Alaarg Amr, Zheng Kang He, van der Valk Fleur M, da Silva Acarilia Eduardo, Versloot Miranda, van Ufford Linda C Quarles, Schulte Dominik M, Storm Gert, Metselaar Josbert M, Stroes Erik S G, Hamers Anouk A J
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, The Netherlands; Department of Biomaterials Science and Technology, Targeted Therapeutics section, MIRA Institute, University of Twente, Enschede, The Netherlands.
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Vascul Pharmacol. 2016 Jul;82:51-9. doi: 10.1016/j.vph.2016.04.006. Epub 2016 May 14.
Macrophages play a central role in atherosclerosis development and progression, hence, targeting macrophage activity is considered an attractive therapeutic. Recently, we documented nanomedicinal delivery of the anti-inflammatory compound prednisolone to atherosclerotic plaque macrophages in patients, which did however not translate into therapeutic efficacy. This unanticipated finding calls for in-depth screening of drugs intended for targeting plaque macrophages.
We evaluated the effect of several candidate drugs on macrophage activity, rating overall performance with respect to changes in cytokine release, oxidative stress, lipid handling, endoplasmic reticulum (ER) stress, and proliferation of macrophages. Using this in vitro approach, we observed that the anti-inflammatory effect of prednisolone was counterbalanced by multiple adverse effects on other key pathways. Conversely, pterostilbene, T0901317 and simvastatin had an overall anti-atherogenic effect on multiple pathways, suggesting their potential for liposomal delivery.
This dedicated assay setup provides a framework for high-throughput assessment. Further in vivo studies are warranted to determine the predictive value of this macrophage-based screening approach and its potential value in nanomedicinal drug development for cardiovascular patients.
巨噬细胞在动脉粥样硬化的发生和发展中起核心作用，因此，靶向巨噬细胞活性被认为是一种有吸引力的治疗方法。最近，我们记录了抗炎化合物泼尼松龙通过纳米药物递送至患者动脉粥样硬化斑块巨噬细胞的情况，但这并未转化为治疗效果。这一意外发现需要对旨在靶向斑块巨噬细胞的药物进行深入筛选。
我们评估了几种候选药物对巨噬细胞活性的影响，并根据细胞因子释放、氧化应激、脂质处理、内质网（ER）应激和巨噬细胞增殖的变化对整体性能进行评分。使用这种体外方法，我们观察到泼尼松龙的抗炎作用被对其他关键途径的多种不良反应所抵消。相反，紫檀芪、T0901317和辛伐他汀对多种途径具有总体抗动脉粥样硬化作用，表明它们具有脂质体递送的潜力。
这种专门的检测设置为高通量评估提供了一个框架。有必要进一步开展体内研究，以确定这种基于巨噬细胞的筛选方法的预测价值及其在心血管疾病患者纳米药物开发中的潜在价值。
