Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Sci Adv. 2020 Jan 22;6(4):eaay8514. doi: 10.1126/sciadv.aay8514. eCollection 2020 Jan.
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.
神经药物通过中枢神经系统（CNS）屏障的传输能力差，限制了中枢神经系统疾病有效治疗方法的发展。我们采用高效点击化学方法，提出了一种新型靶向神经炎症的聚乙二醇基树枝状大分子（PEGOL-60）的简便合成方法。PEGOL-60 通过在低代时实现高羟基表面密度，降低了合成负担，这对树枝状大分子在中枢神经系统疾病中的脑穿透和神经胶质靶向作用至关重要。系统给予的 PEGOL-60 可穿过受损的中枢神经系统屏障，并在脑瘫、胶质母细胞瘤和年龄相关性黄斑变性等多种动物模型中特异性靶向损伤部位的活化小胶质细胞/巨噬细胞，表明其有可能克服血脑、血肿瘤脑和血视网膜屏障的障碍，并靶向中枢神经系统中的关键细胞。PEGOL-60 还在体外炎症小胶质细胞中表现出强大的内在抗氧化和抗炎作用。因此，PEGOL-60 是一种将治疗药物特异性递送至中枢神经系统损伤部位的有效载体，可增强一系列神经炎症性疾病的治疗效果。
