Abstract
The present research investigates the pharmacokinetics and toxicity of a chitosan (CS) and poly(lactic-co-glycolic) acid (PLGA)-based methotrexate (MTX) intravitreal micro-implant in normal rabbit eyes. PLGA and CS-based micro-implants containing 400 µg of MTX were surgically inserted in the vitreous of twenty-four New Zealand rabbits using minimally invasive procedures. The PLGA-coated CS-MTX micro-implant and the placebo micro-implant were inserted in the right eye and in the left eye, respectively, of each rabbit. The intravitreal MTX concentration was evaluated on Days 1, 3, 7, 14, 28 and 56. A therapeutic concentration of MTX (0.1–1.0 µM) in the rabbit vitreous was observed for 56 days. The release of MTX in the therapeutic release phase followed first-order kinetics. Histopathologic evaluation on Days 14, 28 and 56 of the enucleated eyes demonstrated no signs of toxicity or any anatomical irregularity in the vitreoretinal domain. Additionally, the micro-implants were stationary at the position of their implantation throughout the duration of the study. The PLGA-coated CS-MTX micro-implant can serve as a potential alternative to the current treatment modality of intravitreal MTX injections based on its performance, thereby avoiding associated complications and the treatment burden of multiple injections.
Highlights
Methotrexate (MTX), an antimetabolite chemotherapeutic drug, has gained a substantial reputation in treating various types of cancer and autoimmune diseases [1]
In the domain of ophthalmology, intravitreal injections of MTX have been administered to treat various vitreoretinal (VR) diseases such as: (1) primary central nervous system lymphoma (PCNSL) with intraocular involvement [2,3,4], known as primary intraocular lymphoma (PIOL); (2) severe and recalcitrant intraocular inflammation [5,6,7,8]; and (3) certain cases of rhegmatogenous retinal detachment associated with elevated risk for proliferative vitreoretinopathy (PVR) [9,10]
The gross inspection of the position of the micro-implant relative to the crystalline lens and the eye wall incision showed (a) there was no migration of the micro-implants from their respective initial implantation site; (b) the gross appearance of the micro-implant and the vitreous surrounding the micro-implant was not appreciably different in the eyes that received an MTX-containing micro-implant and those that received a placebo microimplant; and (c) there were signs of swelling of the micro-implant in the eyes on the domain were expected at early time-points (Days)
Summary
Methotrexate (MTX), an antimetabolite chemotherapeutic drug, has gained a substantial reputation in treating various types of cancer and autoimmune diseases [1]. In the domain of ophthalmology, intravitreal injections of MTX have been administered to treat various vitreoretinal (VR) diseases such as: (1) primary central nervous system lymphoma (PCNSL) with intraocular (vitreoretinal) involvement [2,3,4], known as primary intraocular lymphoma (PIOL); (2) severe and recalcitrant intraocular inflammation (uveitis) [5,6,7,8]; and (3) certain cases of rhegmatogenous retinal detachment associated with elevated risk for proliferative vitreoretinopathy (PVR) [9,10]. Various administration regimens have been employed when treating with intravitreal. A representative dosing regimen would be either two intravitreal injections every week until apparent clinical improvement is demonstrated or one intravitreal injection every week thereafter until complete clinical regression in the eye(s) is observed.
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