title: Treatment of experimental autoimmune uveoretinitis with poly(lactic acid) nanoparticles encapsulating betamethasone phosphate.
abstract: We have developed nanoparticles (NPs), which are capable of targeting a specific lesion and gradually releasing the agent at the site over a prolonged time period after a single intravenous administration. In this study, we evaluated the effects of intravenously administered poly(lactic acid) nanoparticles encapsulating betamethasone phosphate (BP-PLA NPs) on experimental autoimmune uveoretinitis (EAU) in Lewis rats. To determine the localization of NPs within the retina and choroid of rats with EAU, rhodamine (Rh)-encapsulated PLA NPs were injected intravenously and visualized by confocal microscopy. After the disease onset of EAU induced by S-antigen peptide in Lewis rats, either BP-PLA NPs, BP, or saline was injected intravenously, and the eyes were obtained 7 days following treatment and the histological score was determined. The clinical course of EAU was examined using pathological findings and the expression of the glial fibrillary acidic protein, rod opsin, and the surface markers of inflammatory cells (ED1 and pan T-cell) were immunohistochemically determined. Furthermore, T-cell proliferation and delayed-type hypersensitivity (DTH) to S-antigen were assessed. Intravenously injected Rh-PLA NPs accumulated in the retina and choroid of rats with EAU within 3 hr and remained over the succeeding 7-day-period. Furthermore, systemically administered BP-PLA NPs reduced the clinical scores of rats with EAU in 1 day, which were maintained for 2 weeks and decreased the histological scores. In addition, the ocular infiltration of activated T-cells and macrophages in addition to the hypertrophy of Müller cells were markedly reduced with this treatment. Meanwhile, T-cell proliferation and DTH of BP-PLA NPs-treated rats against S-antigen peptide were not significantly different from those of saline-treated rats. Systemically administered BP-PLA NPs inhibit the development of EAU due to the targeting and the sustained release of steroids in situ. The results of these studies suggest that the systemic administration of BP-PLA NPs may lead to a new therapeutic strategy in controlling intraocular inflammation.
authors.affiliation: Department of Ophthalmology, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan. tstmski@jikei.ac.jp
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sakai
authors.forename: Hideo
authors.initials: H
authors.lastname: Kohno
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ishihara
authors.forename: Megumu
authors.initials: M
authors.lastname: Higaki
authors.forename: Saburo
authors.initials: S
authors.lastname: Saito
authors.forename: Masato
authors.initials: M
authors.lastname: Matsushima
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Mizushima
authors.forename: Kenji
authors.initials: K
authors.lastname: Kitahara
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001623:Betamethasone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002829:Choroid / Q000737:chemistry / Q000473:pathology; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D004195:Disease Models, Animal; D004339:Drug Compounding / Q000379:methods; D007111:Immunity, Cellular / Q000187:drug effects; D007150:Immunohistochemistry / Q000379:methods; D007275:Injections, Intravenous; D019344:Lactic Acid / Q000008:administration & dosage* / Q000032:analysis; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D049329:Nanostructures / Q000032:analysis; D011091:Polyesters; D011108:Polymers / Q000008:administration & dosage* / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D012160:Retina / Q000737:chemistry / Q000473:pathology; D012173:Retinitis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D012235:Rhodamines / Q000008:administration & dosage / Q000032:analysis; D016896:Treatment Outcome; D014605:Uveitis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; D003692:Delayed-Action Preparations; D011091:Polyesters; D011108:Polymers; D012235:Rhodamines; D019344:Lactic Acid; C033616:poly(lactide); C028994:betamethasone sodium phosphate; D001623:Betamethasone