title: Biodegradable chitosan and polylactic acid-based intraocular micro-implant for sustained release of methotrexate into vitreous: analysis of pharmacokinetics and toxicity in rabbit eyes.
abstract: OBJECTIVE
  The purpose of this study was to evaluate the pharmacokinetics and toxicity of a chitosan (CS) and polylactic acid (PLA) based methotrexate (MTX) intravitreal micro-implant in an animal model using rabbit eyes.
  
  
  METHODS
  CS- and PLA-based micro-implants containing 400 μg of MTX were fabricated using lyophilization and dip-coating techniques. The micro-implants were surgically implanted in the vitreous of eight New Zealand rabbits employing minimally invasive technique. The PLA-coated CS-MTX micro-implant was inserted in the right eye and the placebo micro-implant in the left eye of each rabbit. Two rabbits were euthanized at each pre-determined time point post-implantation (days 5, 12, 19, and 33) for pharmacokinetics and histopathology evaluation.
  
  
  RESULTS
  A therapeutic concentration of MTX (0.1-1.0 μM) in the vitreous was detected in the rabbit eyes studied for 33 days. The MTX release from the coated micro-implants followed a first order kinetics (R (2) ~ 0.88), implying that MTX release depends on the concentration of MTX in the micro-implant. Histopathological analysis of the enucleated eyes failed to show any signs of infection or tissue toxicity in any of the specimens.
  
  
  CONCLUSIONS
  The PLA-coated CS-MTX micro-implants were able to deliver therapeutic release of MTX for a period of more than 1 month without detectable toxicity in a rabbit model. The micro-implants can be further investigated as a prospective alternative to current treatment protocols of repeated intravitreal MTX injections in intraocular disorders such as primary intraocular lymphoma, and selected cases of non-microbial intraocular inflammation.
authors.affiliation: Department of Mechanical and Materials Engineering, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Soumyarwit
authors.initials: S
authors.lastname: Manna
authors.forename: Rupak K
authors.initials: RK
authors.lastname: Banerjee
authors.forename: James J
authors.initials: JJ
authors.lastname: Augsburger
authors.forename: Marwan F
authors.initials: MF
authors.lastname: Al-Rjoub
authors.forename: Anna
authors.initials: A
authors.lastname: Donnell
authors.forename: Zelia M
authors.initials: ZM
authors.lastname: Correa
mesh_terms: D020341:Absorbable Implants; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000633:toxicity; D001672:Biocompatible Materials; D048271:Chitosan / Q000493:pharmacokinetics* / Q000633:toxicity; D016503:Drug Delivery Systems; D004343:Drug Implants; D058449:Intravitreal Injections; D019344:Lactic Acid / Q000493:pharmacokinetics* / Q000633:toxicity; D008727:Methotrexate / Q000493:pharmacokinetics* / Q000633:toxicity; D023421:Models, Animal; D011091:Polyesters; D011108:Polymers / Q000493:pharmacokinetics* / Q000633:toxicity; D011817:Rabbits; D012160:Retina / Q000187:drug effects; D014822:Vitreous Body / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D001672:Biocompatible Materials; D004343:Drug Implants; D011091:Polyesters; D011108:Polymers; D019344:Lactic Acid; C033616:poly(lactide); D048271:Chitosan; D008727:Methotrexate