title: Nanotopography facilitates in vivo transdermal delivery of high molecular weight therapeutics through an integrin-dependent mechanism.
abstract: Transdermal delivery of therapeutics is restricted by narrow limitations on size and hydrophobicity. Nanotopography has been shown to significantly enhance high molecular weight paracellular transport in vitro. Herein, we demonstrate for the first time that nanotopography applied to microneedles significantly enhances transdermal delivery of etanercept, a 150 kD therapeutic, in both rats and rabbits. We further show that this effect is mediated by remodeling of the tight junction proteins initiated via integrin binding to the nanotopography, followed by phosphorylation of myosin light chain (MLC) and activation of the actomyosin complex, which in turn increase paracellular permeability.
authors: †Department of Bioengineering and Therapeutic Sciences, University of California-San Francisco, 1700 Fourth Street, Room 204, San Francisco, California 94158-2330, United States.
authors: Laura
authors: L
authors: Walsh
authors: ‡Department of Dermatology, University of California-San Francisco, 1701 Divisadero Street, San Francisco, California 94115, United States.
authors: Jubin
authors: J
authors: Ryu
authors: §Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.
authors: Suzanne
authors: S
authors: Bock
authors: ∥Division of Pulmonary, Allergy, and Critical Care Medicine and Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Suite 205, Atlanta, Georgia 30322, United States.
authors: Michael
authors: M
authors: Koval
authors: ‡Department of Dermatology, University of California-San Francisco, 1701 Divisadero Street, San Francisco, California 94115, United States.|⊥Department of Dermatology, San Francisco Veterans Affairs Hospital, 4150 Clement Street, San Francisco, California 94121, United States.
authors: Theodora
authors: T
authors: Mauro
authors: #Kimberly-Clark Corporation, 8601 Dunwoody Place, Suite 580, Atlanta, Georgia 30350, United States.
authors: Russell
authors: R
authors: Ross
authors: †Department of Bioengineering and Therapeutic Sciences, University of California-San Francisco, 1700 Fourth Street, Room 204, San Francisco, California 94158-2330, United States.
authors: Tejal
authors: T
authors: Desai
mesh_terms: D000279:Administration, Cutaneous; D018938:Caco-2 Cells; D004867:Equipment Design; D019544:Equipment Failure Analysis; D000068800:Etanercept / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008422:Materials Testing; D008845:Microinjections / Q000295:instrumentation*; D008970:Molecular Weight; D036103:Nanotechnology / Q000295:instrumentation / Q000379:methods; D009339:Needles; D012869:Skin Absorption / Q000502:physiology*; D013499:Surface Properties
chemical_list: D016023:Integrins; D000068800:Etanercept
keywords: Nanotopography; drug delivery; etanercept; integrin; transdermal