Engineered Multifunctional Drug-Loaded Dendrimer Nanoparticles for Glaucoma: Triple Mechanism via Antioxidant Activity, Iron Chelation, and Enhanced Ocular Transport

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 (∼80 nm by TEM) and hydrated sizes of ∼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. <i>Ex vivo</i> 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.