title: Ocular drug delivery targeting the retina and retinal pigment epithelium using polylactide nanoparticles.
abstract: OBJECTIVE
  To study the kinetics of polylactide (PLA) nanoparticle (NP) localization within the intraocular tissues and to evaluate their potential to release encapsulated material.
  
  
  METHODS
  A single intravitreous injection (5 micro L) of an NP suspension (2.2 mg/mL) encapsulating either Rh-6G (Rh) or Nile red (Nr) was performed. Animals were killed at various times, and the NPs localization within the intraocular tissues was studied by environmental scanning electron microscopy (ESEM), confocal microscopy, light microscopy histology, fluorescence microscopy, and immunohistochemistry. Eyes injected with blank NPs, free Rh, or PBS solution were used as the control.
  
  
  RESULTS
  ESEM showed the flow of the NPs from the site of injection into the vitreous cavity and their rapid settling on the internal limiting membrane. Histology demonstrated the anatomic integrity of the injected eyes and showed no toxic effects. A mild inflammatory cell infiltrate was observed in the ciliary body 6 hours after the injection and in the posterior vitreous and retina at 18 to 24 hours. The intensity of inflammation decreased markedly by 48 hours. Confocal and fluorescence microscopy and immunohistochemistry showed that a transretinal movement of the NPs was gradually taking place with a later localization in the RPE cells. Rh encapsulated within the injected NPs diffused and stained the retina and RPE cells. PLA NPs were still present within the RPE cells 4 months after a single intravitreous injection.
  
  
  CONCLUSIONS
  Intravitreous injection of PLA NPs appears to result in transretinal movement, with a preferential localization in the RPE cells. Encapsulated Rh diffuses from the NPs and stains the neuroretina and the RPE cells. The findings support the idea that specific targeting of these tissues is feasible. Furthermore, the presence of the NPs within the RPE cells 4 months after a single injection shows that a steady and continuous delivery of drugs can be achieved.
authors.affiliation: Unit 450 of the National Institute of Health and Medical Research (INSERM U450), Paris, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Bourges
authors.forename: Sandrine E
authors.initials: SE
authors.lastname: Gautier
authors.forename: Florence
authors.initials: F
authors.lastname: Delie
authors.forename: Riad A
authors.initials: RA
authors.lastname: Bejjani
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Jeanny
authors.forename: Robert
authors.initials: R
authors.lastname: Gurny
authors.forename: David
authors.initials: D
authors.lastname: BenEzra
authors.forename: Francine F
authors.initials: FF
authors.lastname: Behar-Cohen
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D016503:Drug Delivery Systems; D019084:Fluorescent Antibody Technique, Indirect; D005456:Fluorescent Dyes / Q000493:pharmacokinetics*; D007267:Injections; D008297:Male; D018613:Microscopy, Confocal; D008855:Microscopy, Electron, Scanning; D008856:Microscopy, Fluorescence; D008863:Microspheres; D010078:Oxazines / Q000008:administration & dosage / Q000493:pharmacokinetics; D010857:Pigment Epithelium of Eye / Q000378:metabolism* / Q000473:pathology; D011091:Polyesters / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D011917:Rats, Inbred Lew; D012160:Retina / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D012235:Rhodamines / Q000008:administration & dosage / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014822:Vitreous Body / Q000378:metabolism
chemical_list: D015415:Biomarkers; D005456:Fluorescent Dyes; D010078:Oxazines; D011091:Polyesters; D012235:Rhodamines; C026188:rhodamine 6G; C033616:poly(lactide); C044808:nile red