title: Anti-Inflammatory Effect of Dexamethasone Controlled Released From Anterior Suprachoroidal Polyurethane Implants on Endotoxin-Induced Uveitis in Rats.
abstract: OBJECTIVE
  Targeted drug delivery to the ocular tissues remains a challenge. Biodegradable intraocular implants allow prolonged controlled release of drugs directly into the eye. In this study, we evaluated an anterior suprachoroidal polyurethane implant containing dexamethasone polyurethane dispersions (DX-PUD) as a drug delivery system in the rat model of endotoxin-induced uveitis (EIU).
  
  
  METHODS
  In vitro drug release was studied using PUD implants containing 8%, 20%, and 30% (wt/wt) DX. Cytotoxicity of the degradation products of DX-PUD was assessed on human ARPE-19 cells using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) test. Short-term ocular biocompatibility of suprachoroidal DX-PUD implants was evaluated in normal rat eyes. Endotoxin-induced uveitis was then induced in rat eyes preimplanted with DX-PUD. Clinical examination was performed at 24 hours; eyes were used to assess inflammatory cell infiltration and macrophage/microglial activation. Cytokine and chemokine expression in the iris/ciliary body and in the retina was investigated using quantitative PCR. Feasibility of anterior suprachoroidal PUD implantation was also tested using postmortem human eyes.
  
  
  RESULTS
  A burst release was followed by a sustained controlled release of DX from PUD implants. By-products of the DX-PUD were not toxic to human ARPE-19 cells or to rat ocular tissues. Dexamethasone-PUD implants prevented EIU in rat eyes, reducing inflammatory cell infiltration and inhibiting macrophage/microglial activation. Dexamethasone-PUD downregulated proinflammatory cytokines/chemokines (IL-1β, IL-6, cytokine-induced neutrophil chemoattractant [CINC]) and inducible nitric oxide synthase (iNOS) and upregulated IL-10 anti-inflammatory cytokine. Polyurethane dispersion was successfully implanted into postmortem human eyes.
  
  
  CONCLUSIONS
  Dexamethasone-PUD implanted in the anterior suprachoroidal space may be of interest in the treatment of intraocular inflammation.
authors.affiliation: Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil 2Inserm UMR_S 1138, Team 17: From Physiopathology of Retinal Diseases to Clinical Advances, Centre de Recherche des Cordeliers, Paris, France 3Sorbonne Universit.
authors.forename: Juliana
authors.initials: J
authors.lastname: Barbosa Saliba
authors.affiliation: Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil 2Inserm UMR_S 1138, Team 17: From Physiopathology of Retinal Diseases to Clinical Advances, Centre de Recherche des Cordeliers, Paris, France 3Sorbonne Universit.
authors.forename: Lorena
authors.initials: L
authors.lastname: Vieira
authors.affiliation: Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil 2Inserm UMR_S 1138, Team 17: From Physiopathology of Retinal Diseases to Clinical Advances, Centre de Recherche des Cordeliers, Paris, France 3Sorbonne Universit.
authors.forename: Gabriella Maria
authors.initials: GM
authors.lastname: Fernandes-Cunha
authors.affiliation: School of Pharmacy, Federal University of São João Del Rei, Divinópolis, Minas Gerais, Brazil.
authors.forename: Gisele
authors.initials: G
authors.lastname: Rodrigues Da Silva
authors.affiliation: Pharmaceutical and Biotechnological Development, Ezequiel Dias Foundation, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Ligório Fialho
authors.affiliation: Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Armando
authors.initials: A
authors.lastname: Silva-Cunha
authors.affiliation: Inserm UMR_S 1138, Team 17: From Physiopathology of Retinal Diseases to Clinical Advances, Centre de Recherche des Cordeliers, Paris, France 3Sorbonne Universities, University of Pierre et Marie Curie, Centre de Recherche des Cordeliers, Paris, France 4Pa.
authors.forename: Elodie
authors.initials: E
authors.lastname: Bousquet
authors.affiliation: Inserm UMR_S 1138, Team 17: From Physiopathology of Retinal Diseases to Clinical Advances, Centre de Recherche des Cordeliers, Paris, France 3Sorbonne Universities, University of Pierre et Marie Curie, Centre de Recherche des Cordeliers, Paris, France 4Pa.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Naud
authors.affiliation: State University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Eliane
authors.initials: E
authors.lastname: Ayres
authors.affiliation: Department of Metallurgical and Materials Engineering, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Rodrigo Lambert
authors.initials: RL
authors.lastname: Oréfice
authors.affiliation: Department of Ophthalmology of University of Lausanne, Jules-Gonin Ophthalmic Hospital, CHUV, Lausanne, Switzerland.
authors.forename: Meriem
authors.initials: M
authors.lastname: Tekaya
authors.affiliation: Department of Ophthalmology of University of Lausanne, Jules-Gonin Ophthalmic Hospital, CHUV, Lausanne, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Kowalczuk
authors.affiliation: Inserm UMR_S 1138, Team 17: From Physiopathology of Retinal Diseases to Clinical Advances, Centre de Recherche des Cordeliers, Paris, France 3Sorbonne Universities, University of Pierre et Marie Curie, Centre de Recherche des Cordeliers, Paris, France 4Pa.
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Inserm UMR_S 1138, Team 17: From Physiopathology of Retinal Diseases to Clinical Advances, Centre de Recherche des Cordeliers, Paris, France 3Sorbonne Universities, University of Pierre et Marie Curie, Centre de Recherche des Cordeliers, Paris, France 4Pa.
authors.forename: Francine
authors.initials: F
authors.lastname: Behar-Cohen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002460:Cell Line; D002470:Cell Survival; D002924:Ciliary Body / Q000378:metabolism; D004396:Coloring Agents / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004343:Drug Implants; D005110:Extracellular Space; D005260:Female; D006801:Humans; D007498:Iris / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D011140:Polyurethanes; D051381:Rats; D011917:Rats, Inbred Lew; D055213:Retinal Pigment Epithelium / Q000187:drug effects; D012486:Salmonella typhimurium; D017550:Spectroscopy, Fourier Transform Infrared; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014605:Uveitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D000893:Anti-Inflammatory Agents; D004396:Coloring Agents; D016207:Cytokines; D004343:Drug Implants; D008070:Lipopolysaccharides; D011140:Polyurethanes; D013778:Tetrazolium Salts; D013844:Thiazoles; D003907:Dexamethasone; C022616:thiazolyl blue