title: DOTAM derivatives as active cartilage-targeting drug carriers for the treatment of osteoarthritis.
abstract: Targeted drug-delivery methods are crucial for effective treatment of degenerative joint diseases such as osteoarthritis (OA). Toward this goal, we developed a small multivalent structure as a model drug for the attenuation of cartilage degradation. The DOTAM (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid amide)-based model structure is equipped with the cathepsin D protease inhibitor pepstatin A, a fluorophore, and peptide moieties targeting collagen II. In vivo injection of these soluble probes into the knee joints of mice resulted in 7-day-long local retention, while the drug carrier equipped with a scrambled peptide sequence was washed away within 6-8 h. The model drug conjugate successfully reduced the cathepsin D protease activity as measured by release of GAG peptide. Therefore, these conjugates represent a promising first drug conjugate for the targeted treatment of degenerative joint diseases.
authors: †European Molecular Biology Laboratory (EMBL), Interdisciplinary Chemistry Group, Cell Biology and Biophysics Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany.|‡Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65962 Frankfurt, Germany.|∥Department of Chemical Biology, Helmholtz-Zentrum für Infektionsforschung (HZI), Inhoffenstrasse 7, 38124 Braunschweig, Germany.
authors: Hai-Yu
authors: HY
authors: Hu
authors: §Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, United Kingdom.
authors: Ngee-Han
authors: NH
authors: Lim
authors: ‡Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65962 Frankfurt, Germany.
authors: Danping
authors: D
authors: Ding-Pfennigdorff
authors: ‡Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65962 Frankfurt, Germany.
authors: Joachim
authors: J
authors: Saas
authors: ‡Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65962 Frankfurt, Germany.
authors: K Ulrich
authors: KU
authors: Wendt
authors: ‡Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65962 Frankfurt, Germany.
authors: Olaf
authors: O
authors: Ritzeler
authors: §Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, United Kingdom.
authors: Hideaki
authors: H
authors: Nagase
authors: ‡Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65962 Frankfurt, Germany.
authors: Oliver
authors: O
authors: Plettenburg
authors: †European Molecular Biology Laboratory (EMBL), Interdisciplinary Chemistry Group, Cell Biology and Biophysics Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany.
authors: Carsten
authors: C
authors: Schultz
authors: ‡Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65962 Frankfurt, Germany.|⊥Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Roessle-Str. 10, 13125 Berlin, Germany.
authors: Marc
authors: M
authors: Nazare
mesh_terms: D000081:Acetamides / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004337:Drug Carriers / Q000008:administration & dosage* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D006573:Heterocyclic Compounds, 1-Ring / Q000008:administration & dosage* / Q000378:metabolism; D051379:Mice; D010003:Osteoarthritis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013552:Swine
chemical_list: C522450:1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane; D000081:Acetamides; D004337:Drug Carriers; D006573:Heterocyclic Compounds, 1-Ring