PAMAM dendrimer based injectable gels for the treatment of corneal inflammation

Abstract

Purpose : Corneal inflammation is often encountered as a post-surgical complication or as a key pathological event in many corneal diseases. Current treatments involve frequent topical corticosteroids which often causes corneal toxicity, elevated IOP and corneal discoloration. Hence, new interventions that can provide sustained efficacy and reduce side effects will be highly beneficial. In this study, we evaluate our novel injectable dendrimer-dexamethasone (D-Dex) hydrogels for targeted, sustained attenuation of corneal inflammation in rat mild alkali burn model.

Methods : D-Dex incorporated injectable gel was prepared using PAMAM dendrimer (G4-OH) and hyaluronic acid (HA) using click chemistry. Dendrimer-Cy5 (D-Cy5) was used to evaluate the biodistribution in alkali burn rat model. The efficacy of D-Dex or free Dex in the gel was evaluated for both clinical (POD 0, 3, 7 and 14) and biochemical parameters (POD 7 and 14). The rats were assessed for corneal thickness (CCT), corneal edema, corneal opacity and neovascularization using clinical observation, and IOP was measured using tonometry. Attenuation of corneal inflammation was evaluated using IHC, and PCR for cytokine expression.

Results : Alkali burn results in macrophage accumulation, increased corneal thickness, opacity, and edema in central cornea. Subconjuntivally-administered dendrimers showed pathology dependent biodistribution, targeting macrophages in the central cornea, with minimal dendrimer uptake in healthy corneas. Subconjunctival D-Dex gel treatment resulted in favorable clinical outcomes with reduced CCT (p< 0.05) and improved corneal clarity (p< 0.01) compared to free Dex and untreated positive controls. The extent of corneal NV was significantly reduced in D-Dex groups with no signs of elevated IOP. Compared to free Dex, D-Dex gel treatment attenuated corneal inflammation more effectively by suppressing the expression of inflammatory cytokines in a sustained manner.

Conclusions : Subconjunctival Dendrimer-dexamethasone gel treatment was associated with lower CCT, inflammatory cytokine expression, and macrophage recruitment to the central cornea. These findings suggest that the novel injectable D-Dex gel may be a potential drug delivery platform for the treatment of many inflammatory ocular surface disorders such as dry eye, microbial keratitis and post-surgical complications where frequent dosage are required.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.