Avaliação da segurança e atividade anti-inflamatória de implante intravítreo contendo sirolimus em modelo de uveíte autoimune experimental

Abstract

Uveitis is an ocular inflammation of the uveal tract. Complications affecting the uveal tract may result in impairment or loss of vision and has been a challenge due to the low drug bioavailability in the target tissue. Thus, there is a growing interest in finding drugs that can control inflammation. Sirolimus (SRL), a potent immunosuppressive drug, has shown promising results in the treatment of ocular diseases. Like other therapeutic agents, it has low solubility, and its intravitreal use is related to several side-effects. This scenario stimulates the development of new delivery systems that can deliver the drug inside the vitreous cavity in therapeutic doses and over a prolonged period, reducing the adverse effects and increasing the effectiveness of the treatment. In the present study, we assessed the in vivo release profile and the retinal toxicity, using electroretinography (ERG) and histology, of a poly (lactic-co-glycolic acid) (PLGA) sustained-release SRL intravitreal implant in normal rabbit eyes for 8 weeks after administration. Further, we investigated the effects of SRL-PLGA implant on experimental autoimmune uveitis rabbits, including clinical evaluation, histopathological examination, alterations of protein levels determination of myeloperoxidase (MPO) and N-acetylglucosaminidase (NAG) activity were investigated either in the aqueous or vitreous humor. As a result, the maximum concentration of SRL (199.8 ng/mL) released from the device occurred within 4 weeks. No toxic effects of the implants or increase in the intraocular pressure were observed through clinical evaluation of the eye. ERG responses showed no significant difference between the eyes that received PLGA or SRL-PLGA implants at baseline and throughout the 8 weeks of follow up. No remarkable difference in retinal histopathology was detected in rabbit eyes treated with PLGA or SRL-PLGA implants. Average inflammatory scores analyses of protein concentrations, MPO and NAG activity, showed significant decreases in treated eyes after 35 days. Histopathologic examinations showed less severe inflammation and tissue disorganization in treated eyes. According to the results, the implants developed in this study were safe, reduced the eye inflammation and could overcome the difficulty of promoting a prolongated release of SRL in the posterior segment of the eye. Therefore, the intravitreal SRL-PLGA implants could be a promising alternative for the treatment to autoimmune uveitis.