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.
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.
|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|
|Stewart, Tarianna; Koval, William T; Molina, Samuel A et al. (2017) Calibrated flux measurements reveal a nanostructure-stimulated transcytotic pathway. Exp Cell Res 355:153-161|
|Zamecnik, Colin R; Lowe, Margaret M; Patterson, David M et al. (2017) Injectable Polymeric Cytokine-Binding Nanowires Are Effective Tissue-Specific Immunomodulators. ACS Nano 11:11433-11440|
|Fox, Cade B; Cao, Yuhong; Nemeth, Cameron L et al. (2016) Fabrication of Sealed Nanostraw Microdevices for Oral Drug Delivery. ACS Nano 10:5873-81|
|Cerchiari, Alec E; Samy, Karen E; Todhunter, Michael E et al. (2016) Probing the luminal microenvironment of reconstituted epithelial microtissues. Sci Rep 6:33148|
|Allen, Jessica; Ryu, Jubin; Maggi, Alessandro et al. (2016) Tunable Microfibers Suppress Fibrotic Encapsulation via Inhibition of TGF? Signaling. Tissue Eng Part A 22:142-50|
|Fox, Cade B; Kim, Jean; Schlesinger, Erica B et al. (2015) Fabrication of micropatterned polymeric nanowire arrays for high-resolution reagent localization and topographical cellular control. Nano Lett 15:1540-6|
|Kim, Jean; Schlesinger, Erica B; Desai, Tejal A (2015) Nanostructured materials for ocular delivery: nanodesign for enhanced bioadhesion, transepithelial permeability and sustained delivery. Ther Deliv 6:1365-76|
|Walsh, Laura A; Allen, Jessica L; Desai, Tejal A (2015) Nanotopography applications in drug delivery. Expert Opin Drug Deliv 12:1823-7|
|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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