The Establishment Of Small Molecule Hydrogel Delivery System Of Ranibizumab And Its Therapeutic Effect On RNV

Background and aimsRetinal neovascular diseases are the leading causes of global blindness,such as diabetic retinopathy(DR),retinopathy of prematurity(ROP),and Neovascular age-related macular degeneration(NAMD).Retinal neovascular disease is a blinding vitreoretinal disease caused by neovascular growth accompanied by pathological changes such as bleeding,exudation,and proliferation.Vascular endothelial cells play an important role in the process of retinal neovascularization.Inhibition of vascular endothelial cell proliferation and neovascularization is the key to treating such diseases.Vascular endothelial growth factor can specifically bind to receptors on the surface of endothelial cells(VEGFR),stimulate vascular endothelial cell proliferation,migration and lumen formation,and plays a key role in the process of angiogenesis.Ranibizumab,is the only anti-VEGF drug currently approved by the FDA in the treatment of ophthalmic diseases.Its effect has been confirmed by a large number of clinical trials.However,ranibizumab is a small monoclonal antibody fragment with an Fc segment deleted specifically for intraocular use.The special nature of its synthesis method has led to a significant reduction in its drug half-life.It is difficult to maintain its effect for a long time during treatment.The existing applications of ranibizumab are based on vitreous administration once every 4 weeks.Therefore,the development of ranibizumab ocular sustained-release or controlled-release long-acting preparations will be particularly important in the future treatment of ocular diseases with ranibizumab.The purpose of this study is to extend the retention time of ranibizumab in the eye and improve the therapeutic effect by constructing a ranibizumab ocular drug delivery system based on small molecule hydrogels.Methods1.Preparation of ranibizumab small molecule hydrogel;2.Comparison of ocular pharmacokinetics and safety analysis of ranibizumab small molecule hydrogel and ranibizumab injection;3.Establishment of model of oxygen-induced retinal neovascularization(OIR)in mice;4.Compare the therapeutic effects of ranibizumab small molecule hydrogel and ranibizumab injection in oxygen-induced retinal neovascularization(OIR)model in mice;Results1.Successfully prepared ranibizumab small molecule hydrogel at a concentration of 10mg/ml;2.Detection of ranibizumab concentration in aqueous humor and vitreous by ELISA double antibody sandwich method.It was found that at different time points,ranibizumab small molecule hydrogel has higher drug release concentration in vivo than ranibizumab injection.HE staining showed no significant abnormality in the thickness of each layer of the retina in both groups;3.HE staining and fluorescence staining of whole retinal were used to prove the successful establishment of oxygen-induced retinal neovascularization model in mice;4.Through retinal HE staining,fluorescence staining of whole retinal and PCR,we found that for oxygen-induced mouse retinal neovascularization model,at the same time point,ranibizumab small molecule hydrogel was more effective than ranizumab injection.ConclusionsIn this experiment,we successfully synthesized ranibizumab small molecule hydrogel,and proved that it can prolong the intraocular retention time of razumab and has good histocompatibility;through OIR model,it is proved that ranibizumab small molecular hydrogel has more lasting drug release and therapeutic effect than ranibizumab injection,which provides evidence for the establishment of ophthalmic sustained release drug delivery system for the treatment of retinal neovascularization diseases.