Nanoparticle-Aided Characterization of Arterial Endothelial Architecture during Atherosclerosis Progression and Metabolic Therapy (original) (raw)
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ACS Nano, 2015
Atherosclerosis is a major cause of global morbidity and mortality that could benefit from novel targeted therapeutics. Recent studies have shown efficient and local drug delivery with nanoparticles, although the nanoparticle targeting mechanism for atherosclerosis has not yet been fully elucidated. Here we used in vivo and ex vivo multimodal imaging to examine permeability of the vessel wall and atherosclerotic plaque accumulation of fluorescently labeled liposomal nanoparticles in a rabbit model. We found a strong correlation between permeability as established by in vivo dynamic contrast enhanced magnetic resonance imaging and nanoparticle plaque accumulation with subsequent nanoparticle distribution throughout the vessel wall. These key observations will enable the development of nanotherapeutic strategies for atherosclerosis.
ACS nano, 2017
Hyaluronan is a biologically active polymer, which can be formulated into nanoparticles. In our study, we aimed to probe atherosclerosis-associated inflammation by using hyaluronan nanoparticles and to determine whether they can ameliorate atherosclerosis. Hyaluronan nanoparticles (HA-NPs) were prepared by reacting amine-functionalized oligomeric hyaluronan (HA) with cholanic ester and labeled with a fluorescent or radioactive label. HA-NPs were characterized in vitro by several advanced microscopy methods. The targeting properties and biodistribution of HA-NPs were studied in apoe(-/-) mice, which received either fluorescent or radiolabeled HA-NPs and were examined ex vivo by flow cytometry or nuclear techniques. Furthermore, three atherosclerotic rabbits received (89)Zr-HA-NPs and were imaged by PET/MRI. The therapeutic effects of HA-NPs were studied in apoe(-/-) mice, which received weekly doses of 50 mg/kg HA-NPs during a 12-week high-fat diet feeding period. Hydrated HA-NPs wer...
PLOS ONE, 2021
Atherosclerosis is a lipid-driven chronic inflammatory disease that leads to the formation of plaques in the inner lining of arteries. Plaques form over a range of phenotypes, the most severe of which is vulnerable to rupture and causes most of the clinically significant events. In this study, we evaluated the efficacy of nanoparticles (NPs) to differentiate between two plaque phenotypes based on accumulation kinetics in a mouse model of atherosclerosis. This model uses a perivascular cuff to induce two regions of disturbed wall shear stress (WSS) on the inner lining of the instrumented artery, low (upstream) and multidirectional (downstream), which, in turn, cause the development of an unstable and stable plaque phenotype, respectively. To evaluate the influence of each WSS condition, in addition to the final plaque phenotype, in determining NP uptake, mice were injected with NPs at intermediate and fully developed stages of plaque growth. The kinetics of artery wall uptake were as...
Nanoparticle-Based Approaches towards the Treatment of Atherosclerosis
Pharmaceutics, 2020
Atherosclerosis, being an inflammation-associated disease, represents a considerable healthcare problem. Its origin remains poorly understood, and at the same time, it is associated with extensive morbidity and mortality worldwide due to myocardial infarctions and strokes. Unfortunately, drugs are unable to effectively prevent plaque formation. Systemic administration of pharmaceuticals for the inhibition of plaque destabilization bears the risk of adverse effects. At present, nanoscience and, in particular, nanomedicine has made significant progress in both imaging and treatment of atherosclerosis. In this review, we focus on recent advances in this area, discussing subjects such as nanocarriers-based drug targeting principles, approaches towards the treatment of atherosclerosis, utilization of theranostic agents, and future prospects of nanoformulated therapeutics against atherosclerosis and inflammatory diseases. The focus is placed on articles published since 2015 with additiona...
Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 2011
An estimated 16 million people in the United States have coronary artery disease (CAD), and approximately 325,000 people die annually from cardiac arrest. About two-thirds of unexpected cardiac deaths occur without prior recognition of cardiac disease. A vast majority of these deaths are attributable to the rupture of 'vulnerable atherosclerotic plaques'. Clinically, plaque vulnerability is typically assessed through imaging techniques, and ruptured plaques leading to acute myocardial infarction are treated through angioplasty or stenting. Despite significant advances, it is clear that current imaging methods are insufficiently capable for elucidating plaque composition-which is a key determinant of vulnerability. Further, the exciting improvement in the treatment of CAD afforded by stenting procedures has been buffered by significant undesirable host-implant effects, including restenosis and late thrombosis. Nanotechnology has led to some potential solutions to these problems by yielding constructs that interface with plaque cellular components at an unprecedented size scale. By leveraging the innate ability of macrophages to phagocytose nanoparticles, contrast agents can now be targeted to plaque inflammatory activity. Improvements in nano-patterning procedures have now led to increased ability to regenerate tissue isotropy directly on stents, enabling gradual regeneration of normal, physiologic vascular structures. Advancements in immunoassay technologies promise lower costs for biomarker measurements, and in the near future, may enable the addition of routine blood testing to the clinician's toolbox-decreasing the costs of atherosclerosis-related medical care. These are merely three examples among many stories of how nanotechnology continues to promise advances in the diagnosis and treatment of vulnerable atherosclerotic plaques.
Probing nanoparticle translocation across the permeable endothelium in experimental atherosclerosis
Proceedings of the National Academy of Sciences, 2014
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The Therapeutic Potential of Nanoparticles to Reduce Inflammation in Atherosclerosis
2019
Chronic inflammation is one of the main determinants of atherogenesis. The traditional medications for treatment of atherosclerosis are not very efficient in targeting atherosclerotic inflammation. Most of these drugs are non-selective, anti-inflammatory and immunosuppressive agents that have adverse effects and very limited anti-atherosclerotic effects, which limits their systemic administration. New approaches using nanoparticles have been investigated to specifically deliver therapeutic agents directly on atherosclerotic lesions. The use of drug delivery systems, such as polymeric nanoparticles, liposomes, and carbon nanotubes are attractive strategies, but some limitations exist. For instance, nanoparticles may alter the drug kinetics, based on the pathophysiological mechanisms of the diseases. In this review, we will update pathophysiological evidence for the use of nanoparticles to reduce inflammation and potentially prevent atherogenesis in different experimental models.
Advanced Healthcare Materials, 2019
This narrowed vessel leads to changes in the blood flow pattern. The average shear stress is 15 dyn cm −2 in a healthy coronary artery, which can be elevated to 70-100 dyn cm −2 or even higher by such blockages at the site of advanced lesions. [5] In addition, atherosclerosis preferentially develops within the branching and curved sites of the artery and is influenced by low and oscillatory shear stress (OSS) that mediates low-density lipoprotein (LDL) uptake in endothelial cells. This indicates that hemodynamics plays an important role in the establishment of atherosclerosis. [6] Atherosclerosis starts to develop in the early teenage stage and evolves thereafter. Regardless of the similar progression of atherosclerosis in different races, genders, and geographic locations, the rate of progression in atherosclerosis is faster in patients with risk factors such as hypertension, tobacco smoking, diabetes mellitus, obesity, and genetic inclination. [7] At the cellular level, the endothelium plays key roles in protecting blood vessel walls, participating in inflammatory reactions, secreting proteins on its surface to prevent blood clotting, and developing new blood vessels (angiogenesis). [8,9] Atherosclerosis can be triggered when the endothelium is damaged by high blood pressure (hypertension) [10] and toxins (e.g., smoking [11] and high glucose levels or hyperglycemia). [12] The process is accelerated if there is insufficient high-density lipoprotein (HDL) to remove cholesterol from tissues and carry it back to the liver, known as reverse cholesterol transport (RCT). [13] High ratio of LDL and HDL (more than 3:1) induces high levels of cholesterol in the blood or hypercholesterolemia, which may trigger endothelial dysfunction and promote the accumulation of LDL in the sub-endothelial space. [14-16] The injured or dysfunctional endothelium expresses various adhesion molecules, including endothelial selectin (E-selectin), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), which can capture monocytes and allow them to extravasate into the tunica intima (subendothelial space). [17,18] Free radicals, especially superoxide anions, are released from the damaged endothelium and macrophages in response to LDL accumulation. [19,20] The excessive generation of reactive oxygen species (ROS) promotes oxidative stress [21] and the formation of oxidized LDL (Ox-LDL). [22] The dysfunctional endothelium releases macrophage colony stimulating factor (M-CSF)/colony stimulating factor-1 (CSF-1) that can differentiate monocytes into macrophages. [23,24] These Atherosclerosis is the root of approximately one-third of global mortalities. Nanotechnology exhibits splendid prospects to combat atherosclerosis at the molecular level by engineering smart nanoagents with versatile functionalizations. Significant advances in nanoengineering enable nanoagents to autonomously navigate in the bloodstream, escape from biological barriers, and assemble with their nanocohort at the targeted lesion. The assembly of nanoagents with endogenous and exogenous stimuli breaks down their shells, facilitates intracellular delivery, releases their cargo to kill the corrupt cells, and gives imaging reports. All these improvements pave the way toward personalized medicine for atherosclerosis. This review systematically summarizes the recent advances in stimuli-responsive nanoagents for atherosclerosis management and its progress in clinical trials.
Biodistribution of Nanostructured Lipid Carriers in Mice Atherosclerotic Model
Molecules, 2019
Atherosclerosis is a major cardiovascular disease worldwide, that could benefit from innovative nanomedicine imaging tools and treatments. In this perspective, we here studied, by fluorescence imaging in ApoE-/mice, the biodistribution of non-functionalized and RXP470.1-targeted nanostructured lipid carriers (NLC) loaded with DiD dye. RXP470.1 specifically binds to MMP12, a metalloprotease that is over-expressed by macrophages residing in atherosclerotic plaques. Physico-chemical characterizations showed that RXP-NLC (about 105 RXP470.1 moieties/particle) displayed similar features as non-functionalized NLC in terms of particle diameter (about 60-65 nm), surface charge (about −5-−10 mV), and colloidal stability. In vitro inhibition assays demonstrated that RXP-NLC conserved a selectivity and affinity profile, which favored MMP-12. In vivo data indicated that NLC and RXP-NLC presented prolonged blood circulation and accumulation in atherosclerotic lesions in a few hours. Twenty-four hours after injection, particle uptake in atherosclerotic plaques of the brachiocephalic artery was similar for both nanoparticles, as assessed by ex vivo imaging. This suggests that the RXP470.1 coating did not significantly induce an active targeting of the nanoparticles within the plaques. Overall, NLCs appeared to be very promising nanovectors to efficiently and specifically deliver imaging agents or drugs in atherosclerotic lesions, opening avenues for new nanomedicine strategies for cardiovascular diseases.