Development of hyaluronic acid-triamcinolone acetonide transparent formulation for efficient endotoxin-induced uveitis therapy.

Uveitis is conventionally treated with corticosteroids such as triamcinolone acetonide (TA). However, the clinical outcomes of TA have been jeopardized by long-term side effects including cataract formation, as well as the blurred vision due to white crystalline lens. Thus, this study aimed to enhance the solubility, transparency and selective accumulation of TA in the posterior retinal tissue through covalent conjugation with hyaluronic acid (HA), hereafter referred as HATA. The amphiphilic HATA conjugates demonstrated superior water solubility (80-fold higher) and significantly higher light transmittance (70%) compared to free TA and Shincort (clinical standard), respectively. The HATA-360 conjugate demonstrated relatively modest TA releasing trend and had not significantly inhibited the viability of human retinal epithelial (ARPE-19) cells at the tested doses (25-400 μg/mL) in 24 h. Cy5.5-labeled HATA-360 displayed better retinal trafficking or distribution upon intravitreal injection (IVI). Rats treated with HATA-360 formulation displayed significantly lower TA accumulation the crystalline lens than the Shincort group. Notably, HATA-360 showed statistically significant difference from PBS, but not Shincort, in reducing tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) in an endotoxin-induced uveitis (EIU) model. Overall, the cytocompatability, transparent nature and spatial ocular accumulation of HATA-360 conjugate proved the soundness of our strategy for the development of safe and effective formulation free of cataract risk.