Redox-responsive polyurethane-polyurea nanoparticles targeting to aortic endothelium and atherosclerosis (original) (raw)
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Nanostructured lipid carriers accumulate in atherosclerotic plaques of ApoE−/− mice
Nanomedicine: Nanotechnology, Biology and Medicine, 2020
Autoradiography of 64 Cu-labelled nanostructured lipid carriers (NLC) and Oil Red O histology (neutral lipids staining) of aortas showed significant particle uptake in atherosclerotic lesions 24 h after injection in ApoE −/− mice atherosclerotic models. Produced by well-controlled and up-scalable high pressure homogenization, NLC could present similar features than lipoproteins, and be used as synthetic mimetics to convey drugs and contrast agents to atherosclerotic lesions.
Nanocarriers for vascular delivery of antioxidants
Nanomedicine, 2011
Antioxidant enzymes (AOEs) catalase and superoxide dismutase (SOD) detoxify harmful reactive oxygen species, but the therapeutic utility of AOEs is hindered by inadequate delivery. AOE modification by polyethylene glycol (PEG) and encapsulation in PEG-coated liposomes increases the AOE bioavailability and enhances protective effects in animal models. Pluronic-based micelles formed with AOEs show even more potent protective effects. Furthermore, polymeric nanocarriers (PNCs) based on PEG-copolymers protect encapsulated AOEs from proteolysis and improve delivery to the target cells, such as the endothelium lining the vascular lumen. Antibodies to endothelial determinants conjugated to AOEs or AOE carriers provide targeting and intracellular delivery. Targeted liposomes, protein conjugates and magnetic nanoparticles deliver AOEs to sites of vascular oxidative stress in the cardiovascular, pulmonary and nervous systems. Further advances in nanodevices for AOE delivery will provide a basis for the translation of this approach in the clinical domain.
Development of polymeric drug delivery system for recognizing vascular endothelial dysfunction
Bioorganic & Medicinal Chemistry, 2008
The vascular endothelium plays an important role in regulating vascular homeostasis. Damage to the endothelium can lead to cardiovascular diseases such as arteriosclerosis. Therefore, early-stage detection and evaluation of vascular endothelium dysfunction would be very important for effective diagnosis and therapy. We synthesized a polymeric drug carrier bearing an Evans blue analogue as a probing unit for endothelium injury. The polymeric carrier spontaneously formed stable nanoparticles with micelle-like structure in aqueous media and could encapsulate hydrophobic doxorubicin (DOX). The encapsulated DOX showed a sustainable release profile over a period of 10-60 h depending on the loaded DOX concentration. The polymeric carrier specifically adsorbed against the endothelium-injured site in extracted porcine aorta. These properties of the polymeric drug carrier will be suitable for specific drug delivery to endothelium dysfunctional region.
ACS Appl. Nano Mater., 2021
Cardiovascular disease remains the number one cause of mortality and morbidity worldwide and includes atherosclerosis, which presents as a deadly and chronic inflammatory disease. The initial pathological factor in atherosclerosis is a dysfunctional endothelium (Dys-En), which results in enhanced permeability of the endothelium and enhanced expression of adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1), among others. Nanomedicines represent a growing arsenal of novel therapeutics aimed at treating atherosclerosis; however, nanoparticle (NP) interactions as a function of their biophysiochemical properties with the Dys-En are not currently well understood. In this study, we investigated targeted NP biophysicochemical properties for maximal VCAM-1 binding and permeability across several Dys-En models that we established using cardiovascular inflammatory mediators. We found that NP size governs permeability and binding, regardless of the type and density of VCAM-1 peptide ligand used. Our results suggest that the design of NPs in the range of 30−60 nm can highly increase permeability and binding across the Dys-En. These findings confirm the importance of in vitro models of Dys-En as a preliminary screening and predictive tool for atherosclerosis NP targeting.
Drug Delivery and Nanoformulations for the Cardiovascular System
Research & reviews. Drug delivery, 2017
Therapeutic delivery to the cardiovascular system may play an important role in the successful treatment of a variety of disease state, including atherosclerosis, ischemic-reperfusion injury and other types of microvascular diseases including hypertension. In this review we evaluate the different options available for the development of suitable delivery systems that include the delivery of small organic compounds [adenosin A2A receptor agonist (CGS 21680), CYP-epoxygenases inhibitor (N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide, trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy] benzoic acid), soluble epoxide hydrolase inhibitor (N-methylsulfonyl-12,12-dibromododec-11-enamide), PPARγ agonist (rosiglitazone) and PPARγ antagonist (T0070907)], nanoparticles, peptides, and siRNA to the cardiovascular system. Effective formulations of nanoproducts have significant potential to overcome physiological barriers and improve therapeutic outcomes in patients. As per the literature co...
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.
ACS Nano, 2019
Atherosclerosis is associated with a compromised endothelial barrier, facilitating the accumulation of immune cells and macromolecules in atherosclerotic lesions. In this study, we investigate endothelial barrier integrity and the enhanced permeability and retention (EPR) effect during atherosclerosis progression and therapy in Apoe −/− mice using hyaluronan nanoparticles (HA-NPs). Utilizing ultrastructural and en face plaque imaging, we uncover a significantly decreased junction continuity in the atherosclerotic plaquecovering endothelium compared to the normal vessel wall, indicative of disrupted endothelial barrier. Intriguingly, the plaque advancement had a positive effect on junction stabilization, which correlated with a 3-fold lower accumulation of in vivo administrated HA-NPs in advanced plaques compared to early counterparts. Furthermore, by using superresolution and correlative light and electron microscopy, we trace nanoparticles in the plaque microenvironment. We find nanoparticle-enriched endothelial junctions, containing 75% of detected HA-NPs, and a high HA-NP accumulation in the endothelium-underlying extracellular matrix, which suggest an endothelial junctional traffic of HA-NPs to the plague. Finally, we probe the EPR effect by HA-NPs in the context of metabolic therapy with a glycolysis inhibitor, 3PO, proposed as a vascular normalizing strategy. The observed trend of attenuated HA-NP uptake in aortas of 3PO-treated mice coincides with the endothelial silencing activity of 3PO, demonstrated in vitro. Interestingly, the therapy also reduced the plaque inflammatory burden, while activating macrophage metabolism. Our findings shed light on natural limitations of nanoparticle accumulation in atherosclerotic plaques and provide mechanistic insight into nanoparticle trafficking across continued...
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.
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...
Recent Advances in ROS-Sensitive Nano-Formulations for Atherosclerosis Applications
Pharmaceutics, 2021
Over the past decade, ROS-sensitive formulations have been widely used in atherosclerosis applications such as ROS scavenging, drug delivery, gene delivery, and imaging. The intensified interest in ROS-sensitive formulations is attributed to their unique self-adaptive properties, involving the main molecular mechanisms of solubility switch and degradation under the pathological ROS differences in atherosclerosis. This review outlines the advances in the use of ROS-sensitive formulations in atherosclerosis applications during the past decade, especially highlighting the general design requirements in relation to biomedical functional performance.