Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 7500 AE, The Netherlands; Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584 CG, The Netherlands.
Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medical Biochemistry, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
J Control Release. 2017 Sep 28;262:47-57. doi: 10.1016/j.jconrel.2017.07.013. Epub 2017 Jul 9.
Atherosclerosis is a leading cause of worldwide morbidity and mortality whose management could benefit from novel targeted therapeutics. Nanoparticles are emerging as targeted drug delivery systems in chronic inflammatory disorders. To optimally exploit nanomedicines, understanding their biological behavior is crucial for further development of clinically relevant and efficacious nanotherapeutics intended to reduce plaque inflammation. Here, three clinically relevant nanomedicines, i.e., high-density lipoprotein ([S]-HDL), polymeric micelles ([S]-PM), and liposomes ([S]-LIP), that are loaded with the HMG-CoA reductase inhibitor simvastatin [S], were evaluated in the apolipoprotein E-deficient (Apoe) mouse model of atherosclerosis. We systematically employed quantitative techniques, including in vivo positron emission tomography imaging, gamma counting, and flow cytometry to evaluate the biodistribution, nanomedicines' uptake by plaque-associated macrophages/monocytes, and their efficacy to reduce macrophage burden in atherosclerotic plaques. The three formulations demonstrated distinct biological behavior in Apoe mice. While [S]-PM and [S]-LIP possessed longer circulation half-lives, the three platforms accumulated to similar levels in atherosclerotic plaques. Moreover, [S]-HDL and [S]-PM showed higher uptake by plaque macrophages in comparison to [S]-LIP, while [S]-PM demonstrated the highest uptake by Ly6C monocytes. Among the three formulations, [S]-PM displayed the highest efficacy in reducing macrophage burden in advanced atherosclerotic plaques. In conclusion, our data demonstrate that [S]-PM is a promising targeted drug delivery system, which can be advanced for the treatment of atherosclerosis and other inflammatory disorders in the clinical settings. Our results also emphasize the importance of a thorough understanding of nanomedicines' biological performance, ranging from the whole body to the target cells, as well drug retention in the nanoparticles. Such systematic investigations would allow rational applications of nanomaterials', beyond cancer, facilitating the expansion of the nanomedicine horizon.
动脉粥样硬化是全球发病率和死亡率的主要原因，其治疗可以受益于新型靶向治疗。纳米颗粒作为靶向药物传递系统在慢性炎症性疾病中崭露头角。为了最佳利用纳米药物，了解其生物学行为对于进一步开发旨在减少斑块炎症的临床相关和有效的纳米治疗剂至关重要。在这里，我们评估了三种临床相关的纳米药物，即高密度脂蛋白（[S]-HDL）、聚合物胶束（[S]-PM）和脂质体（[S]-LIP），它们都负载了 HMG-CoA 还原酶抑制剂辛伐他汀 [S]，用于载脂蛋白 E 缺陷（Apoe）小鼠动脉粥样硬化模型。我们系统地采用了定量技术，包括体内正电子发射断层扫描成像、伽马计数和流式细胞术，评估了生物分布、斑块相关巨噬细胞/单核细胞对纳米药物的摄取以及它们减少动脉粥样硬化斑块中巨噬细胞负担的疗效。这三种制剂在 Apoe 小鼠中表现出不同的生物学行为。虽然 [S]-PM 和 [S]-LIP 具有更长的循环半衰期，但这三种平台在动脉粥样硬化斑块中的积累水平相似。此外，与 [S]-LIP 相比，[S]-HDL 和 [S]-PM 显示出更高的斑块巨噬细胞摄取，而 [S]-PM 显示出最高的 Ly6C 单核细胞摄取。在这三种制剂中，[S]-PM 在减少晚期动脉粥样硬化斑块中的巨噬细胞负担方面显示出最高的疗效。总之，我们的数据表明，[S]-PM 是一种很有前途的靶向药物传递系统，可在临床环境中用于治疗动脉粥样硬化和其他炎症性疾病。我们的结果还强调了全面了解纳米药物的生物学性能的重要性，从全身到靶细胞，以及纳米颗粒中的药物保留。这种系统的研究将允许在癌症之外合理应用纳米材料，拓展纳米医学的视野。
