使用鼻内聚合物疗法激活肝 X 受体可防止认知衰退而不改变脂质水平,ACS Nano

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使用鼻内聚合物疗法激活肝 X 受体可防止认知衰退而不改变脂质水平
ACS Nano ( IF 15.8 ) Pub Date : 2021-03-05 , DOI: 10.1021/acsnano.0c09159
María Eugenia Navas Guimaraes _{1,

2} , Roi Lopez-Blanco ₃ , Juan Correa ₃ , Marcos Fernandez-Villamarin ₃ , María Beatriz Bistué ₁ , Pamela Martino-Adami ₄ , Laura Morelli ₄ , Vijay Kumar ₅ , Michael F Wempe ₅ , A C Cuello ₆ , Eduardo Fernandez-Megia ₃ , Martin A Bruno _{1,

2}

Affiliation

淀粉样蛋白-β (Aβ) 在大脑特定区域的逐渐积累是阿尔茨海默病 (AD) 迟发的常见前奏。尽管用激动剂激活肝 X 受体 (LXR) 会降低 Aβ 水平并改善情境记忆缺陷，但伴随的高胆固醇血症/高甘油三酯血症限制了它们的临床应用。DMHCA（N，N-二甲基-3β-羟基胆酰胺）是一种 LXR 部分激动剂，尽管在不增加胆固醇/甘油三酯水平的情况下诱导载脂蛋白 E（主要负责 Aβ 从大脑排出）的表达，但在体内没有活性因为溶解度低，不能穿过血脑屏障。在此，我们描述了一种用于递送 DMHCA 的聚合物治疗剂。DMHCA 通过羧酸酯共价结合到 PEG 树突支架中，产生了一种两亲性共聚物，可有效地自组装成纳米胶束，在中枢神经系统 (CNS) 的原代培养物和使用鼻内途径的实验动物中发挥生物效应。在非转基因小鼠中确定了中枢神经系统的生物分布和 DMHCA 胶束的有效剂量后，用胶束处理脑淀粉样变性的转基因 AD 样小鼠模型 21 天。治疗的好处包括预防记忆力衰退和海马 Aβ 寡聚体的显着减少，而不影响血脂水平。

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Liver X Receptor Activation with an Intranasal Polymer Therapeutic Prevents Cognitive Decline without Altering Lipid Levels

The progressive accumulation of amyloid-beta (Aβ) in specific areas of the brain is a common prelude to late-onset of Alzheimer’s disease (AD). Although activation of liver X receptors (LXR) with agonists decreases Aβ levels and ameliorates contextual memory deficit, concomitant hypercholesterolemia/hypertriglyceridemia limits their clinical application. DMHCA (N,N-dimethyl-3β-hydroxycholenamide) is an LXR partial agonist that, despite inducing the expression of apolipoprotein E (main responsible of Aβ drainage from the brain) without increasing cholesterol/triglyceride levels, shows nil activity in vivo because of a low solubility and inability to cross the blood brain barrier. Herein, we describe a polymer therapeutic for the delivery of DMHCA. The covalent incorporation of DMHCA into a PEG-dendritic scaffold via carboxylate esters produces an amphiphilic copolymer that efficiently self-assembles into nanometric micelles that exert a biological effect in primary cultures of the central nervous system (CNS) and experimental animals using the intranasal route. After CNS biodistribution and effective doses of DMHCA micelles were determined in nontransgenic mice, a transgenic AD-like mouse model of cerebral amyloidosis was treated with the micelles for 21 days. The benefits of the treatment included prevention of memory deterioration and a significant reduction of hippocampal Aβ oligomers without affecting plasma lipid levels. These results represent a proof of principle for further clinical developments of DMHCA delivery systems.

更新日期：2021-03-23

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