title: Thermoresponsive hyaluronic acid nanogels as hydrophobic drug carrier to macrophages.
abstract: Delivery systems for macrophages are particularly attractive since these phagocytic cells play a important role in immunological and inflammatory responses, also acting as host cells for microorganisms that are involved in deadly infectious diseases, such as leishmaniasis. Hyaluronic acid (HA) is specifically recognized by macrophages that are known to express HA receptors. Therefore, in this study, we focused on HA-based nanogels as drug carriers for these cells. The drug delivery was validated in an in vivo study on mice using intravital two-photon laser scanning microscopy. HA derivatives were modified with a biocompatible oligo(ethylene glycol)-based thermoresponsive polymer to form nanogels. These HA conjugates were readily prepared by varying the molar mass of initial HA and the degree of substitution via radical-mediated thiol-ene chemistry in aqueous solution. The derivatives were shown to self-assemble into spherical gel particles with diameters ranging from 150 to 214 nm above 37 °C. A poorly water-soluble two-photon dye was successfully loaded into the nanogels during this self-assembly process. In vitro cellular uptake tests using a RAW 264.7 murine macrophage cell line showed successful intracellular delivery of the hydrophobic dye. After intravenous injection in mice, the nanogels circulated freely in the blood but were rapidly phagocytized within 13 min by circulating macrophages and stored in the liver and spleen, as observed by two-photon microscopy. Benefit can be thus expected in using such a delivery system for the liver and spleen macrophage-associated diseases.
authors.affiliation: University Grenoble Alpes, CERMAV-CNRS, F-38000 Grenoble, France; Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Universidade Estadual de Maringá, Maringá, PR, Brazil.
authors.forename: Talitha
authors.initials: T
authors.lastname: Fernandes Stefanello
authors.affiliation: University Grenoble Alpes, CERMAV-CNRS, F-38000 Grenoble, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Szarpak-Jankowska
authors.affiliation: Intravital Microscopy Platform Grenoble, Institute of Neuroscience Grenoble and Clinatec, Grenoble, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Appaix
authors.affiliation: Department of Pharmaceutics, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Louage
authors.affiliation: Intravital Microscopy Platform Grenoble, Institute of Neuroscience Grenoble and Clinatec, Grenoble, France.
authors.forename: Lauriane
authors.initials: L
authors.lastname: Hamard
authors.affiliation: Department of Pharmaceutics, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium.
authors.forename: Bruno G
authors.initials: BG
authors.lastname: De Geest
authors.affiliation: Intravital Microscopy Platform Grenoble, Institute of Neuroscience Grenoble and Clinatec, Grenoble, France.
authors.forename: Boudewijn
authors.initials: B
authors.lastname: van der Sanden
authors.affiliation: Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Universidade Estadual de Maringá, Maringá, PR, Brazil.
authors.forename: Celso Vataru
authors.initials: CV
authors.lastname: Nakamura
authors.affiliation: University Grenoble Alpes, CERMAV-CNRS, F-38000 Grenoble, France. Electronic address: Rachel.auzely@cermav.cnrs.fr.
authors.forename: Rachel
authors.initials: R
authors.lastname: Auzély-Velty
mesh_terms: D000818:Animals; D002460:Cell Line; D004337:Drug Carriers; D004705:Endocytosis; D005453:Fluorescence; D006820:Hyaluronic Acid / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D000080385:Nanogels; D010316:Particle Size; D017785:Photons; D011092:Polyethylene Glycols / Q000737:chemistry*; D011094:Polyethyleneimine / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D013696:Temperature
chemical_list: D004337:Drug Carriers; D000080385:Nanogels; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D006820:Hyaluronic Acid
keywords: Copolymer; Hyaluronic acid; Hydrophobic drugs; Thermoresponsive nanogel; Two-photon microscopy