Abstract
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 Ly6Chigh 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.
Highlights
Atherosclerosis is a chronic, systemic inflammatory disease of the large and medium-sized arteries, which can lead to life-threating events such as myocardial infarction and stroke [1]
The aim of this study was to target Hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) in atherosclerotic plaques by simvastatin-loaded nanomedicines and to understand the parameters that control their in vivo performance
Liposomes were included as they are often regarded as the gold standard nanomedicine drug delivery system and were the first to make clinical translation [20,43]
Summary
Atherosclerosis is a chronic, systemic inflammatory disease of the large and medium-sized arteries, which can lead to life-threating events such as myocardial infarction and stroke [1]. ⁎⁎ Correspondence to: Gert Storm, Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584 CG, The Netherlands. All deaths worldwide, can be attributed to atherosclerotic cardiovascular diseases [2]. The initiation and progression of atherosclerotic lesions are currently understood to have a central inflammatory component in which immune cells, including inflammatory monocytes and macrophages, play key roles [3,4]. The continued accumulation of lipoproteins and immune cells, including macrophages, accelerates the development of focal lesions known as atherosclerotic plaques [7]. Recent preclinical [10] and clinical [11] work have identified cardiovascular events as key contributors to the aggravation of plaque inflammation, increasing secondary event's risk [12]. Silencing plaque inflammation by targeting monocyte/macrophage burden is a compelling disease management strategy
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