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Aβ-responsive metformin-based supramolecular synergistic nanodrugs for Alzheimer's disease via enhancing microglial Aβ clearance
Biomaterials ( IF 12.8 ) Pub Date : 2022-03-11 , DOI: 10.1016/j.biomaterials.2022.121452
Zhongxiong Fan 1 , Tong Ren 2 , Youjun Wang 2 , Hao Jin 2 , Dao Shi 1 , Xiaofeng Tan 2 , Dongtao Ge 1 , Zhenqing Hou 1 , Xin Jin 2 , Lichao Yang 2
Affiliation  

Here, inspired by the concept of supramolecular inclusion complex, we successfully fabricate metformin (Met)-based supramolecular nanodrugs with the Aβ-responsive on-demand drug release for synergistic Alzheimer's disease (AD) therapy via enhancing microglial Aβ clearance. Interestingly, the introduction of low-dosage Met (1.1 mg/kg) can not only significantly improve the structural stability of nanodrugs but also exert a synergistic anti-dementia effect with donepezil (Don). Besides, such nanodrugs with outstanding physiological stability can selectively penetrate the blood-brain barrier (BBB), target brain, increase efficient uptake of microglia and neurons, and then achieve simultaneous spatiotemporal on-demand drug release under stimuli of the overexpressed amyloid-beta (Aβ). Furthermore, Met and Don released from nanodrugs exhibit a superior synergistic anti-dementia effect by enhancing microglial phagocytosis and Aβ clearance through the lysosomal pathway. Taken together, we report a synergistic strategy based on Aβ-responsive supramolecular nanodrugs for AD therapy, which can be expected to provide a novel clinical therapeutic idea for ameliorating central nervous system disease.



中文翻译:

基于 Aβ 响应性二甲双胍的超分子协同纳米药物通过增强小胶质细胞 Aβ 清除率治疗阿尔茨海默病

在这里,受超分子包合复合物概念的启发,我们成功地制造了基于二甲双胍 (Met) 的超分子纳米药物,该药物具有对 Aβ 响应的按需药物释放,用于通过增强小胶质细胞 Aβ 清除率来协同治疗阿尔茨海默病 (AD)。有趣的是,低剂量Met(1.1 mg/kg)的引入不仅可以显着提高纳米药物的结构稳定性,还可以与多奈哌齐(Don)发挥协同抗痴呆作用。此外,这种具有优异生理稳定性的纳米药物可以选择性地穿透血脑屏障(BBB),靶向大脑,增加小胶质细胞的有效摄取。和神经元,然后在过表达的淀粉样蛋白-β(Aβ)的刺激下实现同时时空的按需药物释放。此外,从纳米药物中释放的 Met 和 Don 通过溶酶体途径增强小胶质细胞的吞噬作用和 Aβ 清除,表现出优异的协同抗痴呆作用。总之,我们报告了一种基于 Aβ 响应性超分子纳米药物的 AD 治疗协同策略,有望为改善中枢神经系统疾病提供一种新的临床治疗思路。

更新日期:2022-03-11
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