title: Nitroxide delivery system for Nrf2 activation and skin protection.
abstract: Cyclic nitroxides are a large group of compounds composed of diverse stable radicals also known as synthetic antioxidants. Although nitroxides are valuable for use in several skin conditions, in in vivo conditions they have several drawbacks, such as nonspecific dispersion in normal tissue, preferential renal clearance and rapid reduction of the nitroxide to the corresponding hydroxylamine. However, these drawbacks can be easily addressed by encapsulating the nitroxides within microemulsions. This approach would allow nitroxide activity and therefore their valuable effects (e.g. activation of the Keap1-Nrf2-EpRE pathway) to continue. In this work, nitroxides were encapsulated in a microemulsion composed of biocompatible ingredients. The nanometric size and shape of the vehicle microemulsion and nitroxide microemulsion displayed high similarity, indicating that the stability of the microemulsions was preserved. Our studies demonstrated that nitroxide microemulsions were more potent inducers of the Keap1-Nrf2-EpRE pathway than the free nitroxides, causing the activation of phase II enzymes. Moreover, microemulsions containing nitroxides significantly reduced UVB-induced cytotoxicity in the skin. Understanding the mechanism of this improved activity may expand the usage of many other Nrf2 modulating molecules in encapsulated form, as a skin protection strategy against oxidative stress-related conditions.
authors.affiliation: The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel; Department of Chemical Engineering, Technion-Israel Institute of Technology, Technion City, Haifa 3200003, Israel; The Russell Berrie Nanotechnology Institute, Technion-Israel Institute of Technology, Haifa 3200003, Israel; Department of Developmental Biology and Cancer Research, The Hebrew University Medical School, Ein-Karem Campus, Jerusalem 9112102, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Ben Yehuda Greenwald
authors.affiliation: The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
authors.forename: Marina
authors.initials: M
authors.lastname: Frušić-Zlotkin
authors.affiliation: The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Soroka
authors.affiliation: Department of Developmental Biology and Cancer Research, The Hebrew University Medical School, Ein-Karem Campus, Jerusalem 9112102, Israel.
authors.forename: Shmuel Ben
authors.initials: SB
authors.lastname: Sasson
authors.affiliation: Department of Chemical Engineering, Technion-Israel Institute of Technology, Technion City, Haifa 3200003, Israel; The Russell Berrie Nanotechnology Institute, Technion-Israel Institute of Technology, Haifa 3200003, Israel.
authors.forename: Havazelet
authors.initials: H
authors.lastname: Bianco-Peled
authors.affiliation: Department of Chemical Engineering, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel; Ilze Kats Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Bitton
authors.affiliation: The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel. Electronic address: ronk@ekmd.huji.ac.il.
authors.forename: Ron
authors.initials: R
authors.lastname: Kohen
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D061745:Antioxidant Response Elements; D000975:Antioxidants / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D020285:Cryoelectron Microscopy; D003497:Cyclic N-Oxides / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers; D004355:Drug Stability; D004655:Emulsions; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D008027:Light; D008055:Lipids / Q000737:chemistry*; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D010316:Particle Size; D012333:RNA, Messenger / Q000378:metabolism; D012542:Scattering, Radiation; D053838:Scattering, Small Angle; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D013501:Surface-Active Agents / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods; D014466:Ultraviolet Rays; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D004337:Drug Carriers; D004655:Emulsions; C508585:IL1B protein, human; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D008055:Lipids; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D013501:Surface-Active Agents; C015527:4-amino-TEMPO; C003959:TEMPO
keywords: Microemulsion; Nitroxides; Nrf2; Oxidative stress; Phase II enzymes; Skin