Transport and equilibrium uptake of a peptide inhibitor of PACE4 into articular cartilage is dominated by electrostatic interactions
Name
Grodzinsky-2010-Transport and equilibrium uptake.pdf
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1.17 MB
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Author(s)
Byun, Sangwon
Tortorella, Micky D.
Malfait, Anne-Marie
Fok, Kam
Grodzinsky, Alan J.
Frank, Eliot
Date Issued
May 2010
Journal
Archives of Biochemistry and Biophysics
Publisher
Elsevier
Citation
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.
Version
Author's final manuscript
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 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.
MIT Department
Massachusetts 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
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DOI of Published Version
https://doi.org/10.1016/j.abb.2010.04.019
