State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
J Control Release. 2019 Feb 28;296:14-28. doi: 10.1016/j.jconrel.2019.01.008. Epub 2019 Jan 9.
Alzheimer's disease (AD) is a multifaceted and progressive neurodegenerative disease characterized by accumulation of amyloid-beta (Aβ) and deficits of acetylcholine. Accordingly, the intra-/extra-cerebral level of high density lipoprotein (HDL) is crucial on the pathogenesis of AD; and most of all, various HDL-protein subtypes play a double-edged role in AD pathology, of which apolipoprotein A-I (apoA-I) gives protective outcomes. Inspired from "HDL bionics", we proposed biologically reassembled nanodrugs, donepezil-loaded apolipoprotein A-I-reconstituted HDL (rHDL/Do) that concurrently executed dual-missions of Aβ-targeting clearance and acetylcholinesterase (AChE) inhibition in AD therapy. Once prepared, rHDL/Do nanodrug achieved high drug encapsulation efficiency of 90.47%, and mimicked the configurations and properties of natural lipoproteins aiming to significantly enhance BBB penetration and modulate Aβ-induced neuronal damage both in vitro and in vivo. Surface plasmon resonance (SPR) analysis confirmed that rHDL/Do facilitated microglial-mediated Aβ intake and degradation, demonstrating low KD value with Aβ affinity (2.45 × 10 of Aβ monomer and 2.78 × 10 of Aβ oligomer). In AD animal models, daily treatment of rHDL/Do efficiently inhibited AChE activity, ameliorated neurologic variation, promoted Aβ clearance, and rescued memory loss at a safe level. The collective findings indicated that the biological nanodrug was provided with the capacities of BBB penetration, Aβ capture and degradation via microglial cells, and cholinergic dysfunction amelioration after controlled donepezil release. In summary, rHDL/Do nanodrugs could offer a promising strategy to synergize both symptom control and disease modification in AD therapy.
阿尔茨海默病（AD）是一种多方面且进行性的神经退行性疾病，其特征是淀粉样蛋白-β（Aβ）的积累和乙酰胆碱的缺乏。因此，脑内/外的高密度脂蛋白（HDL）水平对 AD 的发病机制至关重要；最重要的是，各种 HDL-蛋白亚型在 AD 病理中发挥双重作用，其中载脂蛋白 A-I（apoA-I）具有保护作用。受“HDL 仿生学”的启发，我们提出了生物重组纳米药物，即载有多奈哌齐的载脂蛋白 A-I 重组 HDL（rHDL/Do），该药物在 AD 治疗中同时执行 Aβ 靶向清除和乙酰胆碱酯酶（AChE）抑制的双重任务。一旦制备完成，rHDL/Do 纳米药物的药物包封效率高达 90.47%，并模仿了天然脂蛋白的结构和性质，从而显著增强了 BBB 的穿透性，并调节了体外和体内 Aβ 诱导的神经元损伤。表面等离子体共振（SPR）分析证实，rHDL/Do 促进了小胶质细胞介导的 Aβ 摄取和降解，其对 Aβ 单体的亲和力（KD 值为 2.45×10-9 M）和 Aβ 低聚物的亲和力（KD 值为 2.78×10-9 M）较低。在 AD 动物模型中，rHDL/Do 的每日治疗有效抑制了 AChE 活性，改善了神经功能变化，促进了 Aβ 清除，并在安全水平上恢复了记忆丧失。综上所述，该生物纳米药物具有 BBB 穿透、通过小胶质细胞捕获和降解 Aβ，以及改善胆碱能功能障碍的能力，在控制多奈哌齐释放后发挥作用。总之，rHDL/Do 纳米药物为 AD 治疗提供了一种有前景的协同控制症状和改善疾病的策略。
