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Abstract #125528 Published in IGR 25-2
Colloid-Forming Prodrug-Hydrogel Composite Prolongs Lower Intraocular Pressure in Rodent Eyes after Subconjunctival Injection
Dang M; Slaughter KV; Cui H; Jiang C; Zhou L; Matthew DJ; Sivak JM; Shoichet MSAdvanced materials (Deerfield Beach, Fla.) 2025; 37: e2419306
Colloidal drug aggregates (CDAs) are challenging in drug discovery due to their unpredictable formation and interference with screening assays. These limitations are turned into a strategic advantage by leveraging CDAs as a drug delivery platform. This study explores the deliberate formation and stabilization of CDAs for local ocular drug delivery, using a modified smallmolecule glaucoma drug. A series of timolol prodrugs are synthesized and self-assembled into CDAs. Of four prodrugs, timolol palmitate CDAs have a critical aggregate concentration of 2.72 µM and sustained in vitro release over 28 d. Timolol palmitate CDAs are dispersed throughout in situ gelling hyaluronan-oxime hydrogel and injected into the subconjunctival space of rat eyes. The intraocular pressure is significantly reduced for at least 49 d with a single subconjunctival injection of timolol-palmitate CDAs compared to 6 h for conventional timolol maleate. The systemic blood concentrations of timolol are significantly lower, even after 6 h, for timolol palmitate CDA-loaded hydrogel versus free timolol maleate, thereby potentially reducing the risk of systemic side effects. This innovative approach redefines the role of CDAs and provides a framework for long-acting ocular therapeutics, shifting their perception from a drug screening challenge to a powerful tool for sustained local drug delivery.
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