The epithelial barrier presents a significant obstacle to the delivery of macromolecules in the size range of 20 - 150 kDa. In particular, the tight junctional complex, which links adjacent cells and occludes the paracellular space, presents a significant obstacle to delivery of macromolecules. To improve the transport of macromolecular biologics across epithelia, new approaches need to be developed that enhance paracellular drug transport by specifically and reversibly modulating tight junctions. In this proposal, we investigate the effect of nanostructured surfaces on the modulation of tight junction permeability and transport of key therapeutic molecules in vitro. We seek to determine the mechanisms through which epithelial permeability is enhanced by nanotopography and optimize nanostructured materials to broaden the types of drugs that can be delivered paracellularly. It is expected that the fundamental knowledge gained in these studies will enhance the development of new epithelial drug delivery systems.

Public Health Relevance

Therapeutic macromolecular drugs currently under development are typically administered through IV injection due to their poor epithelial permeability. In this project, we will study how nanotopography can be used to alter drug permeability across the epithelium in a safe and reversible manner and the mechanisms behind this phenomenon. The ability to increase epithelial transport via nanotopography may have dramatic implications for drug delivery applications where the epithelial barrier presents an obstacle to the passage of high molecular weight therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
1R01EB018842-01
Application #
8748142
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Tucker, Jessica
Project Start
2014-09-18
Project End
2018-05-31
Budget Start
2014-09-18
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$357,130
Indirect Cost
$90,131
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Schlingmann, Barbara; Molina, Samuel A; Koval, Michael (2015) Claudins: Gatekeepers of lung epithelial function. Semin Cell Dev Biol 42:47-57

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