Juliana Barbosa Saliba1, Lorena Vieira1, Gabriella Maria Fernandes-Cunha1, Gisele Rodrigues Da Silva2, Sílvia Ligório Fialho3, Armando Silva-Cunha4, Elodie Bousquet5, Marie-Christine Naud5, Eliane Ayres6, Rodrigo Lambert Oréfice7, Meriem Tekaya8, Laura Kowalczuk8, Min Zhao5, Francine Behar-Cohen5. 1. 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. 2. School of Pharmacy, Federal University of São João Del Rei, Divinópolis, Minas Gerais, Brazil. 3. Pharmaceutical and Biotechnological Development, Ezequiel Dias Foundation, Belo Horizonte, Minas Gerais, Brazil. 4. Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. 5. 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. 6. State University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. 7. Department of Metallurgical and Materials Engineering, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. 8. Department of Ophthalmology of University of Lausanne, Jules-Gonin Ophthalmic Hospital, CHUV, Lausanne, Switzerland.
Abstract
PURPOSE: 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.
PURPOSE: 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: Bryce Chiang; Nitin Venugopal; Hans E Grossniklaus; Jae Hwan Jung; Henry F Edelhauser; Mark R Prausnitz Journal: Invest Ophthalmol Vis Sci Date: 2017-01-01 Impact factor: 4.799