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.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Nanotechnology Study Section (NANO)
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Tucker, Jessica
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University of California San Francisco
Schools of Pharmacy
San Francisco
United States
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Fox, Cade B; Nemeth, Cameron L; Chevalier, Rachel W et al. (2017) Picoliter-volume inkjet printing into planar microdevice reservoirs for low-waste, high-capacity drug loading. Bioeng Transl Med 2:9-16
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Walsh, Laura; Ryu, Jubin; Bock, Suzanne et al. (2015) Nanotopography facilitates in vivo transdermal delivery of high molecular weight therapeutics through an integrin-dependent mechanism. Nano Lett 15:2434-41

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