Int. J. Mol. Sci. 2013, 14(4), 8291-8305; doi:10.3390/ijms14048291
Article

Inhibition of Corneal Neovascularization with the Combination of Bevacizumab and Plasmid Pigment Epithelium-Derived Factor-Synthetic Amphiphile INTeraction-18 (p-PEDF-SAINT-18) Vector in a Rat Corneal Experimental Angiogenesis Model

1 Department of Ophthalmology, Chang Gung Memorial Hospital, No.6, W. Sec., Jiapu Rd., Puzi City, Chiayi County 61363, Taiwan 2 Chang Gung University College of Medicine, No.259, Wenhua 1st Rd., Guishan Township, Taoyuan County 33302, Taiwan 3 Chang Gung University of Science and Technology, No.2, W. Sec., Jiapu Rd., Puzi City, Chiayi County 61363, Taiwan 4 Department of Ophthalmology, Changhua Christian Hospital, Yun Lin Branch, No.375, Shichang S. Rd., Xiluo Township, Yunlin County 64866, Taiwan 5 School of Medical and Health Sciences, Fooyin University, No.151, Jinxue Rd., Daliao Dist., Kaohsiung City 83102, Taiwan 6 Department of Ophthalmology, Changhua Christian Hospital. No.135, Nanxiao St., Changhua City, Changhua County 50006, Taiwan 7 School of Medicine, Chung-Shan Medical University, Taichung City 50000, Taiwan 8 Gene Therapy Laboratory, E-DA Hospital, I-Shou University, No.1, Sec. 1, Syuecheng Rd., Dashu District, Kaohsiung City 84001, Taiwan 9 Department of Radiation Oncology, Chang Gung Memorial Hospital, No.6, W. Sec., Jiapu Rd., Puzi City, Chiayi County 61363, Taiwan 10 Department of Dermatology, Chang Gung Memorial Hospital, No.6, W. Sec., Jiapu Rd., Puzi City, Chiayi County 61363, Taiwan 11 Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, Chiayi City 60004, Taiwan
* Author to whom correspondence should be addressed.
Received: 13 December 2012; in revised form: 25 March 2013 / Accepted: 29 March 2013 / Published: 16 April 2013
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Abstract: Bevacizumab, a 149-kDa protein, is a recombinant humanized monoclonal antibody to VEGF. PEDF, a 50-kDa glycoprotein, has demonstrated anti-vasopermeability properties. In this study, we demonstrated that the combination of bevacizumab and plasmid pigment epithelium-derived factor-synthetic amphiphile INTeraction-18 (p-PEDF-SAINT-18) has a favorable antiangiogenic effect on corneal NV. Four groups (Group A: 0 μg + 0 μg, B: 0.1 μg + 0.1 μg, C: 1 μg + 1 μg, and D: 10 μg + 10 μg) of bevacizumab + p-PEDF-SAINT-18 were prepared and implanted into the rat subconjunctival substantia propria 1.5 mm from the limbus on the temporal side. Then, 1 μg of p-bFGF-SAINT-18 was prepared and implanted into the rat corneal stroma 1.5 mm from the limbus on the same side. The inhibition of NV was observed and quantified from days 1 to 60. Biomicroscopic examination, western blot analysis and immunohistochemistry were used to analyze the 18-kDa bFGF, 50-kDa PEDF and VEGF protein expression. No inhibition activity for normal limbal vessels was noted. Subconjunctival injection with the combination of bevacizumab and p-PEDF-SAINT-18 successfully inhibited corneal NV. The bFGF and PEDF genes were successfully expressed as shown by western blot analysis, and a mild immune response to HLA-DR was shown by immunohistochemistry. We concluded that the combination of bevacizumab and p-PEDF-SAINT-18 may have more potent and prolonged antiangiogenic effects, making it possible to reduce the frequency of subconjunctival.Bevacizumab, a 149-kDa protein, is a recombinant humanized monoclonalantibody to VEGF. PEDF, a 50-kDa glycoprotein, has demonstrated anti-vasopermeabilityproperties. In this study, we demonstrated that the combination of bevacizumaband plasmid pigment epithelium-derived factor-synthetic amphiphile INTeraction-18(p-PEDF-SAINT-18) has a favorable antiangiogenic effect on corneal NV. Four groups(Group A: 0 μg + 0 μg, B: 0.1 μg + 0.1 μg, C: 1 μg + 1 μg, and D: 10 μg + 10 μg) ofbevacizumab + p-PEDF-SAINT-18 were prepared and implanted into the ratsubconjunctival substantia propria 1.5 mm from the limbus on the temporal side. Then, 1 μgof p-bFGF-SAINT-18 was prepared and implanted into the rat corneal stroma 1.5 mm fromthe limbus on the same side. The inhibition of NV was observed and quantified from days1 to 60. Biomicroscopic examination, western blot analysis and immunohistochemistry wereused to analyze the 18-kDa bFGF, 50-kDa PEDF and VEGF protein expression. Noinhibition activity for normal limbal vessels was noted. Subconjunctival injection with thecombination of bevacizumab and p-PEDF-SAINT-18 successfully inhibited corneal NV.The bFGF and PEDF genes were successfully expressed as shown by western blot analysis,and a mild immune response to HLA-DR was shown by immunohistochemistry. Weconcluded that the combination of bevacizumab and p-PEDF-SAINT-18 may have morepotent and prolonged antiangiogenic effects, making it possible to reduce the frequency ofsubconjunctival bevacizumab administration combined with a relatively safe profile andlow toxicity.
Keywords: bevacizumab; PEDF; VEGF; bFGF; cornea; angiogenesis; SAINT-18

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MDPI and ACS Style

Kuo, C.-N.; Chen, C.-Y.; Chen, S.-N.; Yang, L.-C.; Lai, L.-J.; Lai, C.-H.; Chen, M.-F.; Hung, C.-H.; Chen, C.-H. Inhibition of Corneal Neovascularization with the Combination of Bevacizumab and Plasmid Pigment Epithelium-Derived Factor-Synthetic Amphiphile INTeraction-18 (p-PEDF-SAINT-18) Vector in a Rat Corneal Experimental Angiogenesis Model. Int. J. Mol. Sci. 2013, 14, 8291-8305.

AMA Style

Kuo C-N, Chen C-Y, Chen S-N, Yang L-C, Lai L-J, Lai C-H, Chen M-F, Hung C-H, Chen C-H. Inhibition of Corneal Neovascularization with the Combination of Bevacizumab and Plasmid Pigment Epithelium-Derived Factor-Synthetic Amphiphile INTeraction-18 (p-PEDF-SAINT-18) Vector in a Rat Corneal Experimental Angiogenesis Model. International Journal of Molecular Sciences. 2013; 14(4):8291-8305.

Chicago/Turabian Style

Kuo, Chien-Neng; Chen, Chung-Yi; Chen, San-Ni; Yang, Lin-Cheng; Lai, Li-Ju; Lai, Chien-Hsiung; Chen, Miao-Fen; Hung, Chia-Hui; Chen, Ching-Hsein. 2013. "Inhibition of Corneal Neovascularization with the Combination of Bevacizumab and Plasmid Pigment Epithelium-Derived Factor-Synthetic Amphiphile INTeraction-18 (p-PEDF-SAINT-18) Vector in a Rat Corneal Experimental Angiogenesis Model." Int. J. Mol. Sci. 14, no. 4: 8291-8305.

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