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Corneal neovascularization is a serious corneal pathological change caused by various factors. The drug delivery system is of great significance for the effective treatment of corneal neovascularization. Herein, we developed and characterized a monolith/hydrogel composite as the triamcinolone acetonide (TA) carrier for curing corneal neovascularization. The composite was prepared by photo-initiated free radical polymerization of multi-methacrylate substituted dodecamine organic molecular cage and post-modified by the sequential photo-initiated free radical polymerization of acrylated gelatin. The globular morphology and structural property of as-prepared composites were evaluated by scanning electron microscopy, Fourier-transform infrared spectroscopy and solid-state cross polarization magic angle spinning carbon-13 nuclear magnetic resonance. Then swelling ratio and the TA loading capacity were investigated then. Compared with gelatin hydrogel, the composites exhibited a decreased swelling ratio and an improved loading capacity. With good biocompatibility, the composite can sustainedly release TA for up to 28 days, and effectively inhibit corneal neovascularization with an alkali burn-induced corneal neovascularization model. Additionally, tandem mass tags-labeled quantitative proteomics were performed to identify differentially expressed proteins between vascularized and devascularized corneas. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that the inhibition process could be primarily linked to the fibrinolytic system. These results demonstrated the potential of monolith/hydrogel composites as delivery systems in the therapy for biomedical diseases.

Naringenin, a flavonoid, possesses antiangiogenic potential and inhibits corneal neovascularization (CNV); however, its therapeutic use is restricted due to poor solubility and limited bioavailability. In this study, we developed a naringenin microemulsion (NAR-ME) for inhibiting CNV. NAR-ME formulation was composed of triacetin (oil phase), Cremophor RH40 (CRH40), PEG400, and water, its droplet size was 13.22 ± 0.13 nm with a narrow size distribution (0.112 ± 0.0014). The results demonstrated that NAR-ME released higher and permeated more drug than NAR suspension (NAR-Susp) in in vitro drug release and ex vivo corneal permeation study. Human corneal epithelial cells (HCECs) toxicity study showed no toxicity with NAR-ME, which is consistent with the result of ocular irritation study. NAR-ME had high bioavailability 1.45-fold, 2.15-fold, and 1.35-fold higher than NAR-Susp in the cornea, conjunctiva, and aqueous humor, respectively. Moreover, NAR-ME (0.5% NAR) presented efficacy comparable to that of dexamethasone (0.025%) in the inhibition of CNV in mice CNV model induced by alkali burning, resulting from the attenuation of corneal vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP-14) expression. In conclusion, the optimized NAR-ME formulation demonstrated excellent physicochemical properties and good tolerance, enhanced ocular bioavailability and corneal permeability. This formulation is promising, safe, and effective for the treatment of CNV.

Sorafenib (SRB), a multikinase inhibitor, is effective in reducing experimental corneal neovascularization (CNV) after oral administration; however, its therapeutic use in ocular surface disorders is restricted due to poor solubility and limited bioavailability. This study aimed to develop and optimize SRB-loaded nanostructured lipid carriers (SRB-NLCs) for topical ocular delivery by a central composite design response surface methodology (CCD-RSM). It was spherical and uniform in morphology with an average particle size of 111.87 ± 0.93 nm and a narrow size distribution. The in vitro drug release from the released SRB-NLC formulation was well fitted to Korsmeyer Peppas release kinetics. The cell counting kit-8 (CCK-8) cell viability assay demonstrated that SRB-NLC was not obviously cytotoxic to human corneal epithelial cells (HCECs). An in vivo ocular irritation test showed that SRB-NLC was well tolerated by rabbit eyes. Ocular pharmacokinetics revealed 6.79-fold and 1.24-fold increase in the area under concentration-time curves (AUC0-12h) over 12 h in rabbit cornea and conjunctiva, respectively, treated with one dose of SRB-NLC compared with those treated with SRB suspension. Moreover, SRB-NLC (0.05% SRB) and dexamethasone (0.025%) similarly suppressed corneal neovascularization in mice. In conclusion, the optimized SRB-NLC formulation demonstrated excellent physicochemical properties and good tolerance, sustained release, and enhanced ocular bioavailability. It is safe and potentially effective for the treatment of corneal neovascularization.

Isoliquiritigenin (ISL), as a natural flavonoid, has been proven to have therapeutic potential for corneal neovascularization (CNV) treatment; however, its therapeutic use is restricted due to its poor aqueous solubility and limited bioavailability. To overcome these limitations, a novel ISL-loaded nanoemulsion (ISL-NE) was designed for inhibiting CNV in this study. ISL-NE formulation was composed of propylene glycol dicaprylate (PGD), Cremophor® EL (EL35), polyethylene glycol 400 (PEG 400) and adding water with sodium hyaluronate, its particle size was 34.56 ± 0.80 nm with a low polydispersity index of less than 0.05, which suggested a narrow size distribution. The results demonstrated that ISL-NE released higher and permeated more drug than ISL suspension (ISL-Susp) in in vitro drug release and ex vivo corneal permeation study. ISL-NE showed no cytotoxicity in human corneal epithelial cells toxicity study, which was consistent with the result of ocular irritation study in rabbit eyes. ISL-NE had bioavailability 5.76-fold, 7.80-fold and 2.13-fold higher than ISL-Sups in tears, cornea and aqueous humor after a single dose of ISL-NE, respectively. Furthermore, the efficacy of ISL-NE treatment (0.2% ISL) was comparable to that of dexamethasone treatment (0.025%) in the inhibition of CNV in mice model. Enzyme-linked immunosorbent assay (ELISA) showed that the expressions of corneal vascular endothelial growth factor (VEGF-A) and matrix metalloproteinase (MMP-2) were decreased. In conclusion, the ISL-NE demonstrated excellent physicochemical properties, good tolerance, and enhanced ocular bioavailability. It could be a promising, safe, and effective treatment for CNV.

Corneal neovascularization (CNV) is the major cause of blindness after eye injury; however, only several drugs can be applied and the invasive administration ways (i.e., intravitreal injection and subconjunctival injection) are used. Resveratrol is a highly effective anti-VEGF agent against CNV. However, its applications are limited due to its strong hydrophobicity and instability. Here, we developed a resveratrol-loaded ocular lamellar crystalline gel (ROLG) for high inhibition of CNV. ROLGs were composed of resveratrol, glyceryl monooleate (GMO), ethanol, and water, and their lamellar crystalline structures were identified by polarizing light microscopy and small-angle X-ray scattering. High drug loading (4.4 mg/g) of ROLGs was achieved due to the hydrogen bonding between GMO and resveratrol. Resveratrol showed sustained release with 67% accumulative release in 7 h, which was attributed to the slow erosion of gels. Resveratrol in ROLGs had a high corneal permeation 3 times higher than resveratrol in hyaluronic acid suspensions (RHSs). ROLGs were administered to rats only once a day because of their strong retention on the cornea surface. ROLGs were safe due to the very little contact of ethanol in ROLGs to the cornea. CNV post-rat corneal alkaline injury was highly inhibited by ROLGs, resulting from the attenuation of corneal VEGF expression and then corneal healing was improved. The ROLG was a promising ocular medicine for the prevention of CNV.

Corneal neovascularization (CNV) is one of the major causes of severe disorders in ocular surface. Subconjunctival administration provides a localized and effective delivery of anti-angiogenic agents to inhibit neovascularization. In the present study, the ABA triblock copolymer of poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol)-block-poly(D,L-lactic-co-glycolic acid) (PLGA-PEG-PLGA) was used as a sustained drug delivery carrier for metformin (MET) and levofloxacin hydrochloride (LFH). Both drugs and PLGA-PEG-PLGA copolymers could be easily dissolved in water at low or room temperature and the mixed solution could form a drug-loaded thermosensitive hydrogel in terms of body temperature response. The in vitro release investigation displayed a sustained release of MET and LFH from the formulation for one month. The in vivo efficacy of subconjunctival injection of the MET + LFH loaded thermosensitive hydrogel in inhibiting CNV was evaluated on a mouse model of corneal alkali burn. Compared with the single administration of MET or LFH loaded thermosensitive hydrogel, the MET + LFH loaded thermosensitive hydrogel remarkably inhibited the formation of CNV. The sustained release of MET and an antibiotic (LFH) provides synergistic therapeutic outcome. As a result, the co-delivery of MET and LFH using PLGA-PEG-PLGA thermosensitive hydrogel by subconjunctival injection has great potential for ocular anti-angiogenic therapy.

Corneal neovascularization (CNV) is one of the major causes of severe disorders in ocular surface. Subconjunctival administration provides a localized and effective delivery of anti-angiogenic agents to inhibit neovascularization. In the present study, the ABA triblock copolymer of poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol)-block-poly(D,L-lactic-co-glycolic acid) (PLGA-PEG-PLGA) was used as a sustained drug delivery carrier for metformin (MET) and levofloxacin hydrochloride (LFH). Both drugs and PLGA-PEG-PLGA copolymers could be easily dissolved in water at low or room temperature and the mixed solution could form a drug-loaded thermosensitive hydrogel in terms of body temperature response. The in vitro release investigation displayed a sustained release of MET and LFH from the formulation for one month. The in vivo efficacy of subconjunctival injection of the MET + LFH loaded thermosensitive hydrogel in inhibiting CNV was evaluated on a mouse model of corneal alkali burn. Compared with the single administration of MET or LFH loaded thermosensitive hydrogel, the MET + LFH loaded thermosensitive hydrogel remarkably inhibited the formation of CNV. The sustained release of MET and an antibiotic (LFH) provides synergistic therapeutic outcome. As a result, the co-delivery of MET and LFH using PLGA-PEG-PLGA thermosensitive hydrogel by subconjunctival injection has great potential for ocular anti-angiogenic therapy. [ABSTRACT FROM AUTHOR]

Sorafenib (SRB), a multikinase inhibitor, is effective in reducing experimental corneal neovascularization (CNV) after oral administration; however, its therapeutic use in ocular surface disorders is restricted due to poor solubility and limited bioavailability. This study aimed to develop and optimize SRB-loaded nanostructured lipid carriers (SRB-NLCs) for topical ocular delivery by a central composite design response surface methodology (CCD-RSM). It was spherical and uniform in morphology with an average particle size of 111.87 ± 0.93 nm and a narrow size distribution. The in vitro drug release from the released SRB-NLC formulation was well fitted to Korsmeyer Peppas release kinetics. The cell counting kit-8 (CCK-8) cell viability assay demonstrated that SRB-NLC was not obviously cytotoxic to human corneal epithelial cells (HCECs). An in vivo ocular irritation test showed that SRB-NLC was well tolerated by rabbit eyes. Ocular pharmacokinetics revealed 6.79-fold and 1.24-fold increase in the area under concentration-time curves (AUC 0-12h ) over 12 h in rabbit cornea and conjunctiva, respectively, treated with one dose of SRB-NLC compared with those treated with SRB suspension. Moreover, SRB-NLC (0.05% SRB) and dexamethasone (0.025%) similarly suppressed corneal neovascularization in mice. In conclusion, the optimized SRB-NLC formulation demonstrated excellent physicochemical properties and good tolerance, sustained release, and enhanced ocular bioavailability. It is safe and potentially effective for the treatment of corneal neovascularization.

Corneal neovascularization is a serious corneal pathological change caused by various factors. The drug delivery system is of great significance for the effective treatment of corneal neovascularization. Herein, we developed and characterized a monolith/hydrogel composite as the triamcinolone acetonide (TA) carrier for curing corneal neovascularization. The composite was prepared by photo-initiated free radical polymerization of multi-methacrylate substituted dodecamine organic molecular cage and post-modified by the sequential photo-initiated free radical polymerization of acrylated gelatin. The globular morphology and structural property of as-prepared composites were evaluated by scanning electron microscopy, Fourier-transform infrared spectroscopy and solid-state cross polarization magic angle spinning carbon-13 nuclear magnetic resonance. Then swelling ratio and the TA loading capacity were investigated then. Compared with gelatin hydrogel, the composites exhibited a decreased swelling ratio and an improved loading capacity. With good biocompatibility, the composite can sustainedly release TA for up to 28 days, and effectively inhibit corneal neovascularization with an alkali burn-induced corneal neovascularization model. Additionally, tandem mass tags-labeled quantitative proteomics were performed to identify differentially expressed proteins between vascularized and devascularized corneas. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that the inhibition process could be primarily linked to the fibrinolytic system. These results demonstrated the potential of monolith/hydrogel composites as delivery systems in the therapy for biomedical diseases.

Naringenin, a flavonoid, possesses antiangiogenic potential and inhibits corneal neovascularization (CNV); however, its therapeutic use is restricted due to poor solubility and limited bioavailability. In this study, we developed a naringenin microemulsion (NAR-ME) for inhibiting CNV. NAR-ME formulation was composed of triacetin (oil phase), Cremophor RH40 (CRH40), PEG400, and water, its droplet size was 13.22 ± 0.13 nm with a narrow size distribution (0.112 ± 0.0014). The results demonstrated that NAR-ME released higher and permeated more drug than NAR suspension (NAR-Susp) in in vitro drug release and ex vivo corneal permeation study. Human corneal epithelial cells (HCECs) toxicity study showed no toxicity with NAR-ME, which is consistent with the result of ocular irritation study. NAR-ME had high bioavailability 1.45-fold, 2.15-fold, and 1.35-fold higher than NAR-Susp in the cornea, conjunctiva, and aqueous humor, respectively. Moreover, NAR-ME (0.5% NAR) presented efficacy comparable to that of dexamethasone (0.025%) in the inhibition of CNV in mice CNV model induced by alkali burning, resulting from the attenuation of corneal vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP-14) expression. In conclusion, the optimized NAR-ME formulation demonstrated excellent physicochemical properties and good tolerance, enhanced ocular bioavailability and corneal permeability. This formulation is promising, safe, and effective for the treatment of CNV.

Isoliquiritigenin (ISL), as a natural flavonoid, has been proven to have therapeutic potential for corneal neovascularization (CNV) treatment; however, its therapeutic use is restricted due to its poor aqueous solubility and limited bioavailability. To overcome these limitations, a novel ISL-loaded nanoemulsion (ISL-NE) was designed for inhibiting CNV in this study. ISL-NE formulation was composed of propylene glycol dicaprylate (PGD), Cremophor® EL (EL35), polyethylene glycol 400 (PEG 400) and adding water with sodium hyaluronate, its particle size was 34.56 ± 0.80 nm with a low polydispersity index of less than 0.05, which suggested a narrow size distribution. The results demonstrated that ISL-NE released higher and permeated more drug than ISL suspension (ISL-Susp) in in vitro drug release and ex vivo corneal permeation study. ISL-NE showed no cytotoxicity in human corneal epithelial cells toxicity study, which was consistent with the result of ocular irritation study in rabbit eyes. ISL-NE had bioavailability 5.76-fold, 7.80-fold and 2.13-fold higher than ISL-Sups in tears, cornea and aqueous humor after a single dose of ISL-NE, respectively. Furthermore, the efficacy of ISL-NE treatment (0.2% ISL) was comparable to that of dexamethasone treatment (0.025%) in the inhibition of CNV in mice model. Enzyme-linked immunosorbent assay (ELISA) showed that the expressions of corneal vascular endothelial growth factor (VEGF-A) and matrix metalloproteinase (MMP-2) were decreased. In conclusion, the ISL-NE demonstrated excellent physicochemical properties, good tolerance, and enhanced ocular bioavailability. It could be a promising, safe, and effective treatment for CNV.

Corneal neovascularization (CNV) is the major cause of blindness after eye injury; however, only several drugs can be applied and the invasive administration ways (i.e., intravitreal injection and subconjunctival injection) are used. Resveratrol is a highly effective anti-VEGF agent against CNV. However, its applications are limited due to its strong hydrophobicity and instability. Here, we developed a resveratrol-loaded ocular lamellar crystalline gel (ROLG) for high inhibition of CNV. ROLGs were composed of resveratrol, glyceryl monooleate (GMO), ethanol, and water, and their lamellar crystalline structures were identified by polarizing light microscopy and small-angle X-ray scattering. High drug loading (4.4 mg/g) of ROLGs was achieved due to the hydrogen bonding between GMO and resveratrol. Resveratrol showed sustained release with 67% accumulative release in 7 h, which was attributed to the slow erosion of gels. Resveratrol in ROLGs had a high corneal permeation 3 times higher than resveratrol in hyaluronic acid suspensions (RHSs). ROLGs were administered to rats only once a day because of their strong retention on the cornea surface. ROLGs were safe due to the very little contact of ethanol in ROLGs to the cornea. CNV post-rat corneal alkaline injury was highly inhibited by ROLGs, resulting from the attenuation of corneal VEGF expression and then corneal healing was improved. The ROLG was a promising ocular medicine for the prevention of CNV.