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Nanoparticle-mediated corneal neovascularization treatments: Toward new generation of drug delivery systems

Chinese Chemical Letters 2023年第3期34卷 90-99页

作者： Huimin Zhu Jingwen Yu Jinfa Ye Yiming Wu Jintao Pan Yingying Li Chuan Chen Li Zheng Gang Liu Chengchao Chu Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed by the Province and Ministry Guangxi Medical UniversityNanning 530021China Eye Institute of Xiamen University Fujian Provincial Key Laboratory of Ophthalmology and Visual ScienceXiamen UniversityXiamen 361102China State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics and Center for Molecular Imaging and Translational Medicine School of Public Health Xiamen Xiamen UniversityXiamen 361102China Department of Pharmacy Xiamen Medical CollegeXiamen 361023China Shenzhen Research Institute of Xiamen University Shenzhen 518057China

corneal neovascularization(CNV) is one of the major factors for vision impairment and blindness worldwide. The current treatment for CNV focuses primarily on topical eyedrops of glucocorticoids,non-steroidal anti-inflammatory drugs, electro-coagulation and laser photo-coagulation. Unfortunately,coagulation-based treatment is restricted by corneal hemorrhage and iris atrophy. And drug treatments have limited therapeutic effects and a short duration of action. Nanoparticle-based drug delivery systems are widely applied due to their improved pharmacokinetics, optimized drug targeting and enhanced biocompatibility. In this article, we provide a comprehensive and systematic overview of the CNV nanodrug system, highlighting some of the recent advances in nanodrug design, preparation, and functional modification. Moreover, we discuss the challenges in the clinical translation and potential risks in CNV treatment. A greater effort is needed for the potential applications of nanotechnology in the field of ophthalmology.

关键词： corneal neovascularization Nanoparticles Drug delivery system Anti-VEGF Supramolecular assembly

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Efficacy and safety of anti-vascular endothelial growth factor agents on corneal neovascularization: A meta-analysis

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World Journal of Clinical Cases 2023年第30期11卷 7337-7349页

作者： Shih-Chung Lai El-Wui Loh Du-I Chiou Chien-Tai Hong Department of Ophthalmology Shuang Ho HospitalNew Taipei City 23561TaiwanChina Center for Evidence-Based Health Care Department of Medical ResearchTaipei Medical University Shuang Ho HospitalNew Taipei City 23561TaiwanChina Cochrane Taiwan Taipei Medical UniversityTaipei 110TaiwanChina Graduate Institute of Clinical Medicine College of MedicineTaipei Medical UniversityTaipei 110TaiwanChina Department of Medical Imaging Taipei Medical University Shuang Ho HospitalNew Taipei City 23561TaiwanChina Department of Neurology Taipei Medical University-Shuang Ho HospitalNew Taipei 23561TaiwanChina

BACKGROUND corneal neovascularization(CoNV)is the second major cause of *** endothelial growth factor(VEGF)inhibitors,e.g.,bevacizumab,have been used to prevent *** We conducted an updated systematic review and meta-analysis of clinical trials to examine the efficacy and safety of anti-VEGF in *** A literature search was conducted using three electronic *** difference(MD),standard mean difference(SMD),and relative risk(RR)are used to estimate the effect *** Nine randomized controlled and three non-randomized trials were *** pooled results demonstrated a significant reduction of CoNV area/Length(SMD=-1.17,95%CI:-1.58 to-0.75),best corrected visual acuity(MD=-0.54,95%CI:-0.91 to-0.17),and graft rejection(RR=0.44,95%CI:0.24 to 0.8)and failure(RR=0.39,95%CI:0.19 to 0.78)rates in the anti-VEGF group than the placebo group.A non-significant reduction of the epithelial defect was also observed in the bevacizumab group compared with the placebo(RR=0.56,95%CI:0.30 to 1.06).Compared with a placebo,the unsynthesizable trials also support that bevacizumab improves visual acuity,CoNV,graft rejection,and failure *** reporting other comparisons revealed the superiority of combined remedy with bevacizumab compared to other treatments in reducing *** Anti-VEGF agents,mainly bevacizumab,are an effective and safe treatment for CoNV of all causes and prevent corneal graft rejection and failure in corneal transplantation.

关键词： Efficacy Safety Anti-vascular endothelial growth factor agents corneal neovascularization Bevacizumab

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Therapeutic approaches for corneal neovascularization

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Eye and Vision 2017年第1期4卷 164-173页

作者： Sepehr Feizi Amir A.Azari Sharareh Safapour Ophthalmic Research Center Labbafinejad Medical CenterShahid Beheshti University of Medical SciencesTehran 16666Iran

Angiogenesis refers to new blood vessels that originate from pre-existing vascular *** neovascularization which can lead to compromised visual acuity occurs in a wide variety of corneal pathologies.A large subset of measures has been advocated to prevent and/or treat corneal neovascularization with varying degrees of *** approaches include topical corticosteroid administration,laser treatment,cautery,and fine needle *** the imbalance between proangiogenic agents and antiangiogenic agents primarily mediate the process of corneal neovascularization,recent therapies are intended to disrupt the different steps in the synthesis and actions of proangiogenic *** approaches,however,are only partially effective and may lead to several side *** aim of this article is to review the most relevant treatments for corneal neovascularization available so far.

关键词： corneal neovascularization Angiogenesis Angiogenic therapies

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The phototherapy toward corneal neovascularization elimination:An efficient,selective and safe strategy

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Chinese Chemical Letters 2021年第1期32卷 99-101页

作者： Jingwen Yu Chengchao Chu Yiming Wu Gang Liu Wei Li Eye Institute of Xiamen University Fujian Provincial Key Laboratory of Ophthalmology and Visual ScienceSchool of MedicineXiamen UniversityXiamen 361102China State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics&Center for Molecular Imaging and Translational Medicine School of Public HealthXiamen UniversityXiamen 361102China

corneal neovascularization(CNV) can induce severe visual impairment and even *** treatments have limited efficacy and some undesirable side ***(FT) is a modern medical technique in CNV treatment and worth further *** has various advantages and nanoparticle-mediated drug delive ry also contributes to CNV *** combined with functional nanoparticles featuring photoacoustic imaging contrast properties can accomplish accurate and safe inhibition of CNV,thus is promising in clinical application.

关键词： corneal neovascularization Phototherapy Nanotechnology R-nano ICG Photoacoustic imaging

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Inhibitory effect of polysulfated heparin endostatin on alkali burn induced corneal neovascularization in rabbits

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International Journal of Ophthalmology(English edition) 2015年第2期8卷 234-238页

作者： Zhao-Na Li Zhong-Fang Yuan Guo-Ying Mu Ming Hu Li-Jun Cao Ya-Li Zhang Lei Liu Ming-Xu Ge Department of Ophthalmology the Second People's Hospital of Jinan Department of Ophthalmology Jinan Central Hospital Affiliated to Shandong University Department of Ophthalmology Shandong Provincial Hospital Affiliated to Shandong University Department of Neurosurgery Shandong Provincial Hospital Affiliated to Shandong University

AIM: To investigate anti-angiogenic effects of polysulfated heparin endostatin(PSH-ES) on alkali burn induced corneal neovascularization(NV) in ***: An alkali burn was made on rabbit corneas to induce corneal NV in the right eye of 24 rabbits. One day after burn creation, a 0.2 m L subconjunctival injection of 50 μg/m L PSH-ES, 50 μg/m L recombinant endostatin(ES), or normal saline was administered every other day for a total of 14d(7 injections). Histology and immunohistochemisty were used to examine *** NV growth was evaluated as microvessel quantity and corneal vascular endothelial growth factor(VEGF)expression was measured by immunohistochemical ***: Subconjunctival injection of ES and PSHES resulted in significant corneal NV suppression, but PSH-ES had a more powerful anti-angiogenic effect than ES. Mean VEGF concentration in PSH-ES treated corneas was significantly lower than in ES treated and saline treated corneas. Histological examination showed that corneas treated with either PSH-ES or ES had significantly fewer microvessels than eyes treated with saline. Additionally corneas treated with PSH-ES had significantly fewer microvessels than corneas treated with ***: Both PSH-ES and recombinant ES effectively inhibit corneal NV induced by alkali ***, PSH-ES is a more powerful anti-angiogenic agent than ES. This research has the potential to provide a new treatment option for preventing and treating corneal NV.

关键词： polysulfated heparin endostatin corneal neovascularization chemical burns rabbits

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The Active Metabolite of Leflunomide A771726 Inhibits corneal neovascularization

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2008年第3期28卷 364-368页

作者：张明昌郝念边芳 Department of Ophthalmology Union HospitalTongji Medical CollegeHuazhong University of Science and Technology

The effects of A771726, the active metabolite of leflunomide, on experimental rat corneal neovascularization （NV） in vivo and on cultured human umbilical vein endothelial cells in vitro were studied. The corneal NV was induced by alkali burn in 40 SD rats. The rats were randomly divided into 4 groups with 10 rats in each group. Group A was treated with 0.9% sodium chloride （control group）, and group B, group C and group D were given different concentrations of A771726 eye drops （0.5%, 1.0%, 2.0% respectively） 4 times daily during days 0--28. The occurrence and development of corneal NV were observed at 4, 7, 14, 21 and 28 day after alkali burn by a slit lamp microscope. The cultured human umbilical vein endothelial cells （ECV-304） were incubated with A771726 solution at different concentrations （20, 40, 80, 160, 320 μmol/L） for 36 h. The proliferation of cells was assessed by methyl thiazolyl tetrazolium （MTT）, and the expression of proliferating cell nuclear antigen （PCNA） in cells was detected by using immunofluorescence under the laser confocal microscope. The rat model showed that the onset of corneal NV was delayed and progression of corneal NV was inhibited in the groups C and D. The corneal NV areas in groups C and D were significantly smaller than in groups A and B （P〈0.01）. No significant difference was found in corneal NV areas between groups C and group D （P〉0.05）. A771726 solution （940 μmol/L） could inhibit proliferation of human umbilical vein endothelial cells and decrease the expression of PCNA in cells significantly, A771726, as the active metabolite of leflunomide, strongly prevented corneal NV induced by alkali burn in the in vivo model, and inhibited proliferation of human umbilical vein endothelial cells in the in vitro model. Therefore, A771726 may serve as an angiogenic inhibitor in the treatment of corneal NV.

关键词： A771726 leflunomide corneal neovascularization human umbilical vein endothelial cells proliferating cell nuclear antigen

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Comparison of the inhibitory effect of different doses of subconjunctival bevacizumab application in an experimental model of corneal neovascularization

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International Journal of Ophthalmology(English edition) 2018年第7期11卷 1090-1095页

作者： Burak Ulas Rana Altan-Yaycioglu Nebil Bal Department of Ophthalmology Baskent University School of Medicine Department of Pathology Baskent University School of Medicine

AIM： To evaluate the inhibitory effect of subconjunctival bevacizumab as single-and multiple-dose application, and compare their effects on corneal neovascularization in a rat model. METHODS： Thirty adult Sprague-Dawley rats were used in this experimental study. The central cornea of the rats was cauterized chemically. The rats were randomly enrolled into three groups. All groups received subconjunctival injections. In Group 1（control group, n=10）, 0.05 m L 0.9% Na Cl solution was injected on the first day. In Group 2（single-dose group, n=10）, 0.05 m L bevacizumab（1.25 mg） was injected on the first day. In Group 3（multiple-dose group, n=10）, four doses of 0.05 m L bevacizumab（1.25 mg） were injected on the first, third, fifth and seventh day. Slit-lamp examination of all rats was performed at the third and ninth day. Digital images of the corneas were taken and analyzed using image analysis software to calculate corneal neovascularization area. All rats were sacrificed on the tenth day. In corneal sections, the number of blood vessels, state of inflammation and collagen formation was evaluated histopathologically. RESULTS： In Group 3, corneal edema grades were significantly lower than Group 1 and Group 2（P=0.02, and P=0.035, respectively）. The mean percentage of neovascularized corneal area in Group 3 was significantly lower than Group 2（P=0.005）. On histopathological examination, Group 2 and Group 3 showed significantly less number of blood vessels than Group 1（P=0.005, and P=0.001, respectively）. Additionally, Group 3 showed significantly less number of blood vessels compared to Group 2（P=0.019）. Inflammation and edema grades were significantly lower in Group 3 compared to Group 1（P=0.001）. CONCLUSION： Subconjunctival bevacizumab injection is effective in inhibition of newly formed corneal neovascularization. The multiple-dose bevacizumab treatment seems to be more effective compared to single-dose treatment.

关键词： cornea corneal neovascularization bevacizumab inflammation rat

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Comparison of the therapeutic effects of extracts from Spirulina platensis and amnion membrane on inflammation-associated corneal neovascularization

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International Journal of Ophthalmology(English edition) 2012年第1期5卷 32-37页

作者： Ling-Ling Yang Qing-Jun Zhou Yao Wang Yan Gao and Yi-Qiang Wang State Key Laboratory Cultivation Base Shandong Provincial Key Lab of Ophthalmology Shandong Eye Institute Qingdao China

AIM: To compare the therapeutic effects of polysaccharide extract from Spirulina platensis (PSP) and extract from amnion membrane CAME) on alkali burn-induced corneal neovascularization (CorNV). METHODS: PSP and AME were Extracted from dry powder of Spirulina platensis and human aminion membrane respectively. Murine CorNV was induced by applying 1N sodiumhydroxide (NaOH) solution directly on the mice corneas. PSP and AME extracts were administered topically on the corneas 4 times daily for 7 days. The therapy effects of PSP and AME extracts were evaluated daily using slit-lamp. At the end of the therapy, corneas were harvested for H&E staining, masson trichrome staining, immunohistochemical study, and semi-quantification reverse transcriptive PCR (RT-PCR) was utilized for measurement of inflammation-related molecules. RESULTS: Topical application of PSP extract had significant therapeutic effects on CorNV that could be shown in various assays of the corneas. Compared with AME Extract, PSP extract treatment was more effective in suppressing CorNV in berms of vessel length and levels of cluster of differentiation 31 (CD31) proteins or the angiogenesis related genes like vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9). PSP also inhibited inflammation more markedly by more effectively inhibiting mononuclear and polymorphonuclear cells infiltration into the corneal stroma and reducing levels of stromal cell-derived factor-1 (SDF1), tumor necrosis factor-alpha (TNF alpha) and macrophage inflammatory protein-3 (MIP3a). In addition, corneas of PSP group had a more regular and compact architecture of collagen with thinner corneal thickness than in the AME group. ' CONCLUSION: Polysaccharide extract from Spirulina platensis inhibited alkali burn-induced inflammation and CorNV more effectively than AME Extract at the studied doses, thus may be used for the therapy of corneal diseases involving neovascularizatio

关键词： Spirulina platensis aminion membrane corneal neovascularization inflammation

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Effects of AMD3100 subconjunctival injection on alkali burn induced corneal neovascularization in mice

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International Journal of Ophthalmology(English edition) 2011年第1期4卷 44-48页

作者： Liang-Hong Peng, Lin Liu Department of Ophthalmology General Hospital of Guangzhou Military Command of PLA Guangzhou 510010 Guangdong Province China Department of Ophthalmology the First Affiliated Hospital of Second Military Medical University Shanghai 200433 China

AIM: To investigate the therapeutic effects of local and systemic administration of AMD3100 for alkali burn induced corneal neovascularization (CNV) in mice. METHODS: CNV was induced in vivo by alkaline burn of cornea in C57BL/6 mice. AMD3100 was administrated topically by subconjunctival injection or systemically by intraperitoneal injection for 7 days; balanced salt solution was administrated topically or systemically as a control respectively. Inflammatory index was evaluated by slit-lamp biomicroscopy and inflammatory cells infiltrated to cornea tissue were detected by histologic analysis at multiple time points. CNV was compared between the local and systemic treated mice 2 weeks after alkali burn, as quantified by CD34 immunostaining. Fluorescence-Activated Cell Sorter Analysis was used to investigate the mobilizing effects of EPC in mice after subconjunctival injected or intraperitoneal injected AMD3100. Immunohistochemistry was used to detect the expression of endothelial progenitor cells (EPC) marker proteins VEGFR2 and CD34. RESULTS: Three days after alkali burn, infiltration of inflammatory cells was found in corneal tissue. At the first 7 days of local injection group, the number of inflammatory cells was significantly lower than that in systemic injection group. CNV could be seen at the 7(th) day, and at the 14(th) day reached the peak, then started to decrease. The number of CNV in the subconjunctival injection group was 7.57 +/- 1.26 per 0.034mm(2), compared to a number of 14.87 +/- 2.21 per 0.034mm(2) in the control group (P<0.05). On the contrary, the number of CNV in the intraperitoneal injection group was a little higher than that in the control group, 16.34 +/- 1.53 per 0.034mm(2) vs 13.26 +/- 1.87 per 0.034mm(2). The research also showed that intraperitoneally, but not subconjunctivally injected AMD3100 could mobilize EPC. On the other hand, subconjunctival, but not intraperitoneally injected AMD3100 could reduce the expression of EPC marker pro

关键词： alkali burn corneal neovascularization AMD3100 inflammatory cells EPC

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Inhibitory effects of regorafenib, a multiple tyrosine kinase inhibitor, on corneal neovascularization

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International Journal of Ophthalmology(English edition) 2014年第2期7卷 220-225页

作者： Halil Ibrahim Onder Mesut Erdurmus Yasin Yücel Bucak Hüseyin Simavli Murat Oktay Ahmet Sahap Kukner Department of Ophthalmology Duzce University Medical Faculty Department of Ophthalmology Abant Izzet Baysal University Medical School Ophthalmology Clinic Izzet Baysal State Hospital Department of Pathology Duzce University Medical Faculty

AIM:To evaluate the inhibitory effects of regorafenib(BAY 73-4506),a multikinase inhibitor,on corneal neovascularization(NV).METHODS:Thirty adult male Sprague-Dawley rats weighing 250-300 g,were *** NV was induced by NaOH in the left eyes of each *** the establishment of alkali burn,the animals were randomized into five groups according to topical *** 1(n=6)received 0.9%NaCl,Group 2(n=6)received dimethyl sulfoxide,Group 3(n=6)received regorafenib 1 mg/mL,Group 4(n=6)received bevacizumab 5 mg/mL and Group 5(n=6)received 0.1%dexamethasone *** the 7d,the corneal surface covered with neovascular vessels was measured on photographs as the percentage of the cornea’s total area using computer-imaging *** corneas obtained from rats were semiquantitatively evaluated for caspase-3 and vascular endothelial growth factor by ***:A statistically significant difference in the percent area of corneal NV was found among the groups(Pcorneal NV,there was no difference among Groups 3,4 and 5(P>0.005).There was a statistically significant difference among the groups in apoptotic cell density(P=0.002).The staining intensity of vascular endothelial growth factor in the epithelial and endothelial layers of cornea was significantly different among the groups(Pcorneal NV in rats.

关键词： corneal neovascularization regorafenib tyrosine kinase inhibitor

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