You Suyeon, Kim Hyoungtai, Jung Hye-Youn, Kim Boram, Lee Eun Jung, Kim Jin Woo, Kim Yoonkyung
Division of Biomedical Sciences, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea.
Biomaterials. 2020 Oct;255:120188. doi: 10.1016/j.biomaterials.2020.120188. Epub 2020 Jun 15.
Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness, generally affecting people over 50 years of age in industrialized countries. Despite the effectiveness of anti-vascular endothelial growth factor (VEGF) therapy in attenuating the growth of new blood vessels, substantial visual improvements are rare with this complex disease. Furthermore, the current regimen of repeated monthly intravitreal injections of drugs can result in serious side effects. Combination therapies-to complement anti-VEGF alone-with a prolonged therapeutic effect and efficient delivery to the intended site are urgently needed, which could be realized through the use of carefully designed nanocarriers. To understand the physicochemical effects (e.g., size, charge, geometry) of intravitreally administered nanocarriers on their bioavailability, distribution, and targeting efficiency across multiple layers of the retina, here we prepared seven different types of surface-functionalized water-soluble dendritic nanocarriers with hydrodynamic sizes mostly under 5 nm. A similar stoichiometric amount of fluorophore was covalently attached to each of these biocompatible nanocarriers for quantitative analyses by confocal microscopy of cryosectioned healthy mouse eyes. Interestingly, at 24 h post-injection, the nanocarrier with multiple copies of glucosamine on the surface (D) accumulated predominantly in the photoreceptor layer and the retinal pigment epithelium (RPE), which are speculated to be associated with AMD pathogenesis (i.e., target sites). Furthermore, extended residence at these outer retinal layers was demonstrated by D, which appeared to gradually turn into micron-scale particles potentially through aggregation. Our systematic findings may provide useful guidelines for the rational design of intravitreal nanocarriers to treat vision-threatening retinal diseases, including AMD.
年龄相关性黄斑变性（AMD）是不可逆失明的主要原因之一，在工业化国家通常影响50岁以上的人群。尽管抗血管内皮生长因子（VEGF）疗法在抑制新生血管生长方面有效，但对于这种复杂疾病，显著的视力改善却很少见。此外，目前每月重复进行玻璃体内注射药物的治疗方案可能会导致严重的副作用。迫切需要联合疗法（仅作为抗VEGF的补充），以获得延长的治疗效果并有效递送至目标部位，这可以通过使用精心设计的纳米载体来实现。为了了解玻璃体内注射的纳米载体的物理化学效应（例如，大小、电荷、几何形状）对其在视网膜多层中的生物利用度、分布和靶向效率的影响，我们制备了七种不同类型的表面功能化水溶性树枝状纳米载体，其流体动力学尺寸大多在5纳米以下。将相似化学计量的荧光团共价连接到这些生物相容性纳米载体中的每一个上，以便通过对冷冻切片的健康小鼠眼睛进行共聚焦显微镜定量分析。有趣的是，在注射后24小时，表面带有多个氨基葡萄糖拷贝的纳米载体（D）主要积聚在光感受器层和视网膜色素上皮（RPE）中，据推测这与AMD发病机制（即靶位点）有关。此外，纳米载体D显示出在这些视网膜外层的停留时间延长，它似乎可能通过聚集逐渐变成微米级颗粒。我们的系统研究结果可能为合理设计用于治疗包括AMD在内的威胁视力的视网膜疾病的玻璃体内纳米载体提供有用的指导。
