Facile method to incorporate high-affinity ACAT/SOAT1 inhibitor F12511 into stealth liposome-based nanoparticle and demonstration of its efficacy in blocking cholesteryl ester biosynthesis without overt toxicity in neuronal cell culture.
Facile method to incorporate high-affinity ACAT/SOAT1 inhibitor F12511 into stealth liposome-based nanoparticle and demonstration of its efficacy in blocking cholesteryl ester biosynthesis without overt toxicity in neuronal cell culture.
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DOI：
10.1016/j.jneumeth.2021.109437
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发表时间：
2022-02-01
影响因子：
3
通讯作者：
Chang TY
中科院分区：
文献类型：
--
作者：
De La Torre AL;Smith C;Granger J;Anderson FL;Harned TC;Havrda MC;Chang CCY;Chang TY
酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂已被认为是治疗多种疾病的潜在治疗药物，包括阿尔茨海默病，动脉粥样硬化和癌症。虽然许多ACAT抑制剂是容易获得的，但将它们包封为纳米颗粒的方法尚未报道。我们报告了一种简单的方法来封装ACAT抑制剂，使用有效的疏水性ACAT抑制剂F12511为例。通过将DSPE-PEG 2000、卵磷脂（PC）和F12511在乙醇中混合，然后在缓冲液中干燥、重悬和超声处理，我们表明F12511可以以高浓度封装为隐形脂质体。我们成功地将F12511掺入纳米颗粒中，并发现纳米颗粒中PC的增加显著增加了隐形脂质体中F12511的掺入量。含有F12511的纳米颗粒（纳米颗粒F）表现出约200 nm的平均尺寸，并且在4°C下稳定至少6个月。纳米颗粒F在抑制人类和小鼠神经元和小胶质细胞系中的ACAT方面非常有效。使用小鼠原代神经元细胞进行的毒性试验表明，单独使用F12511或以2-10μM浓度添加的纳米颗粒F持续24、48和72小时产生最小毒性（如果有）。与现有方法不同，目前的方法简单，成本效益高，并且可以扩展以产生标记的脂质体以增加递送的特异性。这也提供了将水溶性试剂包含在纳米颗粒的水性隔室内用于潜在的组合治疗的机会。该方法显示出在体内以高浓度递送疏水性ACAT抑制剂的前景。
Acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors have been considered as potential therapeutic agents to treat several diseases, including Alzheimer’s disease, atherosclerosis, and cancer. While many ACAT inhibitors are readily available, methods to encapsulate them as nanoparticles have not been reported. We report a simple method to encapsulate ACAT inhibitors, using the potent hydrophobic ACAT inhibitor F12511 as an example. By mixing DSPE-PEG2000, egg phosphatidylcholine (PC), and F12511 in ethanol, followed by drying, resuspension and sonication in buffer, we show that F12511 can be encapsulated as stealth liposomes at high concentration. We successfully incorporated F12511 into nanoparticles and found that increasing PC in the nanoparticles markedly increased the amount of F12511 incorporated in stealth liposomes. The nanoparticles containing F12511 (Nanoparticle F) exhibit average size of approximately 200nm and are stable at 4°C for at least 6 months. Nanoparticle F is very effective at inhibiting ACAT in human and mouse neuronal and microglial cell lines. Toxicity tests using mouse primary neuronal cells show that F12511 alone or Nanoparticle F added at concentrations from 2–10μM for 24-, 48-, and 72-hours produces minimal, if any, toxicity. Unlike existing methods, the current method is simple, cost effective, and can be expanded to produce tagged liposomes to increase specificity of delivery. This also offers opportunity to embrace water soluble agent(s) within the aqueous compartment of the nanoparticles for potential combinatorial therapy. This method shows promise for delivery of hydrophobic ACAT inhibitors at high concentration in vivo.
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影响因子：
29
作者：
Ge, Liang;Wang, Jing;Song, Bao-Liang
通讯作者：
Song, Bao-Liang
影响因子：
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Ashok, B;Arleth, L;Önyüksel, H
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Önyüksel, H
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Rudel, LL
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10.1097/nen.0b013e3181e77ed9
发表时间：
2010-08
影响因子：
3.2
作者：
Huttunen HJ;Havas D;Peach C;Barren C;Duller S;Xia W;Frosch MP;Hutter-Paier B;Windisch M;Kovacs DM
通讯作者：
Kovacs DM
DOI：
10.1073/pnas.0913828107
发表时间：
2010-02-16
影响因子：
11.1
作者：
Bryleva, Elena Y.;Rogers, Maximillian A.;Chang, Ta-Yuan
通讯作者：
Chang, Ta-Yuan