Sustained Nitric Oxide-Providing Small Molecule and Precise Release Behavior Study for Glaucoma Treatment

Abstract

Incidence ofglaucoma, a severe disease leading to irreversible loss of vision, is increasing with global aging populations. Lowering intraocular pressure (IOP) is the only proven treatment method for glaucoma. Nitric oxide (NO) is an emerging material targeting the conventional outflow pathway by relaxing the trabecular meshwork (TM). However, there is little understanding on the NO level effective in IOP lowering without toxicity. Here, we report a novel long-term NO-releasing polydiazeniumdiolate (NOP) that enables lowering IOP via the conventional outflow pathway. NOP is composed of carbon-bound polydiazeniumdiolate, a stable NO donor moiety. NO release was monitored with accurate parameters by real-time detection of gas and analysis of the accumulated release profile. Based on the NO release information, the selected safe level of NOP exhibited effective TM relaxation and a potential IOP lowering effect in vivo without side effects. This work provides new insights into nitric oxide release behavior that should be considered for glaucoma treatment.

Nitric Oxide Interaction with the Eye

“…NO and its messenger cGMP directly act on trabecular meshwork cells to help increase the outflow. Studies have exhibited similarities between trabecular cells and smooth muscle cells, and both are very reactive to NO [ 47 , 48 , 49 , 50 ]. Stress or pressure trigger the production of NO, which then leads to the relaxation and dilation of the distal outflow tract, thus lowering the IOP.…”

“…Stress or pressure trigger the production of NO, which then leads to the relaxation and dilation of the distal outflow tract, thus lowering the IOP. There are indications that NO is also produced in Schlemm’s canal cells, indicating a direct regulatory role, as well as evidence that NO has a dilatory effect as well on myosin-containing cells on the outer wall of Schlemm’s canal distal to the trabecular meshwork [ 47 , 48 , 49 , 50 ].…”

“…One of the challenges to create therapies including NO is its short half-life in tissues of two seconds and only two milliseconds in blood [ 34 , 54 ]. A way to overcome this is to utilize known effective drugs for lowering IOP combined with NO-donor substances that are metabolized inside the eye and then release NO in the targeted tissue [ 46 , 49 , 55 ]. Some of the promising NO donor drugs being developed and thoroughly investigated are Latanoprostene bunod 0.024% (Bausch and Lomb) in a phase 3 trial, which is designed to increase the aqueous outflow both by uveoscleral and trabecular pathways, and are also being compared to other conventional glaucoma drugs, as well as various dosage efficacies [ 56 , 57 , 58 ].…”

Effect of dietary modification and antioxidant supplementation on intraocular pressure and open-angle glaucoma

“…For instance, recent in vitro and in vivo studies demonstrated an IOP lowering by 24% of a sustained NOP (100 μM) without significant complications. 74 At present, latanoprostene bunod (formerly BOL-303259-X), a combination of latanoprost and butanediol mononitrate, a NO donating molecule, has been approved by the FDA for glaucoma treatment. 75 Based on the potential benefits of vegetables and fruits, glaucoma patients may counseled to adhere to the standard CDC recommendations of 1.5 to two cups of fruits and two to three cups of vegetables per day, as part of a healthy diet.…”

Nanochemistry Modulates Intracellular Decomposition Routes of S‐Nitrosothiol Modified Silica‐Based Nanoparticles

“…[1] Manipulation of intracellular NO level using exogenous NO donors is important in many biomedical applications. [4][5][6] Among different NO donating compounds, S-nitrosothiol (SNO) is a common NO releasing moiety. [7] For example, S-nitrosoglutathione (GSNO) is one of the widely used commercial SNO based NO donors [8] that releases NO under various endogenous (e.g., pH, glutathione, GSH) or exogenous (e.g., X-ray) stimuli.…”