2. Academic Validation
  3. Colloid-Forming Prodrug-Hydrogel Composite Prolongs Lower Intraocular Pressure in Rodent Eyes after Subconjunctival Injection

Colloid-Forming Prodrug-Hydrogel Composite Prolongs Lower Intraocular Pressure in Rodent Eyes after Subconjunctival Injection

  • Adv Mater. 2025 Jan 6:e2419306. doi: 10.1002/adma.202419306.
Mickael Dang 1 2,  Kai V Slaughter 2 3,  Hong Cui 2,  Christopher Jiang 1,  Lisa Zhou 1,  David J Matthew 4 5,  Jeremy M Sivak 4 5 6,  Molly S Shoichet 1 2 3
Affiliations

Affiliations

  • 1 Department of Chemical Engineering & Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON, M5S 3E5, Canada.
  • 2 Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON, M5S 3E1, Canada.
  • 3 Institute of Biomedical Engineering University of Toronto, 164 College Street, Toronto, ON, M5S 3G9, Canada.
  • 4 Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada.
  • 5 Department of Ophthalmology and Vision Sciences, University of Toronto, 340 College Street, Toronto, ON, M5T 3A9, Canada.
  • 6 Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
PMID: 39763100 DOI: 10.1002/adma.202419306
Abstract

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.

Keywords

colloidal drug aggregate; glaucoma; hydrogel; long‐acting; prodrug; subconjunctival space; timolol.

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