Dendrimer-Triamcinolone Acetonide Reduces Neuroinflammation, Pathological Angiogenesis, and Neuroretinal Dysfunction in Ischemic Retinopathy
Dendrimer-Triamcinolone Acetonide Reduces Neuroinflammation, Pathological Angiogenesis, and Neuroretinal Dysfunction in Ischemic Retinopathy
复制标题
树突状曲安奈德减少缺血性视网膜病变的神经炎症、病理性血管生成和神经视网膜功能障碍
DOI：
10.1002/adtp.202000181
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发表时间：
2020-11-09
影响因子：
4.6
通讯作者：
Duh, Elia J.
中科院分区：
文献类型：
--
作者：
Cho, Hongkwan;Kambhampati, Siva P.;Duh, Elia J.
糖尿病视网膜病变（DR）是工作年龄成人失明的主要原因。DR中的严重视力丧失主要是由于增殖性糖尿病视网膜病变，其特征在于由视网膜缺血驱动的病理性视网膜前血管生成。小胶质细胞，视网膜的常驻免疫细胞，已成为一个潜在的重要调节病理性视网膜血管生成。皮质类固醇包括曲安奈德（TA），已知其抗血管生成作用，用于治疗视网膜疾病，但其使用受到包括白内障和青光眼的副作用的显著限制。在氧诱导的视网膜病变（OIR）的小鼠模型中，使用第4代羟基聚酰胺胺树状聚合物纳米颗粒将TA递送至缺血视网膜中的活化小胶质细胞。在玻璃体内注射后，树枝状聚合物缀合的TA（D-TA）在视网膜的疾病相关区域中的活化的小胶质细胞中表现出选择性定位和持续保留。D-TA而非游离TA可抑制OIR中炎性细胞因子的产生、小胶质细胞活化和视网膜前新生血管形成。此外，D-TA而非游离TA可改善OIR诱导的神经视网膜和视觉功能障碍。这些结果表明，活化的小胶质细胞是一个有前途的治疗靶点，视网膜血管生成和缺血性视网膜疾病的神经保护。此外，基于树枝状聚合物的靶向治疗，特别是D-TA，构成了一种有前途的DR治疗方法，提供了增加和持续的药物疗效，减少了副作用。
Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults. Severe visual loss in DR is primarily due to proliferative diabetic retinopathy, characterized by pathologic preretinal angiogenesis driven by retinal ischemia. Microglia, the resident immune cells of the retina, have emerged as a potentially important regulator of pathologic retinal angiogenesis. Corticosteroids including triamcinolone acetonide (TA), known for their antiangiogenic effects, are used in treating retinal diseases, but their use is significantly limited by side effects including cataracts and glaucoma. Generation-4 hydroxyl polyamidoamine dendrimer nanoparticles are utilized to deliver TA to activated microglia in the ischemic retina in a mouse model of oxygen-induced retinopathy (OIR). Following intravitreal injection, dendrimer-conjugated TA (D-TA) exhibits selective localization and sustained retention in activated microglia in disease-associated areas of the retina. D-TA, but not free TA, suppresses inflammatory cytokine production, microglial activation, and preretinal neovascularization in OIR. In addition, D-TA, but not free TA, ameliorates OIR-induced neuroretinal and visual dysfunction. These results indicate that activated microglia are a promising therapeutic target for retinal angiogenesis and neuroprotection in ischemic retinal diseases. Furthermore, dendrimer-based targeted therapy and specifically D-TA constitute a promising treatment approach for DR, offering increased and sustained drug efficacy with reduced side effects.