Modulating aqueous humor outflow with engineered nanoparticles for glaucoma

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PROJECT SUMMARY Glaucoma remains the second leading cause of blindness worldwide. Elevated intraocular pressure (IOP) is a characteristic risk factor for glaucoma, and all current treatments are to lower or control IOP and thereby slow down or reduce the subsequent vision loss. Elevated IOP in glaucoma is primarily due to impaired aqueous outflow drainage and consequently increased outflow resistance. Current IOP-reducing strategies include reduction of aqueous humor using beta-blockers, adrenergic agonists, or carbonic anhydrase inhibitors, promotion of aqueous humor outflow via the uveoscleral pathway using prostaglandins, or combination of both actions. Various formulations, including nanoparticulate systems, have been developed to deliver antiglaucoma drugs topically to promote outflow through the uveoscleral pathway. The trabecular meshwork (TM) pathway is another major independent route for controlling the intraocular pressure. Nevertheless, how to design nanoparticle-based delivery systems to fully utilize the outflow pathway in TM for more effective IOP reduction has not been systematically investigated but will be the focus of this project. We pioneered an unconventional concept of utilizing highly-branched tunable dendrimers to form nanostructured dendrimer hydrogel particles (nDHPs). We showed that nDHPs overcome the pulsatile delivery of most antiglaucoma drugs, synchronize drug release following zero-order kinetics (i.e., constant release rate), have good corneal permeation and enable long- acting effects. Based on nDHPs, we will test a three-pronged strategy to reduce IOP by reducing aqueous humor production and simultaneous outflow promotion through the two independent pathways—the TM and uveoscleral. Our objective is to maximize antiglaucoma therapeutic benefits by our newly designed nDHP-based system. We hypothesize that nDHP-based delivery systems provide a modular platform incorporating drugs in different modes of action to increase their dose effectiveness and coordinate their release for extended antiglaucoma effects. To test the hypothesis, we propose the following aims. Aim 1) Establish nDHP-mediated short- and long- term IOP lowering effects by modulation of aqueous humor production and outflow in a mouse model of glaucoma. Aim 2) Gain mechanistic understanding of dynamic ocular distributions of nDHPs and drugs delivered by nDHPs through the outflow pathways. Aim 3) Determine the antiglaucoma effects of nDHP-based fixed-combination formulations in controlling IOP and slowing down vision loss. Our proposed research will investigate the three- pronged strategy that it has potential to be more effective in achieving IOP reduction. The new formulation based on this novel therapeutic intervention will be clinically impactful for improving glaucoma treatment and patient adherence.