Review: Neuroprotective Nanocarriers in Glaucoma
Abstract
:1. Introduction
Neuroprotectant Class | Drug (Mode of Delivery) | Mechanism |
---|---|---|
α2-adrenoceptor agonists | Brimonidine [60] (topical, SC) | It decreases the production of aqueous humor and increases uveoscleral outflow, meaning it is commonly used to manage glaucoma due to these hypotensive properties. Alpha2-adrenoceptors have been found in the retinal ganglion layer and inner nuclear layer, indicating potential neuroprotective advantages. They can upregulate retinal expression of anti-apoptotic proteins, including bcl-2 and bcl-x, thereby protecting the RGCs. |
N-methyl-D-aspartate (NMDA) receptor antagonists | Memantine [61] (oral) | A non-competitive NMDA receptor antagonist that specifically targets activated glutamatergic receptors, reducing toxic calcium influx and excessive glutamatergic activity, while preserving normal neurotransmission. It has demonstrated protective effects on RGCs in rat models. |
Calcium channel blockers | Brovincamine [62] (topical) Flunarizine [63] Nilvadipine [64] | Prevent calcium-mediated apoptosis and increase ocular blood flow by inhibiting calcium influx into vascular smooth muscle cells. This leads to peripheral vasodilation, reduced vascular resistance, and increased blood flow to the optic nerve. |
Metabolic-targeting compounds | Metformin [65] (oral) | Reduces oxidative stress by targeting fibrotic signaling, oxidation of nicotinamide adenine dinucleotide (NAD), and mitochondrial energetics. |
Insulin (SC) [66] | A peptide hormone with receptors distributed throughout the central nervous system, including the retina, which operates through the PI3K/Akt signaling pathway to protect retinal neurons, glial cells, and vasculature from excessive glucose flux and apoptosis. | |
Neurotrophins | NGF [67] (topical, IVT) | Neurotrophins are transported to the retina in a retrograde manner and regulate neuronal growth, function, and survival. Elevated IOP in glaucomatous conditions obstructs this retrograde transport. NGF is expressed in both the retina and target brain cells. In the retina, NGF binds to Tyrosine kinase receptor A (TrkA) on RGCs to promote neural differentiation and prevent apoptosis. |
BDNF [68] | BDNF, through its receptor TrkB, demonstrates strong neuroprotective effects by reducing dendritic degeneration in mouse models. | |
Dietary supplements | Nicotinamide (oral) [69] | A dietary supplement and redox reaction coenzyme which increases extracellular NAD+ levels, thereby increasing mitochondrial NAD+ concentration. Animal glaucoma models have demonstrated a declining capacity to retain NAD during early disease. |
Citicoline [70] (oral, IM, topical) | A structural and functional precursor for essential components cell membranes, which also reduces oxidative stress in the central nervous system through the promotion of glutathione production. | |
Phosphoserine [71] | A structural matrix of cellular membranes which plays a fundamental role in the synthesis of neurotransmitters. | |
Anti-inflammatory therapies | Anti-complement: ANX005 [72] (IV) ANX007 [73] (IVT) | A recombinant antibody humanized against complement C1q. C1q, along with C1s2 and C1r2, constitutes the C1 complex, which helps initiate the complement pathway. In glaucoma animal models, C1q is upregulated in the retina. It contributes to the formation of the membrane attack complex, which phagocytoses weakened synapses and RGCs. |
Anti-fas–ONL1204 [74] (IVT) | Fas ligand (fragment apoptosis stimulator), a member of the TNF family, exhibits distinct properties in ocular inflammation. Soluble FasL does not trigger inflammation in the eye, whereas membrane-bound FasL induces potent inflammation. Additionally, soluble FasL inhibits corneal inflammation, which is exacerbated by the pro-inflammatory effects of membrane-bound FasL in mice models. | |
MicroRNA-124 [75] | Regulates target genes expression through post-transcriptional regulation. |
Method of Delivery | Advantages | Disadvantages |
---|---|---|
Topical eye drops [76] | Non-invasive. | Ocular surface side effects. Low bioavailability especially for posterior segment tissues. |
Subconjunctival injections [27] | Bypasses ocular surface. | Invasive. Limited for anterior segment pathologies. |
Intracameral injections [27] | Commonly for delivering antibiotics post-operatively, especially cataract surgery, to reduce endophthalmitis rates. | Invasive. Risk of toxic anterior segment syndrome, toxic endothelial cell destruction syndrome. |
Intra-vitreal injections [76] | Higher bioavailability. Relatively less technically demanding compared to other delivery methods of posterior segment pathologies. | Invasive. Risk of endophthalmitis, hemorrhage, retinal detachment. |
Subretinal injections [27] | Higher bioavailability. Targeted treatment for RPE and outer retina, especially useful in gene therapy. | Invasive, requires vitrectomy. Technically challenging. Effects confined to site of injection with limited distribution. |
Suprachoroidal injections [77] | Higher bioavailability. Targeted treatment for choroid, RPE, outer retina. | Technically challenging. |
Systemic [27] | Non-invasive for oral administration. | Higher risk of systemic side effects. Low bioavailability. |
Neuroprotective Strategy | Year | Nanocarrier | Neuroprotective Agent | Administration | Size | PDI | Zeta | EE | Subject | Assesment | Outcome |
---|---|---|---|---|---|---|---|---|---|---|---|
Antioxident | 2024 | GelCA, a gelatin-modified hydrogel (Cur@PDA NPs) | Curcumin | Intravitreal | 328.6 nm | less than 0.3 | −26.7 ± 1.1 mV | 70.5 ± 10% | ONC ICR mice, RGC-5 (H2O2 induced) | Vitro: AmplexTM Red reagent (10-acetyl-3,7-dihydroxyphenoxazine), Vivo: H&E staining (Bio-Compatibility), tissue staining (Antioxidative Performance) | Cur@PDA@GelCA shows strong biocompatibility, protects retinal tissue from oxidative stress, and offers lasting adhesion. |
Antioxident, anti-inflammation | 2023 | chitosan-hyaluronic acid (CS/HA) | EPOβ | Topical | 330 ± 15 nm | 0.174 ± 0.016 | +28 ± 1 mV | 38.4 ± 0.3% | Wistar Hannover Rat (cauterizing three episcleral veins) | ERG, IOP, Histologic Evaluation | The nanoparticle reaches the retina through topical use, significantly improving ERG and retinal thickness earlier in treated animals. |
Antioxident | 2023 | hydroxyl PAMAM dendrimers | N-acetylcysteine (NAC) (D-NAC) | intravitreal, intravenous | 5.8 nm | NA | +6.5 mV | NA | Wistar rat model of laser-induced, Translimbal laser (TLL) | IOP, Immunostaining, transcriptomic studies were performed on RNA isolated from retina | Hydroxyl PAMAM dendrimers target activated microglia/macrophages quickly post-injury and remain for 28 days, while NAC conjugation offers neuroprotection. |
Antioxident, anti-inflammation | 2022 | chitosan-hyaluronic acid nanoparticles (CS/HA) | epoetin beta (EPOβ) | Subconjunctival | 289 ± 3 nm | 0.126 ± 0.085 | 39 ± 1 mV | 38.4 ± 0.3% | Wistar Hannover rat | IOP, ERG and microhematocrit evaluations; histological evaluation (immunofluorescence and HE) | CS/HA nanoparticles enhance mucoadhesion and retention on the ocular surface, safely delivering EPOβ to the retina. |
Antioxident | 2018 | Pluronic-F127 stabilised TPGS | Curcumin | Topical | 17.9 nm | 0.002 | +18.69 mV | 94.20% | R28 cell line, DA rat (OHT, pONT) | IOP, Immunostaining | Boosts the drug’s solubility by nearly 400,000 times, significantly preserving RGC density. |
a2-adrenergic agonist | 2022 | Polydopamine (PDA) | brimonidine | Intravitreal | 223.9 ± 4.7 nm | NA | −28.5 ± 0.58 mV | 20% | vitro: Human umbilical vein endothelial cells (HUVECs), Raw 264.7, N2a, 661W and ARPE-19; vivo: C57BL/6 mice (ONC) | Nissl staining, Propidium iodide (PI) uptake and cell death analysis, RT-PCR, transcriptome analysis, Immunostaining, vivo: Optomotor Test; Light/Dark Transition Test | PDA nanoparticles effectively eliminate reactive species and reduce cellular ROS. Brimonidine-loaded PDA (Br@PDA) offers superior protection against RGC loss and visual impairment. |
a2-adrenergic agonist | 2016 | Alkoxylphenacyl-based polycarbonates | Brimonidine tartrate (BRT) | Intravitreal | 189.9–199.8 nm | NA | around −0.2 mV | less than 20% | human trabecular meshwork (HTM) cell, Wistar rats | Immunostaining, cytotoxicity studies | AP-PCL microfilms sustained BRT release for over 90 days due to slow degradation and microporous formation, showing good biocompatibility in cell studies and rat models. |
a2-adrenergic agonist, IOP lowering | 2015 | nanosponge (NS) | Brimonidine, Travoprost, Bimatoprost | Intravitreal, Topical | Bimatoprost: 400 nm and 700 nm; Brimonidine, Travoprost: 50 nm | NA | NA | NA | C57BL/6 (C57) mice | IOP, qualification of Neuro-DiO | A single NS injection delivers ocular hypotensive drugs continuously for up to 32 days and may effectively target RGCs. |
a2-adrenergic agonist | 2015 | human serum albumin nanoparticle (HSA-NP) | Brimonidine | Intravitreal | 152.8 ± 51.1 nm | NA | −29.7 ± 7.5 mV | NA | RGC-5 cells; Sprague–Dawley (SD) rat (ONC) | Immunostaining | Br-loaded HSA-NPs provide a prolonged therapeutic effect and enhanced neuroprotection synergistically. |
Neurotrophic factors | 2023 | Cell adhesion peptide (CAP)-gemini surfactants (18-7N(p1-5)-18) | BDNF | Intravitreal | 180–320 nm | 0.2–0.5 | +53.7 ± 1.15 or 13.1 ± 0.5 mV | NA | CD1 mice, Rat A7 astrocyte, 3D retinal neurosphere model from CD 1–4 multipotent retinal stem cells (MRSC) | Vitro: Flow cytometry (Transfection efficiency and viability studies), Transfection study, Vivo: stained with Syto™ 13 nucleic acid stain observed CLSM, BDNF-ELISA (for BDNF expression) | IgSF CAPs were successfully used to improve the adhesion and delivery of gemini NPXs to retinal cells through conjugation with gemini surfactant gene vectors. |
Neurotrophic factors | 2016 | K2® nanoparticle gene delivery system (K2-NPs) | BDNF | NA | 83.9 ± 0.4 nm | 0.17 ± 0.01 | +57.3 ± 2.8 mV | NA | two-layer contact-independent 3D neuronal co-culture model | flow cytometry, and enzyme-linked immunosorbent assay (ELISA) | Quantifying neurite growth in astrocyte-SH-SY5Y cell co-cultures serves as an effective bioassay model for evaluating non-viral gene delivery systems. |
NMDA receptor antagonists | 2018 | memantine-loaded PLGA-PEG nanoparticles (MEM-NP) | Memantine | Topical | 141.8 nm | 0.078 ± 0.018 | −26.5 mV | 80.60% | retinoblastoma (Y-79) and keratinocytes (HaCaT) cells. Dark Agouti rat (OHT). New Zealand rabbits. (DA) rats | IOP, Immunostaining, Corneal and scleral permeation | In vitro epithelial and neuronal cell cultures, this formulation was better tolerated than free memantine and effectively preserved RGC density. |
blockade of glutamate transmission | 2022 | PLGA nanoparticles in situ gelling system (NPs-Gel) | Riluzole | Topical | below 200 nm | below 0.2 | −30.0 mV | 94% | C57BL6 mice | Immunostaining | Optimized PLGA nanoparticles penetrate the blood-retinal barrier, delivering RLZ for 24 h, while RLZ NP gels enhance retention, clear vision, and comfort for glaucoma and dry eye patients. |
IOP lowering/antioxidant | 2020 | Soluplus | Melatonin/Agomelatine | Topical | 61.78 ± 1.61 nm | 0.068 ± 0.022 | NA | NA | Vivo: Sprague–Dawley RAT (Methylcellulose (MCE) model) | IOP, ERG, Western Blot Analysis, Immunostaining | In the MCE model, melatonin/agomelatine significantly reduced IOP elevation more effectively than timolol or brimonidine. |
IOP lowering, anti-inflammatory | 2020 | The diblock poly ethylene glycol-co-polysebacic acid (PSA-PEG) | brinzolamide and mi-RNA-124 | Intravitreal | 250–400 nm | NA | 0.015–0.020 mV | 90% | dutch-belted rabbits and 69 C57/BL6 mice | IOP, Immunostaining, real time PCR | The miRNA/NP-BRZ system is safe, non-toxic, and effectively reduces IOP while providing neuroprotection. The novel nanoparticles offer a slow release and accurately deliver BRZ to the target site, ensuring a long-lasting effect. |
2. Therapeutic Agents
2.1. Brimonidine
2.2. Brain-Derived Neurotrophic Factor (BDNF)
2.3. Memantine
2.4. Riluzole (RLZ)
2.5. Curcumin
2.6. Epoetin Beta (EPOβ)
2.7. N-Acetylcysteine (NAC)
2.8. Melatonin
2.9. MicroRNA (miRNA)
3. Limitations
4. Future Work
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Neuroprotective Drug | Nanocarrier | Efficacy | Safety | Key Findings |
---|---|---|---|---|
Brimonidine | Standard eye drops–Topical concentrations: 0.1%, 0.15%, 0.2% | Limited bioavailability (1–7%) and rapid clearance necessitate frequent dosing. | Common side effects include asthenia; drowsiness; eye discomfort (dry eye, eye inflammation); hyperemia; hypersensitivity; sensation of foreign body; taste altered. | Limited by frequent administration needs due to low bioavailability. |
Polydopamine (PDA) | Enhances RGC protection and significantly boosts axon regeneration compared to brimonidine alone; superior efficacy in reducing microglial activation and increasing visual function. | Demonstrates good ocular biocompatibility; intravitreal injections show no adverse effects. | PDA nanoparticles provide a synergistic neuroprotective effect, improve RGC density, and boost visual outcomes. | |
Brimonidine with human serum albumin (HSA) nanoparticles | Prolongs RGC survival, extending treatment efficacy compared to brimonidine alone. | High biocompatibility: no toxic effects reported. | HSA improves brimonidine’s duration of action, suggesting potential for more sustained neuroprotection. | |
alkoxylphenacyl-based polycarbonates copolymerized with polycaprolactone (AP-PCL) | Sustained release up to 90 days with consistent therapeutic levels; effective long-term IOP management. | Well tolerated; no retinal detachment observed in vivo; no toxic effects on human trabecular meshwork cells. | Demonstrates potential for extended-release formulations, reducing dosing frequency. | |
Brimonidine with nanosponges | Effective IOP reduction sustained for up to 3 weeks, depending on nanoparticle size; promising for long-term management. | No major adverse effects reported in animal studies. | Enhanced IOP control with longer-lasting effects compared to standard formulations, though further testing is needed for functional RGC protection assessment. |
Neuroprotective Drug | Formulation/Approach | Efficacy | Safety | Key Findings | References |
---|---|---|---|---|---|
Brain-Derived Neurotrophic Factor (BDNF) | BDNF (Standard Injections) | Provides neuroprotection to RGCs by acting directly through TrkB receptors or indirectly via glial cells. Effective in improving RGC survival. | Generally safe, but repeated injections are needed due to the transient nature of BDNF, which can raise safety concerns over time. | Challenges include rapid degradation, limited nuclear translocation, and difficulty sustaining therapeutic levels. | [68] |
K2® Nanoparticle-Based BDNF Gene Delivery | Superior retinal transfection and increased gene expression levels compared to conventional methods; 3.4× higher BDNF levels in animal models. | Good biocompatibility: no major adverse reactions noted in studies. | Effective BDNF gene delivery via nanoparticles demonstrated in co-culture models; promising for sustained gene therapy. | [70] | |
Combined BDNF and TrkB Gene Therapy | Provides superior neuroprotection and axonal transport compared to individual therapies; prevents receptor downregulation, ensuring sustained activation. | Safe in experimental settings. | Synergistic effects improve therapeutic outcomes, offering enhanced and prolonged RGC protection. | [72] | |
PACAP38-Linked Exosomes (Non-Glaucoma Model) | Markedly improves survival rates, nerve layer thickness, and visual recovery in traumatic optic neuropathy models. | High biocompatibility observed; no significant adverse effects reported. | Demonstrates the effectiveness of neurotrophic factor delivery via exosomes for enhanced neuroprotection. | [73] |
Agents | IOP Reduction | Photopic Negative Response | Pattern ERG | Gliosis-Related Inflammation | RGC Density (% of Healthy Control) |
---|---|---|---|---|---|
MelAgo | 60% | PhNR amplitude close to normal. | Reduced MCE-induced prolonged implicit time. | Reduced Iba1 and GFAP by 2.3- and 3.2-fold. Reduced levels of TNF-α, IL-1β and IL-6 (by 2.0-, 2.1-, and 2.3-fold). Increased levels of IL-4 and IL-10 (by about 2.0- and 2.5-fold). | Central 92 ± 5 Middle 94 ± 5 Peripheral 94 ± 5 |
Timolol | 32% | No effects. | No effects. | No effects. | Central 78 ± 4 Middle 83 ± 3 Peripheral 81 ± 4 |
Brimonidine | 34% | PhNR amplitude close to normal. | Reduced MCE-induced prolonged implicit time. | Reduced GFAP by 1.6-fold. | Central 88 ± 3 Middle 91 ± 6 Peripheral 91 ± 3 |
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Pei, K.; Georgi, M.; Hill, D.; Lam, C.F.J.; Wei, W.; Cordeiro, M.F. Review: Neuroprotective Nanocarriers in Glaucoma. Pharmaceuticals 2024, 17, 1190. https://doi.org/10.3390/ph17091190
Pei K, Georgi M, Hill D, Lam CFJ, Wei W, Cordeiro MF. Review: Neuroprotective Nanocarriers in Glaucoma. Pharmaceuticals. 2024; 17(9):1190. https://doi.org/10.3390/ph17091190
Chicago/Turabian StylePei, Kun, Maria Georgi, Daniel Hill, Chun Fung Jeffrey Lam, Wei Wei, and Maria Francesca Cordeiro. 2024. "Review: Neuroprotective Nanocarriers in Glaucoma" Pharmaceuticals 17, no. 9: 1190. https://doi.org/10.3390/ph17091190