PMID- 26093066 OWN - NLM STAT- MEDLINE DCOM- 20160527 LR - 20220309 IS - 1878-7568 (Electronic) IS - 1742-7061 (Print) IS - 1742-7061 (Linking) VI - 24 DP - 2015 Sep TI - Therapeutic intradermal delivery of tumor necrosis factor-alpha antibodies using tip-loaded dissolvable microneedle arrays. PG - 96-105 LID - S1742-7061(15)00284-6 [pii] LID - 10.1016/j.actbio.2015.05.036 [doi] AB - Tumor necrosis factor-alpha (TNF-alpha) specific antibodies (anti-TNF-alpha Ab) have been shown to be potent TNF inhibitors and effective therapeutics for a range of inflammatory diseases. Typically, these drugs are administered systemically, but systemic dosing sufficient to achieve locally effective concentrations in peripheral tissues has been associated with systemic immunosuppression and related adverse events. Here, we evaluated the use of tip-loaded dissolvable microneedle arrays (MNAs) for localized intradermal delivery of anti-TNF-alpha Ab. MNAs with obelisk shape microneedles that incorporate the antibody cargo in the needle tips were created from carboxymethylcellulose (CMC) using a micromilling/spin-casting fabrication method. We found that anti-TNF-alpha Ab integrated into MNAs using this room temperature fabrication process maintained conformationally dependent TNF-alpha binding activity. Further, these MNAs efficiently delivered anti-TNF-alpha antibodies to the dermis of human skin with clinically applicable release profiles. To evaluate MNA delivered anti-TNF-alpha Ab function, we applied anti-TNF-alpha Ab containing MNAs to established psoriasiform lesions on the skin of mice. MNA anti-TNF-alpha Ab treatment reduced key biomarkers of psoriasiform inflammation including epidermal thickness and IL-1beta expression. Taken together, these results demonstrate efficient and biologically effective MNA delivery of anti-TNF-alpha Ab to the intradermal microenvironment of the skin in mice and humans, and support the development of MNA mediated antibody delivery for clinical applications. STATEMENT OF SIGNIFICANCE: Tumor necrosis factor-alpha (TNF-alpha) specific antibodies (anti-TNF-alpha Ab) have been shown to be potent TNF inhibitors and effective therapeutics for a range of inflammatory diseases. Typically, these drugs are administered systemically, but systemic dosing sufficient to achieve locally effective concentrations in peripheral tissues has been associated with systemic immunosuppression and related adverse events. Here we demonstrate efficient and biologically effective MNA delivery of anti-TNF-alpha Ab to the intradermal microenvironment of the skin in mice and humans. These results support the development of MNA mediated antibody delivery of therapeutic antibodies for clinical applications. CI - Copyright (c) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. FAU - Korkmaz, Emrullah AU - Korkmaz E AD - Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, United States. FAU - Friedrich, Emily E AU - Friedrich EE AD - Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, United States. FAU - Ramadan, Mohamed H AU - Ramadan MH AD - Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, United States. FAU - Erdos, Geza AU - Erdos G AD - Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States. FAU - Mathers, Alicia R AU - Mathers AR AD - Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States. FAU - Burak Ozdoganlar, O AU - Burak Ozdoganlar O AD - Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, United States; Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, United States; Department of Material Science and Engineering, Carnegie Mellon University, Pittsburgh, PA, United States. FAU - Washburn, Newell R AU - Washburn NR AD - Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, United States; Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, United States; The McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States. FAU - Falo, Louis D Jr AU - Falo LD Jr AD - Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States; Clinical and Translational Science Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; The University of Pittsburgh Cancer Institute, Pittsburgh, PA, United States; The McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States. Electronic address: lof2@pitt.edu. LA - eng GR - R01 EB012776/EB/NIBIB NIH HHS/United States GR - R01EB012776/EB/NIBIB NIH HHS/United States GR - R01 AR071277/AR/NIAMS NIH HHS/United States GR - R01 AR074285/AR/NIAMS NIH HHS/United States GR - R01 AR068249/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150618 PL - England TA - Acta Biomater JT - Acta biomaterialia JID - 101233144 RN - 0 (Antibodies) RN - 0 (IL1B protein, mouse) RN - 0 (Interleukin-1beta) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Animals MH - Antibodies/*pharmacology MH - *Drug Delivery Systems/instrumentation/methods MH - Epidermis/metabolism/pathology MH - Gene Expression Regulation/drug effects MH - Humans MH - Inflammation/drug therapy/metabolism/pathology MH - Injections, Intradermal/instrumentation/methods MH - Interleukin-1beta/biosynthesis MH - Mice MH - *Needles MH - Psoriasis/drug therapy/metabolism/pathology MH - Tumor Necrosis Factor-alpha/*antagonists & inhibitors PMC - PMC8266287 MID - NIHMS705040 OTO - NOTNLM OT - Dissolvable microneedle arrays OT - Intradermal delivery OT - Therapeutic antibody OT - Tumor necrosis factor-alpha EDAT- 2015/06/21 06:00 MHDA- 2016/05/28 06:00 PMCR- 2021/07/08 CRDT- 2015/06/21 06:00 PHST- 2015/02/10 00:00 [received] PHST- 2015/04/29 00:00 [revised] PHST- 2015/05/28 00:00 [accepted] PHST- 2015/06/21 06:00 [entrez] PHST- 2015/06/21 06:00 [pubmed] PHST- 2016/05/28 06:00 [medline] PHST- 2021/07/08 00:00 [pmc-release] AID - S1742-7061(15)00284-6 [pii] AID - 10.1016/j.actbio.2015.05.036 [doi] PST - ppublish SO - Acta Biomater. 2015 Sep;24:96-105. doi: 10.1016/j.actbio.2015.05.036. Epub 2015 Jun 18.