Nanotopography Facilitates <i>in Vivo</i> Transdermal Delivery of High Molecular Weight Therapeutics through an Integrin-Dependent Mechanism

Walsh, Laura A.; Ryu, Jubin; Bock, Suzanne; Koval, Michael; Mauro, Theodora M.; Ross, Robert T.; Desai, Tejal A.

doi:10.1021/nl504829f

Cited by 35 publications

(70 citation statements)

References 40 publications

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“…Moreover, the study noted a significant increase in transport of large molecules, such as etanercept (MW = 150 kDa), across a Caco-2 layer upon contact with nanostructured films. While its underlying mechanism has yet been fully elucidated, the notable increase in transport is thought to be due to active modulation of tight junctional complexes by formation of focal adhesion complexes at the site of nanostructure-epithelial cell contact [167, 168]. …”

Section: Epithelial Permeation Enhancementmentioning

confidence: 99%

Micro/nanofabricated platforms for oral drug delivery

Fox

Kim

et al. 2015

Journal of Controlled Release

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The oral route of drug administration is most preferred due to its ease of use, low cost, and high patient compliance. However, the oral uptake of many small molecule drugs and biotherapeutics is limited by various physiological barriers, and, as a result, drugs suffer from issues with low solubility, low permeability, and degradation following oral administration. The flexibility of micro- and nanofabrication techniques has been used to create drug delivery platforms designed to address these barriers to oral drug uptake. Specifically, micro/nanofabricated devices have been designed with planar, asymmetric geometries to promote device adhesion and unidirectional drug release toward epithelial tissue, thereby prolonging drug exposure and increasing drug permeation. Furthermore, surface functionalization, nanotopography, responsive drug release, motion-based responses, and permeation enhancers have been incorporated into such platforms to further enhance drug uptake. This review will outline the application of micro/nanotechnology to specifically address the physiological barriers to oral drug delivery and highlight technologies that may be incorporated into these oral drug delivery systems to further enhance drug uptake.

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Section: Epithelial Permeation Enhancementmentioning

confidence: 99%

Micro/nanofabricated platforms for oral drug delivery

Fox

Kim

et al. 2015

Journal of Controlled Release

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“…Furthermore, this nanotopography, in combination with microneedles, was able to increase trans-dermal drug delivery across epidermis in two animal models (Figure 2). [15] Microneedles were used to pierce the dead cells of the stratum corneum, putting the nanostructures in contact with the keratinocytes. Nanostructured microneedles were able to increase the maximum serum concentration of antibody-based therapeutics to 30 and 24 times that of uncoated needles in rats and rabbits, respectively.…”

Section: Transepithelial Deliverymentioning

confidence: 99%

Nanotopography applications in drug delivery

Walsh

Allen

Desai

2015

Expert Opinion on Drug Delivery

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Refinement of micro- and nanofabrication in the semiconductor field has led to innovations in biomedical technologies. Nanotopography, in particular, shows great potential in facilitating drug delivery. The flexibility of fabrication techniques has created a diverse array of topographies that have been developed for drug delivery applications. Nanowires and nanostraws deliver drug cytosolically for in vitro and ex vivo applications. In vivo drug delivery is limited by the barrier function of the epithelium. Nanowires on microspheres increase adhesion and residence time for oral drug delivery, while also increasing permeability of the epithelium. Low aspect ratio nanocolumns increase paracellular permeability, and in conjunction with microneedles increase transdermal drug delivery of biologics in vivo. In summary, nanotopography is a versatile tool for drug delivery. It can deliver directly to cells or be used for in vivo delivery across epithelial barriers. This editorial highlights the application of nanotopography in the field of drug delivery.

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“…In this study, we examined two specific nanopatterns, Defined Nanostructure 2 (DN2) and Defined Nanostructure 3 (DN3), that were nanoimprinted on either polypropylene (PP) or polyether ether ketone (PEEK) generated from molds using electron-beam lithography [16, 17]. We previously discovered that nanostructured surfaces have the capacity to enhance the delivery of macromolecules across epithelial monolayers by an integrin-dependent pathway that activates myosin light chain kinase to increase tight junction permeability [16, 17].…”

Section: Introductionmentioning

confidence: 99%

“…We previously discovered that nanostructured surfaces have the capacity to enhance the delivery of macromolecules across epithelial monolayers by an integrin-dependent pathway that activates myosin light chain kinase to increase tight junction permeability [16, 17]. The effect of NSFs on transport of substrates ranging from less than 1 kDa to 900 kDa across Caco-2 human intestinal epithelial cells in vitro was assessed and compared to the maximum flux rate for these same substrates through fully disassembled tight junctions in calcium-depleted cells.…”

Section: Introductionmentioning

confidence: 99%

Calibrated flux measurements reveal a nanostructure-stimulated transcytotic pathway

Stewart

Koval

Molina

et al. 2017

Experimental Cell Research

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Transport of therapeutic agents across epithelial barriers is an important element in drug delivery. Transepithelial flux is widely used as a measure of transit across an epithelium, however it is most typically employed as a relative as opposed to absolute measure of molecular movement. Here, we have used the calcium switch approach to measure the maximum rate of paracellular flux through unencumbered intercellular junctions as a method to calibrate the flux rates for a series of tracers ranging in 0.6 to 900 kDa in size across barriers composed of human colon epithelial (Caco-2) cells. We then examined the effects of nanostructured films (NSFs) on transepithelial transport. Two different NSF patterns were used, Defined Nanostructure (DN) 2 imprinted on polypropylene (PP) and DN3 imprinted on polyether ether ketone (PEEK). NSFs made direct contact with cells and decreased their barrier function, as measured by transepithelial resistance (TER), however cell viability was not affected. When NSF-induced transepithelial transport of Fab fragment (55 kDa) and IgG (160 kDa) was measured, it was unexpectedly found to be significantly greater than the maximum paracellular rate as predicted using cells cultured in low calcium. These data suggested that NSFs stimulate an active transport pathway, most likely transcytosis, in addition to increasing paracellular flux. Transport of IgG via transcytosis was confirmed by immunofluorescence confocal microscopy, since NSFs induced a significant level of IgG endocytosis by Caco-2 cells. Thus, NSF-induced IgG flux was attributable to both transcytosis and the paracellular route. These data provide the first demonstration that transcytosis can be stimulated by NSFs and that this was concurrent with increased paracellular permeability. Moreover, NSFs with distinct architecture paired with specific substrates have the potential to provide an effective means to regulate transepithelial transport in order to optimize drug delivery.

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Nanotopography Facilitates in Vivo Transdermal Delivery of High Molecular Weight Therapeutics through an Integrin-Dependent Mechanism

Cited by 35 publications

References 40 publications

Micro/nanofabricated platforms for oral drug delivery

Micro/nanofabricated platforms for oral drug delivery

Nanotopography applications in drug delivery

Calibrated flux measurements reveal a nanostructure-stimulated transcytotic pathway

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