Development of Ophthalmic Nanomedicine for Corneal Neovascularization Treatment

The normal cornea is transparent and maintains itself as an immunoprivileged site, in part because it is avascular. Neovascularization of the cornea can disrupt visual function causing graft failure and blindness. Therefore, the public health impact of treatment cornea neovascularization is significant. The most common dosage for ophthalmic delivery is eye-drop formulation, but only 5 % of the administered dose retained in the ocular tissue after five min. The role of the ophthalmology care is focused on raising drug bioavailability in ocular tissue now. Although intraocular injection can highly increase drug concentration in ocular tissue, but repeat injection could lead to sever ocular diseases such as cataract or retinal detachment. To solve low dosage in ocular part, one way is using nanoparticles with therapeutic agent, nanomedicine, for treat various ocular diseases. Due to small sizes, they can improve bioavailability of therapeutic agents and pass through biological barriers of the eye, such as the cornea-barrier and blood–retinal barriers. These years, the treatment for corneal neovascularization (NV) is focused on the anti-vascular endothelial growth factor (VEGF) monoclonal antibodies therapies therapeutics for prolonged bioavailability and targeted delivery to neovascular lesions. But has no great help to treat the developed vessels. Synthetic arginineglycine-aspartic acid RGD peptides can bind toavb3 integrins to mediate cellular uptake and block avb3 integrin function to reduce the blood flow in vascular area. So this peptide is example of targeting moieties that could be combined with nanomedicine to treat vascular endothelia cells in the cornea. However, long-term improvement in visual acuity and general long-term efficacy are unknown. Corneal NV can also be induced by inflammation. So, green tea polyphenolics, (–)- Epigallocatechin gallate (EGCG), can be a bifunctional agent, not only inhibit the growth of endothelial cells then reduce the vascular formation, but also treat the inflammation condition. Gelatin nanoparticle (GP) for ocular delivery has been developed in this group, the preliminary data showed it could penetrate and distribution in the cornea. Thus, the general goal of the current study is to investigate the bioactivity and bioavailability of nanoparticles with therapeutic agents designed to target neovascular endothelial cells in cornea for inhibit angiogenesis in it and clarify their underlying mechanisms. The working hypothesis of this proposal is that long term effects of antiangiogenesis provide by the targetable nanomedicine can effectively inhibit neovascular formation in eye to prevent cornea dysfunction. By using this newly nanomedicine, RGD grafted nanoparticle with EGCG loading, which not only provide strong interaction with cornea surface but also maintain the effective dosage in cornea. Thus, the specific aims of this 3-year proposal are: (1)To fabricate RGD peptide decorated gelatin- hyaluronic acid copolymer nanoparticles with EGCG encapsulation for target neovascular endothelia cells; (2) To delineate the difference of slow released nanomedicine for the anti-angiogenesis inhibition and it mechanism in vitro and (3) To elucidate the therapeutic efficiency by topical delivery in a rabbit model with corneal neovascular ingrowth.