Specific and general binding in arterial drug delivery
Name
62147535-MIT.pdf
Description
Full printable version
Size
7.57 MB
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Checksum (MD5)
5b60ccb9a1d9efb4f68ad087061262ae
Author(s)
Levin, Andrew D. (Andrew David), 1976-
Advisor(s)
Elazer R. Edelman.
Date Issued
2005
Publisher
Massachusetts Institute of Technology
Abstract
Drug-eluting stents have emerged as the most effective method for treating restenosis following percutaneous coronary interventions. This thesis investigates how drugs with similar physiochemical properties but different specific binding targets yield drastically different tissue transport, retention and ultimately efficacy independent of their putative biological effects. Our central hypothesis is that both specific and general binding of drugs to tissue proteins, as mediated by drug-specific physiochemical properties, plays a central role in arterial transport and distribution. We define and compare the kinetic and transport properties of clinically implemented compounds with different binding modes. While hydrophilic compounds are rapidly cleared, hydrophobic ones are retained with an arterial transmural distribution dependent upon the distribution of specific and general binding sites. Common systemically administered cardiac drugs compete with locally delivered agents through displacement of general binding sites. Exploration of drug binding in thrombus indicates significant specific and general binding capacity. Stent-to- arterial wall drug transfer is acutely sensitive to stent strut position in clot relative to the wall due to thrombus binding capacity. A poorly controlled microthrombotic environment around a stent strut can drastically enhance systemic washout while reducing delivery to the tissue. Together this body of work implies that specific and general binding plays a critical role in the clinical efficacy of locally delivered drugs, and must be a consideration in the rational design of stent-based delivery devices.
Description
Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2005.
Includes bibliographical references.
Subjects
Harvard University--MIT Division of Health Sciences and Technology.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
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