4.7 Article

Novel Thiol Containing Hybrid Antioxidant-Nitric Oxide Donor Small Molecules for Treatment of Glaucoma

期刊

ANTIOXIDANTS
卷 10, 期 4, 页码 -

出版社

MDPI
DOI: 10.3390/antiox10040575

关键词

nitric oxide; superoxide radical; hybrid small molecule; glaucoma; intra-ocular pressure; nanosuspension

资金

  1. Applied Research Seed grant from UNTHSC [2400018]
  2. Bright Focus Foundation [G2018056]
  3. National Institute of Health [R01EY029823]

向作者/读者索取更多资源

Oxidative stress-induced death and dysregulation of trabecular meshwork (TM) cells contribute to increased intraocular pressure (IOP) in primary open angle (POAG) glaucoma, while nitric oxide (NO) can lower IOP by reducing reactive oxygen species (ROS). The novel sulfur containing hybrid NO donor-antioxidants were designed to scavenge ROS and maintain NO bioavailability in TM cells, demonstrating potential for glaucoma treatment. The slow-release nanosuspension of these molecules significantly lowered IOP in a mouse model, showing lasting effects up to 72 hours.
Oxidative stress induced death and dysregulation of trabecular meshwork (TM) cells contribute to the increased intraocular pressure (IOP) in primary open angle (POAG) glaucoma patients. POAG is one of the major causes of irreversible vision loss worldwide. Nitric oxide (NO), a small gas molecule, has demonstrated IOP lowering activity in glaucoma by increasing aqueous humor outflow and relaxing TM. Glaucomatous pathology is associated with decreased antioxidant enzyme levels in ocular tissues causing increased reactive oxygen species (ROS) production that reduce the bioavailability of NO. Here, we designed, synthesized, and conducted in vitro studies of novel second-generation sulfur containing hybrid NO donor-antioxidants SA-9 and its active metabolite SA-10 to scavenge broad-spectrum ROS as well as provide efficient protection from t-butyl hydrogen peroxide (TBHP) induced oxidative stress while maintaining NO bioavailability in TM cells. To allow a better drug delivery, a slow release nanosuspension SA-9 nanoparticles (SA-9 NPs) was prepared, characterized, and tested in dexamethasone induced ocular hypertensive (OHT) mice model for IOP lowering activity. A single topical eye drop of SA-9 NPs significantly lowered IOP (61%) at 3 h post-dose, with the effect lasting up to 72 h. This class of molecule has high potential to be useful for treatment of glaucoma.

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