Dang Mickael, Slaughter Kai V, Cui Hong, Jiang Christopher, Zhou Lisa, Matthew David J, Sivak Jeremy M, Shoichet Molly S
Department of Chemical Engineering & Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON, M5S 3E5, Canada.
Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON, M5S 3E1, Canada.
Adv Mater. 2025 Feb;37(8):e2419306. doi: 10.1002/adma.202419306. Epub 2025 Jan 6.
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.
胶体药物聚集体（CDAs）在药物研发中颇具挑战，因为其形成难以预测且会干扰筛选测定。通过将CDAs用作药物递送平台，这些局限性转变为了一种战略优势。本研究利用一种改良的小分子青光眼药物，探索用于局部眼部药物递送的CDAs的可控形成与稳定化。合成了一系列噻吗洛尔前药并使其自组装成CDAs。在四种前药中，棕榈酸噻吗洛尔CDAs的临界聚集浓度为2.72 µM，且在体外持续释放超过28天。棕榈酸噻吗洛尔CDAs分散于原位凝胶化的透明质酸肟水凝胶中，并注入大鼠眼的结膜下间隙。与传统马来酸噻吗洛尔作用6小时相比，单次结膜下注射棕榈酸噻吗洛尔CDAs可使眼内压显著降低至少49天。对于负载棕榈酸噻吗洛尔CDAs的水凝胶，即使在6小时后，其噻吗洛尔的全身血药浓度也显著低于游离马来酸噻吗洛尔，从而有可能降低全身副作用的风险。这种创新方法重新定义了CDAs的作用，并为长效眼部治疗提供了一个框架，将它们的认知从药物筛选挑战转变为持续局部药物递送的有力工具。
