Synthetic anti-angiogenic genomic therapeutics for treatment of neovascular age-related macular degeneration.
Synthetic anti-angiogenic genomic therapeutics for treatment of neovascular age-related macular degeneration.
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用于治疗新生血管性年龄相关性黄斑变性的合成抗血管生成基因组疗法
DOI：
10.1016/j.ajps.2021.04.001
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发表时间：
2021-09
影响因子：
10.2
通讯作者：
Sun X
中科院分区：
文献类型：
--
作者：
Wang J;Shi X;Bo Q;Wang H;Wei F;Liu J;Wang H;Zhang L;Qi Y;Li Z;Chen Q;Sun X
鉴于抗血管生成方法在抑制脉络膜新生血管形成中的有趣潜力，我们试图阐述封装抗血管生成质粒DNA的合成基因递送系统作为基于临床抗体的疗法的替代方案。本文中，具有多功能组分的环状Arg-Gly-Asp-poly（ethylene glycol）-poly（lysine-thiol）[RGD-PEG-PLys（thiol）]的嵌段共聚物被定制用于核-壳DNA递送纳米颗粒的制造。注意，聚阳离子PLys区段与阴离子质粒DNA静电复合成纳米级核心，并且拴系的生物相容性PEG区段呈现为空间壳（最小化生物环境中的非特异性反应）。此外，由于硫醇偶联，上述自组装被引入氧化还原响应性二硫化物交联。因此，可逆稳定性，即在细胞外环境中稳定，但在细胞内还原性微环境中易于分解以释放DNA有效载荷，被证实有助于跨细胞基因转运。此外，考虑到RGD受体在其细胞膜表面特异性过表达，将RGD安装到所提出的自组装体的表面上，目的是靶向积累和内化到血管生成内皮细胞中。所提出的抗血管生成DNA治疗剂经验证可在内皮细胞中有效表达抗血管生成蛋白，并在玻璃体内给药后引起眼部新生血管的有效抑制。因此，本研究证实了基因治疗在脉络膜新生血管治疗中的潜力。鉴于DNA治疗的可持续基因表达特性，我们提出的合成基因递送系统在脉络膜新生血管的长期治疗中激发了繁荣的潜力，应强调进一步向临床转化发展。
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.
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影响因子：
3.9
作者：
Ehlken, C.;Jungmann, S.;Pielen, A.
通讯作者：
Pielen, A.
影响因子：
158.5
作者：
Brown, David M.;Kaiser, Peter K.;Schneider, Susan
通讯作者：
Schneider, Susan
DOI：
10.1136/bjophthalmol-2015-306972
发表时间：
2016-01
期刊：
The British journal of ophthalmology
影响因子：
--
作者：
Hanus J;Zhao F;Wang S
通讯作者：
Wang S
影响因子：
15.9
作者：
Michaelsen SR;Staberg M;Pedersen H;Jensen KE;Majewski W;Broholm H;Nedergaard MK;Meulengracht C;Urup T;Villingshøj M;Lukacova S;Skjøth-Rasmussen J;Brennum J;Kjær A;Lassen U;Stockhausen MT;Poulsen HS;Hamerlik P
通讯作者：
Hamerlik P
影响因子：
3.7
作者：
Huang H;Ding Y;Sun XS;Nguyen TA
通讯作者：
Nguyen TA