Intravitreal Sustained Release of Dexamethasone from a Self-Healing Injectable Hydrogel: An In Vivo Safety and Release Study.

Abstract

Corticosteroids, such as dexamethasone, are clinically used in intravitreal injections for the treatment of inflammatory and age-related ocular diseases; however, frequent injections can cause complications. To prolong the retention of dexamethasone in the eye after intravitreal administration, sustained-release drug delivery systems have previously been investigated. The aim of this study was to evaluate the in vivo release of dexamethasone from a self-healing thermosensitive hydrogel consisting of a thermosensitive ABA triblock copolymer and to investigate its safety after its injection into the eyes of rats and rabbits. The polymer building block for hydrogel preparation was synthesized by copolymerization of a methacrylated dexamethasone prodrug (mDEX) with N-isopropylacrylamide (NIPAM) and N-acryloxysuccinimide (NAS) through reversible addition-fragmentation chain transfer (RAFT) polymerization, using poly(ethylene glycol) (PEG; 6 kDa) functionalized at both ends with a chain transfer agent (CTA). This yielded a thermosensitive triblock copolymer (p(NIPAM-co-NAS-co-mDEX)-PEG-P(NIPAM-co-NAS-co-mDEX) with a cloud point of 23 °C. Upon incubation of an aqueous solution of this polymer at 37 °C, thermogelation occurs. The resulting thermogel is chemically stabilized by cross-linking with cystamine, a compound with two amino groups that react with the succinimide functionalities present in the polymer chains. Intravitreal injections of a preformed fluorescently labeled hydrogel into rats were carried out, and hydrogel degradation and retinal health were followed using optical coherence tomography (OCT) and fundus imaging. The hydrogel started to degrade 2-3 weeks post injection, and it was cleared from the eye after 5 weeks. Adverse effects, mainly cataract and mild retinal bleeding, were observed, which were probably caused by injection trauma. No histological differences were seen between the treated and untreated eyes. In rabbits, unlabeled hydrogel was injected into the vitreous, and no side effects were observed in the animals. After 3 weeks, the hydrogels could not be seen by fundus imaging, but released dexamethasone was quantifiable with LC-MS/MS in the aqueous humor for 9 weeks post injection. A compartmental model fit of the experimental data showed that the in vivo release of dexamethasone followed first-order kinetics with a half-life of 16.5 days. The good tolerance of the formulation and the sustained dexamethasone release for 2 months make this delivery system an interesting candidate for further preclinical testing.