title: Tip-Loaded Dissolvable Microneedle Arrays Effectively Deliver Polymer-Conjugated Antibody Inhibitors of Tumor-Necrosis-Factor-Alpha Into Human Skin.
abstract: Autoinflammatory skin diseases are characterized by a disequilibrium of cytokines in the local skin microenvironment, suggesting that local delivery of therapeutics, including anticytokine antibodies, may provide benefit without the unwanted off-target effects of systemically delivered therapies. Rapid diffusion of therapeutics away from the target site has been a challenge to the development of local therapies. Conjugation of high molecular weight hydrophilic polymers to cytokine neutralizing mAbs has been shown to be an effective strategy for local control of inflammation in healing burn wounds. However, the burn application is unique because the skin barrier is already breached. For the treatment of autoinflammatory skin diseases, the major challenge for local delivery lies in penetrating the stratum corneum. Here, we investigate a new therapeutic approach combining the use of tip-loaded dissolvable microneedle arrays (TL-dMNAs) for local application of polymer-conjugated antibody inhibitors of tumor-necrosis-factor-alpha (TNF-α). Specifically, intradermal delivery and pharmacokinetics of (anti-TNF-α-Ab)-(high molecular weight hyaluronic acid [HA]) conjugates from tip-loaded, obelisk-shaped dissolvable microneedle arrays were investigated in living human skin. The results indicate (1) TL-dMNAs can be successfully fabricated to integrate (anti-TNF-α-Ab)-HA at the tip portion of the microneedles while preserving the biological activity necessary for antibody ligand binding; (2) (anti-TNF-α-Ab)-HA can be effectively delivered into human skin using obelisk-shaped TL-dMNAs; and (3) polymer conjugation effectively inhibits antibody diffusion from the delivery site. Taken together, these results support the evaluation of microneedle array-based delivery of varying polymer-antibody conjugates for the treatment of inflammatory skin diseases.
authors.affiliation: Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213.
authors.forename: Emrullah
authors.initials: E
authors.lastname: Korkmaz
authors.affiliation: Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Friedrich
authors.affiliation: Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213.
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Ramadan
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors.forename: Geza
authors.initials: G
authors.lastname: Erdos
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Mathers
authors.affiliation: Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213; Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213; Department of Material Science and Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213.
authors.forename: O Burak
authors.initials: OB
authors.lastname: Ozdoganlar
authors.affiliation: Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213; Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213; The McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors.forename: Newell R
authors.initials: NR
authors.lastname: Washburn
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; Clinical and Translational Science Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; The University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213; The McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213. Electronic address: lof2@pitt.edu.
authors.forename: Louis D
authors.initials: LD
authors.lastname: Falo
mesh_terms: D000279:Administration, Cutaneous; D016503:Drug Delivery Systems / Q000379:methods*; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008845:Microinjections / Q000379:methods*; D011108:Polymers / Q000008:administration & dosage / Q000378:metabolism*; D012869:Skin Absorption / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D011108:Polymers; D014409:Tumor Necrosis Factor-alpha
keywords: dissolvable microneedles; hyaluronic acid; intradermal drug delivery; monoclonal antibody; tumor-necrosis-factor-alpha; water-soluble polymer