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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.

Original publication

DOI

10.1021/bc500557s

Type

Journal article

Journal

Bioconjug Chem

Publication Date

18/03/2015

Volume

26

Pages

383 - 388

Keywords

Acetamides, Animals, Arthritis, Experimental, Cartilage, Drug Carriers, Drug Delivery Systems, Heterocyclic Compounds, 1-Ring, Mice, Osteoarthritis, Swine