Department of Orthopaedic Surgery, University of Connecticut Health, Farmington, CT, USA.
Department of Biomedical Engineering, University of Connecticut, Storrs, CT, USA.
Biomater Sci. 2023 Dec 5;11(24):7856-7866. doi: 10.1039/d3bm00951c.
Ischemic stroke causes acute CNS injury and long-term disability, with limited treatment options such as surgical clot removal or clot-busting drugs. Neuroprotective therapies are needed to protect vulnerable brain regions. The purinergic receptor P2X4 is activated during stroke and exacerbates post-stroke damage. The chemical compound 5-(3-Bromophenyl)-1,3-dihydro-2-Benzofuro[3,2-]-1,4-diazepin-2-one (5BDBD) inhibits P2X4 and has shown neuroprotective effects in rodents. However, it is difficult to formulate for systemic delivery to the CNS. The current manuscript reports for the first time, the synthesis and characterization of 5BDBD PEGylated liposomal formulations and evaluates their feasibility to treat stroke in a preclinical mice model. A PEGylated liposomal formulation of 5BDBD was synthesized and characterized, with encapsulation efficacy of >80%, and release over 48 hours. and experiments with Nile red encapsulation showed cytocompatibility and CNS infiltration of nanocarriers. Administered 4 or 28 hours after stroke onset, the nanoformulation provided significant neuroprotection, reducing infarct volume by ∼50% compared to controls. It outperformed orally-administered 5BDBD with a lower dose and shorter treatment duration, suggesting precise delivery by nanoformulation improves outcomes. The fluorescent nanoformulations may serve as a platform for delivering and tracking therapeutic agents for stroke treatment.
缺血性中风会导致中枢神经系统急性损伤和长期残疾，目前的治疗选择有限，例如手术清除血栓或溶栓药物。因此，需要神经保护疗法来保护易受损伤的大脑区域。嘌呤能受体 P2X4 在中风期间被激活，并加重中风后的损伤。化学化合物 5-(3-溴苯基)-1,3-二氢-2-苯并呋喃[3,2-e]-1,4-二氮杂卓-2-酮（5BDBD）可抑制 P2X4，并且已在啮齿动物中显示出神经保护作用。然而，它很难制成用于全身递送到中枢神经系统的制剂。本手稿首次报道了 5BDBD 聚乙二醇化脂质体制剂的合成和表征，并评估了它们在治疗中风的临床前小鼠模型中的可行性。合成并表征了 5BDBD 的聚乙二醇化脂质体制剂，包封效率＞80%，并在 48 小时内释放。尼罗红包封实验表明纳米载体具有细胞相容性和向中枢神经系统的渗透。在中风发作后 4 或 28 小时给药，纳米制剂提供了显著的神经保护作用，与对照组相比，梗死体积减少了约 50%。它的疗效优于口服给予的 5BDBD，所需剂量更低，治疗时间更短，这表明纳米制剂的精确递药可改善治疗效果。荧光纳米制剂可用作递送和跟踪治疗中风的治疗剂的平台。
