbH. Materials described may be obtained through an MTA.
PY - 2018/9/10
Y1 - 2018/9/10
N2 - 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 (kcat/KM = 6.5 × 105m−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.
AB - 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 (kcat/KM = 6.5 × 105m−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.
KW - early detection
KW - live imaging
KW - MMP-13 nanoprobes
KW - osteoarthritis
KW - polymer therapeutics
UR - http://www.scopus.com/inward/record.url?scp=85052989822&partnerID=8YFLogxK
U2 - 10.1002/adfm.201802738
DO - 10.1002/adfm.201802738
M3 - Article
AN - SCOPUS:85052989822
VL - 28
JO - Advanced functional materials
JF - Advanced functional materials
SN - 1616-301X
IS - 37
M1 - 1802738
ER -