title: Thermosensitive dendritic polyglycerol-based nanogels for cutaneous delivery of biomacromolecules.
abstract: Genetic skin diseases caused by mutations resulting in diminished protein synthesis could benefit from local substitution of the missing protein. Proteins, however, are excluded from topical applications due to their physicochemical properties. We prepared protein-loaded thermoresponsive poly(N-isopropylacrylamide)-polyglycerol-based nanogels exhibiting a thermal trigger point at 35°C, which is favorable for cutaneous applications due to the native thermal gradient of human skin. At≥35°C, the particle size (~200nm) was instantly reduced by 20% and 93% of the protein was released; no alterations of protein structure or activity were detected. Skin penetration experiments demonstrated efficient intraepidermal protein delivery particularly in barrier deficient skin, penetration of the nanogels themselves was not detected. The proof of concept was provided by transglutaminase 1-loaded nanogels which efficiently delivered the protein into transglutaminase 1-deficient skin models resulting in a restoration of skin barrier function. In conclusion, thermoresponsive nanogels are promising topical delivery systems for biomacromolecules.
  
  
  BACKGROUND
  Many skin disorders are characterized by an absence of a specific protein due to underlying gene mutation. In this article, the authors described the use of a thermoresponsive PNIPAM-dPG nanogel for cutaneous protein delivery in a gene knock-down model of human skin. The results may have implication for nano-based local delivery of therapeutic agents in skin.
authors: Ludwig-Maximilians University Munich, Department of Pharmacy, Munich, Germany.
authors: Madeleine
authors: M
authors: Witting
authors: Freie Universität Berlin, Institute of Chemistry and Biochemistry, Berlin, Germany.
authors: Maria
authors: M
authors: Molina
authors: Freie Universität Berlin, Institute for Pharmaceutical Sciences, Berlin, Germany.
authors: Katja
authors: K
authors: Obst
authors: Center for Dermatogenetics, Division of Human Genetics & Department of Dermatology, Innsbruck Medical University, Innsbruck, Austria; Center for Dermatogenetics, Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors: Roswitha
authors: R
authors: Plank
authors: Center for Dermatogenetics, Division of Human Genetics & Department of Dermatology, Innsbruck Medical University, Innsbruck, Austria.
authors: Katja Martina
authors: KM
authors: Eckl
authors: Center for Dermatogenetics, Division of Human Genetics & Department of Dermatology, Innsbruck Medical University, Innsbruck, Austria; Center for Dermatogenetics, Cologne Center for Genomics, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: Hans Christian
authors: HC
authors: Hennies
authors: Freie Universität Berlin, Institute of Chemistry and Biochemistry, Berlin, Germany.
authors: Marcelo
authors: M
authors: Calderón
authors: Ludwig-Maximilians University Munich, Department of Pharmacy, Munich, Germany.
authors: Wolfgang
authors: W
authors: Friess
authors: Freie Universität Berlin, Institute for Pharmaceutical Sciences, Berlin, Germany. Electronic address: sarah.hedtrich@fu-berlin.de.
authors: Sarah
authors: S
authors: Hedtrich
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry*; D000279:Administration, Cutaneous; D000818:Animals; D001215:Asparaginase / Q000008:administration & dosage / Q000493:pharmacokinetics; D002417:Cattle; D003692:Delayed-Action Preparations / Q000737:chemistry* / Q000378:metabolism; D005782:Gels / Q000737:chemistry* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005990:Glycerol / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D011108:Polymers / Q000737:chemistry* / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000493:pharmacokinetics; D012867:Skin / Q000378:metabolism* / Q000648:ultrastructure; D012869:Skin Absorption; D013552:Swine; D013696:Temperature; D013739:Testosterone / Q000008:administration & dosage / Q000493:pharmacokinetics; D011503:Transglutaminases / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics
chemical_list: D000180:Acrylic Resins; D003692:Delayed-Action Preparations; D005782:Gels; D011108:Polymers; C052970:poly-N-isopropylacrylamide; C043941:polyglycerol; D012710:Serum Albumin, Bovine; D013739:Testosterone; D011503:Transglutaminases; C105804:transglutaminase 1; D001215:Asparaginase; D005990:Glycerol
keywords: Cutaneous protein delivery; Dendritic polyglycerol; Reconstructed human skin; Skin barrier restoration; Thermoresponsive nanogels