Synthetic anti-angiogenic genomic therapeutics for treatment of neovascular age-related macular degeneration  

作　　者：Jing Wang Xiang Shi Qiyu Bo Hong Wang Fang Wei Jun Liu Hao Wang Liuwei Zhang Yan Qi Zhen Li Qixian Chen Xiaodong Sun 

机构地区：[1]Department of Ophthalmology,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200080,China [2]Shanghai Key Laboratory of Ocular Fundus Diseases,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200080,China [3]Shanghai Engineering Center for Visual Science and Photomedicine,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200080,China [4]National Clinical Research Center for Eye Diseases,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200080,China [5]Ningbo Hygeia Medical Technology Co.,Ltd.,Ningbo 315201,China [6]School of Bioengineering,Dalian University of Technology,Dalian 116024,China [7]College of Pharmacy,Dalian Medical University,Dalian 116044,China

出　　处：《Asian Journal of Pharmaceutical Sciences》2021年第5期623-632,共10页亚洲药物制剂科学（英文）

基　　金：funded by National Natural Science Foundation of China(81900869,81730026,81802482);National Key R&D Program(2019YFC0840607,2017YFA0105301);Science and Technology Commission of Shanghai Municipality(17411953000,19495800700);Shanghai Sailing Program(19YF1439500);Talent Project of Revitalizing Liaoning(XLYC1807184);Dalian Science&Technology Innovation Fund(2020JJ26SN050)。

摘　　要：In light of the intriguing potential of anti-angiogenic approach in suppressing choroidal neovascularization, we attempted to elaborate synthetic gene delivery systems encapsulating anti-angiogenic plasmid DNA as alternatives of clinical antibody-based therapeutics. Herein, block copolymer of cyclic Arg-Gly-Asp-poly(ethylene glycol)-poly(lysine-thiol) [RGD-PEG-PLys(thiol)] with multifunctional components was tailored in manufacture of core-shell DNA delivery nanoparticulates. Note that the polycationic PLys segments were electrostatically complexed with anionic plasmid DNA into nanoscaled core, and the tethered biocompatible PEG segments presented as the spatial shell(minimizing non-specific reactions in biological milieu). Furthermore, the aforementioned self-assembly was introduced with redox-responsive disulfide crosslinking due to the thiol coupling. Hence, reversible stabilities, namely stable in extracellular milieu but susceptible to disassemble for liberation of the DNA payloads in intracellular reducing microenvironment, were verified to facilitate transcellular gene transportation. In addition, RGD was installed onto the surface of the proposed self-assemblies with aim of targeted accumulation and internalization into angiogenic endothelial cells given that RGD receptors were specifically overexpressed on their cytomembrane surface. The proposed anti-angiogenic DNA therapeutics were validated to exert efficient expression of anti-angiogenic proteins in endothelial cells and elicit potent inhibition of ocular neovasculature post intravitreous administration. Hence, the present study approved the potential of gene therapy in treatment of choroidal neovascularization. In light of sustainable gene expression properties of DNA therapeutics, our proposed synthetic gene delivery system inspired prosperous potentials in long-term treatment of choroidal neovascularization, which should be emphasized to develop further towards clinical translations.

关 键 词：Age-related macular degeneration ANTI-ANGIOGENESIS Gene therapy Polymer Vascular endothelial growth factor 

分 类 号：R774.5[医药卫生—眼科]