Evaluation of the Combined Effect of Recombinant High-Density Lipoprotein Carrier and the Encapsulated Lovastatin in RAW264.7 Macrophage Cells Based on the Median-Effect Principle,Molecular Pharmaceutics

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Evaluation of the Combined Effect of Recombinant High-Density Lipoprotein Carrier and the Encapsulated Lovastatin in RAW264.7 Macrophage Cells Based on the Median-Effect Principle
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-01-30 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00923
Cuiping Jiang ₁ , Yi Zhao ₁ , Yun Yang ₁ , Jianhua He ₁ , Wenli Zhang ₁ , Jianping Liu ₁

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Recombinant high-density lipoprotein (rHDL) displays a similar anti-atherosclerotic effect with native HDL and could also be served as a carrier of cardiovascular drug for atherosclerotic plaque targeting. In our previous studies, rHDL has shown a more potent anti-atherosclerotic efficacy as compared to the other conventional nanoparticles with a payload of lovastatin (LS). Therefore, we hypothesized that a synergistic anti-atherosclerotic effect of the rHDL carrier and the encapsulated LS might exist. In this study, the dose–effect relationships and the combined effect of the rHDL and LS were quantitatively evaluated in RAW 264.7 macrophage cells using the median-effect analysis, in which the rHDL carrier was regarded as a drug combined. Median-effect analysis suggested that rHDL and LS exerted a desirable synergistic inhibition on the oxLDL internalization at a ratio of 6:1 (D_m,LS:D_m,rHDL) in RAW 264.7 macrophage cells. About 50% of the reduction on the intracellular lipid contents was found when RAW264.7 cells were treated with LS-loaded rHDLs at their respective median-effect dose (D_m) concentrations and a synergistic effect on the mediating cholesterol efflux was also observed, which verified the accuracy of the results obtained from the median-effect analysis. The mechanism underlying the synergistic effect of the rHDL carrier and the drug might be attributed to their potent inhibitory effects on SR-A expression. In conclusion, the median-effect analysis was proven to be a feasible method to quantitatively evaluate the synergistic effect of the biofunctional carrier and the drug encapsulated.

中文翻译：

基于中位效应原理评估重组高密度脂蛋白载体和包封的洛伐他汀对RAW264.7巨噬细胞的联合作用

重组高密度脂蛋白（rHDL）与天然HDL表现出相似的抗动脉粥样硬化作用，也可以用作心血管药物的靶点。在我们以前的研究中，与其他具有洛伐他汀（LS）负载的常规纳米颗粒相比，rHDL已显示出更有效的抗动脉粥样硬化功效。因此，我们假设可能存在rHDL载体和封装的LS的协同抗动脉粥样硬化作用。在这项研究中，使用中值效应分析在RAW 264.7巨噬细胞中定量评估了rHDL和LS的剂量效应关系和联合效应，其中rHDL载体被视为药物组合。RAW 264.7巨噬细胞中的D _m，LS：D _m，rHDL）。当以各自中位有效剂量（D _m）浓度的LS加载的rHDLs处理RAW264.7细胞时，发现细胞内脂质含量降低了约50％，并且还观察到对介导的胆固醇外流有协同作用，这验证了从中值效应分析获得的结果的准确性。rHDL载体和药物协同作用的潜在机制可能归因于它们对SR-A表达的有效抑制作用。总之，中值效应分析被证明是定量评估生物功能载体与包封药物协同作用的可行方法。

更新日期：2018-01-30

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