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    Engineered Multifunctional Drug-Loaded Dendrimer Nanoparticles for Glaucoma: Triple Mechanism via Antioxidant Activity, Iron Chelation, and Enhanced Ocular Transport
    (Amer Chemical Soc, 2025) Ates, Burhan; Trital, Ashish; Mani, Vimalin Jeyalatha; Xu, Lei; Kenlee, Jonathan; Ercal, Nuran; Yang, Hu
    In this study, we developed multifunctional nanoparticles based on polyamidoamine (PAMAM) dendrimers functionalized with caffeic acid (CA) and poly(ethylene glycol) maleimide (PEGM) for the topical delivery of hydrophobic antiglaucoma drugs brimonidine (BM) and betaxolol (BX). The PAMAM-CA and PAMAM-CA-PEGM conjugates exhibited antioxidant and iron-chelating activities in a dose-dependent manner. BM- and BX-loaded dendrimer nanoparticles produced using a multi-inlet vortex mixer showed uniform spherical morphology (similar to 80 nm by TEM) and hydrated sizes of similar to 135-144 nm by DLS. Both nanoformulations demonstrated high cytocompatibility with human corneal epithelial cells and were nonirritant in the HET-CAM assay, with PEGM further improving cytocompatibility. Drug release was sustained for 8 h. Ex vivo corneal permeation studies revealed significantly enhanced drug transport, with PAMAM-CA and PAMAM-CA-PEGM nanoparticles achieving approximately 2- and 3-fold higher permeation, respectively, compared to commercial formulations. Conjugation of CA within our formulations effectively promoted the removal of ferric ions from the surrounding environment. Both PAMAM-CA and PAMAM-CA-PEGM nanoparticles exhibited concentration-dependent antioxidant activity comparable to that of CA. These findings suggest the potential of this multifunctional dendrimer-based nanoparticle system as an innovative strategy for glaucoma medication.
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    Ionic Liquid Pilocarpine Serves as Therapeutic Cosolvent and Permeation Enhancer for Glaucoma Medication
    (Amer Chemical Soc, 2026) Trital, Ashish; Xu, Lei; Ates, Burhan; Wang, Tzu-Chen; Mani, Vimalin; Yang, Hu
    The efficacy of hydrophobic ocular drugs is significantly hindered by their low bioavailability, for which poor water solubility is a major contributing factor. In this work, we synthesized pilocarpine-derived ionic liquid [Pilo-OEG] Cl (PO) and evaluated its cosolvent properties for the codelivery of the hydrophobic antiglaucoma drug brimonidine (BM) for glaucoma therapy. Pilocarpine was quaternized with 2-[2-(2-chloroethoxy)ethoxy] ethanol in a one-pot reaction to yield PO, and its structure was confirmed using 1H NMR and FT-IR spectroscopy methods and further characterized for its rheological property and thermal stability. The HET-CAM assay and cell viability study showed that PO was nonirritating and cytocompatible with trabecular meshwork cells. As a cosolvent, PO increased the solubility of BM and shifted its logP toward hydrophilicity and increased its ex vivo corneal permeability to be 2.7-fold higher. Following topical administration, a single dose of the PO:BM formulation decreased intraocular pressure (IOP) in rats and effectively maintained the IOP reduction for 48 h, whereas the IOP in the rats topically treated with brimonidine tartrate returned to the baseline in less than 12 h. A sustained IOP reduction over 7 days was achieved in a multiple-dose experiment, with efficacy still observed on day 8 by PO: BM. By combining intrinsic muscarinic activity with potent cosolvent properties, PO ionic liquid addresses the solubility and bioavailability challenges of hydrophobic drugs (BM) in a simple formulation (PO:BM), presenting a promising next-generation therapy for the treatment of glaucoma.