Pharmacological Potential of Small Molecules for Treating Corneal Neovascularization
Abstract
:1. Introduction
2. Models of CoNV
3. Synthetic Small Molecules
3.1. Tyrosine Kinase Inhibitors
3.2. Repurposed Antimicrobials
3.3. Other Synthetics
4. Natural Products
4.1. Polyphenols: Flavonoids
4.2. Non-Flavonoid Phytochemicals
4.3. Immunosuppressants
Macrolides
4.4. Vitamins and Photoactivatable Compounds
4.5. HDAC Inhibitors
5. Discussion/Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Tyrosine Kinase Inhibitor | Source | Mechanism | Routes | Dose | Model | Ref |
---|---|---|---|---|---|---|
Sunitinib | Synthetic | Inhibition of the VEGFR and PDGFR pathways | Oral | 40 mg/kg | Murine thermal cauterization | [23] |
Topical | 0.5 mg/mL | Rabbit suture model | [24] | |||
Subconjunctival Topical | 0.25 mg/0.1 mL 0.5 mg/mL | Rabbit suture model | [25] | |||
AG 1296 | Synthetic | PI3K-RTK inhibition | Systemic via osmotic pump implantation | 10 ng/mL | Murine alkali burn model | [27] |
Vatalanib succinate | Synthetic | VEGFR inhibition | Oral | 75 mg/kg; 2x/day | Murine suture model | [28] |
ZK261991 | Synthetic | VEGFR inhibition | Oral | 50 mg/kg; 2x/day | Murine suture model | [28] |
Sorafenib | Synthetic | Inhibition of ERK and VEGFR2 phosphorylation | Oral | 30 mg/kg; 60 mg/kg | Rat silver-nitrate burn model | [31] |
Semaxanib | Synthetic | Selective VEGFR2 inhibition | Intraperitoneal | 25 mg/kg | Rat silver-nitrate burn model | [33] |
Rivoceranib | Synthetic | Selective VEGFR2 inhibition | Topical | 0.1%; 0.5% | Murine alkali burn model | [36] |
Regorafenib | Synthetic | Decreases epithelial and endothelial VEGF levels | Topical | 1 mg/mL | Rat alkali burn model | [38] |
Lapatinib | Synthetic | Decreases corneal epithelial and stromal VEGF expression | Oral | 50 mg/kg | Rat silver-nitrate burn model | [41] |
Axitinib | Synthetic | Inhibition of VEGFR2 and PDGFR | Topical | 0.02, 0.35, 0.5 mg/mL | Rabbit suture model | [43] |
Dovitinib | Synthetic | Inhibition of VEGFRs, PDGFR, FGFR-1 and -3, | Topical | 5 mg/mL; 2x/day | Rat silver-nitrate burn model | [45] |
Antimicrobial | Source | Mechanism | Routes | Dose | Model | Ref |
---|---|---|---|---|---|---|
Doxycycline | Semisynthetic | MMP inhibition, and modulation of the MMP-independent PI3K/Akt-eNOS pathway | Oral | 40 mg/kg | Murine alkali burn model | [49] |
Topical | 0.5 mg/mL | Murine silver-nitrate model | [50] | |||
Minocycline | Semisynthetic | Inhibition of MMP and downregulation of the ERK1/2 and Akt pathways | Intraperitoneal | 30 mg/kg; 60 mg/kg; 2x/day | Murine alkali burn model | [53] |
Tigecycline | Synthetic derived from minocycline | Unknown | Topical Subconjunctival | 1 mg/mL 1 mg/mL | Rat silver-nitrate model | [55] |
Itraconazole | Synthetic | Inhibition of cholesterol biosynthesis | Topical Subconjunctival Intraperitoneal | 10 mg/mL 10 mg/mL 19 mg/mL | Rat silver-nitrate model | [57] |
Dihydroartemisinin | Semisynthetic derivative of artemisinin | Modulation of the ERK1/2 and p38 pathways | Topical | 5 mg/L, 10 mg/L, 20 mg/L | Rat suture model | [60] |
Molecule | Source | Mechanism | Routes | Dose | Model | Ref |
---|---|---|---|---|---|---|
JSM5562 (Exact structure not reported) | Synthetic | Impairing EC migration, adhesion, and tube formation. Exact mechanism unknown | Systemic via osmotic pump implantation | 0.1 mg/mL, 0.5 mg/mL, 2.5 mg/mL | Murine alkali burn model | [62] |
LCB54–0009 | Imidazole-based alkaloid derivative | Regulation of HIF-1α protein stability and HIF-1α/NF-κB redox sensitivity. Inhibits Ang expression and VEGF signaling cascade | Subconjunctival | 50 µg/ 20 µL | Rat silver-nitrate burn model | [64] |
N-acetyl-l-cysteine | Synthetic | Antioxidant; downregulates VEGF | Intraperitoneal | 200 mg/kg | Murine alkali burn model | [66] |
IMD0354 | Synthetic | Inhibition of NF-κB through selective blockage of IKK complex, IKK2 | Systemic | 30 mg/kg | Rat suture model | [68] |
Lanepitant | Synthetic | NK1R antagonist | Topical Subconjunctival | 0.4, 1.6, 6.4 mg/mL 12.8 mg/mL | Murine alkali burn and suture models | [71] |
SB-328437 | Synthetic | CCR3 antagonist; reduces MCP-1 and -3. Exact mechanism unknown | Topical | 125 µg/mL, 250 µg/mL, 500 µg/mL | Murine alkali burn model | [74] |
AMD3100 | Synthetic | CXCR4 antagonist; Downregulates VEGF expression and inflammation | Subconjunctival Intraperitoneal | 5 µL 2.5 mg/kg | Murine alkali burn model | [77] |
33-DFTG | Synthetic | Downregulates VEGF through unknown mechanism | Subconjunctival | 50 mM | Murine alkali burn and murine silver-nitrate models | [79] |
TNP-470 | Synthetic analogue of fumagillin | Targets MetAP2 | Topical Subconjunctival injection | 5 ng/nL; 3x/day 30 mg/kg | Murine alkali burn model | [17] |
Flavonoid | Source | Mechanism | Routes | Dose | Model | Ref |
---|---|---|---|---|---|---|
Epigallocatechin gallate (EGCG) | Green tea (Camellia sinensis) | Unknown; downregulation of VEGF and COX-2 | Topical | 0.01 µg/mL 0.1 µg/mL | Rabbit suture model | [89] |
Nanoparticle-mediated delivery via eye drops | 30 mg/mL | Murine alkali burn model | [91] | |||
Kaempferol | Fruits and vegetables | Unknown; downregulation of MMP and VEGF | Nanoparticle- mediated delivery via eye drops | 7.5 µg/mL | Murine silver-nitrate/ potassium model | [94] |
Isoliquiritigenin | Licorice root (Glycyrrhiza uralensis) | Unknown; downregulates VEGF and upregulates PEDF | Topical | 0.5, 1, 5, 10, 50 µM | Murine silver-nitrate model | [96] |
Fisetin | Fruits and vegetables | Unknown | Topical | 1.0 mg/mL; 4x/day | Rabbit corneal micropocket b-FGF model | [97] |
Luteolin | Fruits and vegetables | Unknown | Topical | 0.5 mg/mL; 4x/day | Rabbit corneal micropocket b-FGF model | [97] |
Genistein | Soybeans | Unknown; downregulates VEGF and TGF-β | Topical | 0.5 mg/mL; 4x/day | Rabbit corneal micropocket b-FGF model | [97] |
Naringenin | Citrus fruits and vegetables | Unknown; Downregulates NF-κB activity, proangiogenic factors, and reduces production of cytokines IL-1β and IL-6 | Topical | 0.08, 0.8, 8, 80 µg | Rat alkali burn model | [102] |
Non-Flavonoid Phytochemical | Source | Mechanism | Routes | Dose | Model | Ref |
---|---|---|---|---|---|---|
Curcumin | Turmeric (Curcuma longa) | Unknown; inhibition of several signal transduction pathways, including NF-κB activation | Topical | 40 µM; 2x/day | Rat alkali burn model | [111] |
Topical | 40, 80, and 160 µM | Rabbit suture model | [110] | |||
Nanoparticle-mediated delivery via eye drops | 80 mg | Rat silver-nitrate model | [112] | |||
Resveratrol | Grapes and other fruits | Unknown; Downregulates FGF-2 and VEGF | Oral | 48 mg/kg | Murine FGF-2 and VEGF-micropocket model | [115] |
Subconjunctival | 10 mg/mL | Rabbit alkali burn model | [116] | |||
Withaferin A | Steroidal lactone (Withania somnifera) | Targets and downregulates vimentin | Intraperitoneal | 2 mg/kg | Murine de-epithelializ-ation model using wild type and vimentin-null mice | [118] |
Xanthatin | Sesquiterpene lactone (Xanthium sibiricum) | Inhibition of the VEGFR2-mediated STAT3/PI3K/Akt signaling pathways | Topical | 10 µM; 4x/day | Rat alkali burn model | [123] |
Triptolide | Tripterygium wilfordii Hook F | Unknown; downregulates VEGF | Topical | 100 nM; 3x/day | Murine alkali burn model | [126] |
Thymoquinone | Volatile oil of black seed (Nigella sativa) | Unknown; Likely related to antioxidant and anti-inflammatory properties | Topical | 0.1%, 0.4% | Rat silver-nitrate model | [131] |
Glycyrrhizin | Saponin from licorice root (Glycyrrhiza glabra) | Unknown | Topical | 1% | Rabbit alkali burn model | [133] |
Immunosuppressant | Source | Mechanism | Routes | Dose | Model | Ref |
---|---|---|---|---|---|---|
Tetramethylpyrazine | Bioactive component of chuanxiong (Ligusticum striatum) | Unknown; Downregulates CXCR-4 | Topical | 1.5 mg/mL 4x/day | Murine alkali burn model | [137] |
Methotrexate | Synthetic | Unknown; Downregulates VEGF and IL-6 | Topical Subconjunctival | 2 mg/mL, 4 mg/mL 2 mg/mL | Rabbit suture model | [140] |
CC-3052 | Thalidomide analogue | Unknown; Downregulates VEGF and TNF-α | Topical Subconjunctival | 0.25%, 0.5%, and 1% 0.5% | Rabbit suture model | [147] |
DAID | Thalidomide analogue | Unknown; Downregulates VEGF | Topical | 0.25% | Murine alkali burn model | [149] |
LASSBio-596 | Thalidomide and arylsulfonamide derivative | Unknown | Topical | 1%; 3x/day | Rabbit alkali burn model | [152] |
Cyclosporine A | Secondary metabolite of fungal genus Tolypocladium | Calcineurin inhibition; downregulates MMP-9, VEGF, and iNOS | Topical Subconjunctival | 4% 5 mg/kg | Rat silver-nitrate model | [153] |
Topical | 0.05% | Rabbit immune-mediated CoNV model | [154] | |||
Nanofibers | 0.25 mg/mm2 | Rabbit alkali burn model | [156] | |||
Rapamycin | Product of Streptomyces hygroscopicus | mTOR inhibition; downregulates VEGF, TNF-α, TGF-β, IL-6, and Substance P | Topical Intraperitoneal | 1 mg/mL 0.2 mg/kg | Murine alkali burn model | [160] |
Intraperitoneal | 2 mg/kg; 1x/day | Murine alkali burn model | [159] | |||
Tacrolimus | Product of Streptomyces tsukubaensis | Calcineurin inhibition; downregulates VEGF, TNF-α, IL-1β, and MCP-1 | Topical Subconjunctival | 5 mg/5 mL 0.25 mg/ 0.05 mL | Rabbit suture model | [164] |
Vitamin/Photoactivatable Compound | Source | Mechanism | Routes | Dose | Model | Ref |
---|---|---|---|---|---|---|
Ascorbic acid | Diet | Unknown; Downregulation of VEGF and MMP-9 | Topical | 0.5, 1, 10 mg/mL | Rabbit suture model | [167] |
Riboflavin | Diet | Induction of apoptosis in vascular ECs; downregulation of macrophages and CD45+ cells | Topical riboflavin followed by UVA exposure | 0.1% | Murine suture model | [171] |
Verteporfin | Synthetic | Suppressed blood vessels and lymphatic vessels | Intravenous followed by light exposure | 6 mg/m2 | Murine suture model | [174] |
1α,25-dihydroxyvitamin D3 | Diet | Inhibited migration of Langerhans cells into cornea | Topical | 10−7 M, 10−8 M, and 10−9 M | Murine suture model | [177] |
HDAC Inhibitor | Source | Mechanism | Routes | Dose | Model | Ref |
---|---|---|---|---|---|---|
Largazole | Macrocyclic depsipeptide from marine cyanobacterium Symploca species | Class I HDAC inhibition; downregulates VEGF, b-FGF, TGF-β1, and EGF; Upregulates Tsp-1, Tsp-2, and ADAMTS-1 | Topical | 5 µL; 2x/day | Murine alkali burn model | [180] |
Vorinostat | Synthetic | HDAC inhibition; targets unknown | Topical | 10 µM; 3x/day | Murine alkali burn model | [182] |
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Barry, Z.; Park, B.; Corson, T.W. Pharmacological Potential of Small Molecules for Treating Corneal Neovascularization. Molecules 2020, 25, 3468. https://doi.org/10.3390/molecules25153468
Barry Z, Park B, Corson TW. Pharmacological Potential of Small Molecules for Treating Corneal Neovascularization. Molecules. 2020; 25(15):3468. https://doi.org/10.3390/molecules25153468
Chicago/Turabian StyleBarry, Zachary, Bomina Park, and Timothy W. Corson. 2020. "Pharmacological Potential of Small Molecules for Treating Corneal Neovascularization" Molecules 25, no. 15: 3468. https://doi.org/10.3390/molecules25153468