Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 499, Issue 1-2, Pages 32-39Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2010.04.019
Keywords
Cartilage; Intra-tissue transport; Glycosaminoglycan; Donnan partitioning; PACE4; ADAMTS-4/5
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Funding
- NIH [AR45779, AR33236]
- Pfizer
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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 similar to 1 x 10(-6) cm(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. (c) 2010 Elsevier Inc. All rights reserved.
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