Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1926038 | Archives of Biochemistry and Biophysics | 2010 | 8 Pages |
Abstract
The availability of therapeutic molecules to targets within cartilage depends on transport through the avascular matrix. We studied equilibrium partitioning and non-equilibrium transport into cartilage of Pf-pep, a 760Â Da positively charged peptide inhibitor of the proprotein convertase PACE4. Competitive binding measurements revealed negligible binding of Pf-pep to sites within cartilage. Uptake of Pf-pep depended on glycosaminoglycan charge density, and was consistent with predictions of Donnan equilibrium given the known charge of Pf-pep. In separate transport experiments, the diffusivity of Pf-pep in cartilage was measured to be â¼1Â ÃÂ 10â6Â cm2/s, close to other similarly-sized non-binding solutes. These results suggest that small positively charged therapeutics will have a higher concentration within cartilage than in the surrounding synovial fluid, a desired property for local delivery; however, such therapeutics may rapidly diffuse out of cartilage unless there is additional specific binding to intra-tissue substrates that can maintain enhanced intra-tissue concentration for local delivery.
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Authors
Sangwon Byun, Micky D. Tortorella, Anne-Marie Malfait, Kam Fok, Eliot H. Frank, Alan J. Grodzinsky,