Poor transport of neuropharmaceutics through central nervous system (CNS) barriers limits the development of effective treatments for CNS disorders. We present the facile synthesis of a novel neuroinflammation-targeting polyethylene glycol-based dendrimer (PEGOL-60) using an efficient click chemistry approach. PEGOL-60 reduces synthetic burden by achieving high hydroxyl surface density at low generation, which plays a key role in brain penetration and glia targeting of dendrimers in CNS disorders. Systemically administered PEGOL-60 crosses impaired CNS barriers and specifically targets activated microglia/macrophages at the injured site in diverse animal models for cerebral palsy, glioblastoma, and age-related macular degeneration, demonstrating its potential to overcome impaired blood-brain, blood-tumor-brain, and blood-retinal barriers and target key cells in the CNS. PEGOL-60 also exhibits powerful intrinsic anti-oxidant and anti-inflammatory effects in inflamed microglia in vitro. Therefore, PEGOL-60 is an effective vehicle to specifically deliver therapies to sites of CNS injury for enhanced therapeutic outcomes in a range of neuroinflammatory diseases.

中文翻译：

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密集羟基聚乙二醇树枝状聚合物靶向多种中枢神经系统疾病中激活的神经胶质细胞。


神经药物通过中枢神经系统 (CNS) 屏障的转运不良限制了中枢神经系统疾病有效治疗方法的开发。我们使用有效的点击化学方法轻松合成了一种新型神经炎症靶向聚乙二醇树枝状聚合物（PEGOL-60）。 PEGOL-60 通过在低代数下实现高羟基表面密度来减少合成负担，这在中枢神经系统疾病中树枝状聚合物的大脑渗透和神经胶质细胞靶向中发挥着关键作用。在脑瘫、胶质母细胞瘤和年龄相关性黄斑变性的多种动物模型中，全身给药的 PEGOL-60 可以穿过受损的中枢神经系统屏障，并特异性地靶向损伤部位活化的小胶质细胞/巨噬细胞，证明了其克服受损的血脑、血液肿瘤的潜力-大脑和血视网膜屏障以及中枢神经系统中的目标关键细胞。 PEGOL-60 还在体外对发炎的小胶质细胞表现出强大的内在抗氧化和抗炎作用。因此，PEGOL-60 是一种有效的载体，可以特异性地向中枢神经系统损伤部位提供治疗，以增强一系列神经炎症疾病的治疗效果。