Transport and equilibrium uptake of a peptide inhibitor of PACE4 into articular cartilage is dominated by electrostatic interactions
Author(s)Byun, Sangwon; Tortorella, Micky D.; Malfait, Anne-Marie; Fok, Kam; Grodzinsky, Alan J.; Frank, Eliot; ... Show more Show less
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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 760 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 ~1 × 10[superscript −6] cm[superscript 2]/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.
DepartmentMassachusetts Institute of Technology. Center for Biomedical Engineering; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science; Massachusetts Institute of Technology. Department of Mechanical Engineering
Archives of Biochemistry and Biophysics
Byun, Sangwon, Micky D. Tortorella, Anne-Marie Malfait, Kam Fok, Eliot H. Frank, and Alan J. Grodzinsky. “Transport and Equilibrium Uptake of a Peptide Inhibitor of PACE4 into Articular Cartilage Is Dominated by Electrostatic Interactions.” Archives of Biochemistry and Biophysics 499, no. 1–2 (July 2010): 32–39.
Author's final manuscript