Recent advances in inhibiting atherosclerosis and restenosis: from pathogenic factors, therapeutic molecules to nano-delivery strategies.
Journal of materials chemistry. B
Due to dominant atherosclerosis etiology, cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide. In clinical trials, advanced atherosclerotic plaques can be removed by angioplasty and vascular transplantation, but the severe risk of vascular restenosis remains, which needs to be urgently improved. After understanding and generalizing the pathological processes and cellular mechanism of certain atherosclerosis and restenosis, their essential pathogenic factors show noteworthy similarity, primarily including endothelium injury, excessive proliferation of smooth muscle cells (SMCs), and pathogenic inflammatory responses. These common pathogenic factors inspire researchers to develop co-target treatments for these atherosclerosis and restenosis. Numerous therapeutic agents such as nucleic acids, proteins, small molecule drugs and gas signaling molecules for co-target treatments are summarized in this paper. To improve the safety and effectiveness of therapeutic agents, high-performance nanodelivery strategies have been developed for anti-atherosclerosis systemic administration and anti-restenosis local administration. They can augment blood circulation time and targeting ability for systemic administration, as well as efficient nanodrug load and precise release. Overall, this review aims to recapitulate the emerging therapeutic molecules and nanodelivery strategies for the treatment of atherosclerosis and restenosis, with the goal of mutual enlightenment in exploring therapeutic approaches for these diseases.
10.1039/d2tb00003b
Plaque-targeted, proteolysis-resistant, activatable and MRI-visible nano-GLP-1 receptor agonist targets smooth muscle cell differentiation in atherosclerosis.
Theranostics
Glucagon-like peptide-1 receptor (GLP-1R) agonists are powerful glycemia-lowering agents, which have systematically been shown to lower cardiovascular events and mortality. These beneficial effects were difficult to pinpoint within atherosclerotic plaque due to lack of particular specificity of such agonists to the vascular cells and an inadequate understanding of the GLP-1R expression in atherosclerosis. Here, we hypothesized that the direct engagement of the GLP-1R in atherosclerosis by targeted agonists will alleviate vascular inflammation and plaque burden, even at a very low dose. The expression of GLP-1 receptor (GLP-1R, mRNA) in human lesions with pathologic intimal thickening, Apoe mouse atheroma and cultured immune/non-immune cells was investigated using genetic lineage tracing, Southern blotting and validated antisera against human GLP-1R. Protease-resistant and "activatable" nanoparticles (NPs) carrying GLP-1R agonist liraglutide (GlpNP) were engineered and synthesized. Inclusion of gadolinium chelates into GlpNP allowed for imaging by MRI. Atherosclerotic Apoe mice were treated intravenously with a single dose (30 µg/kg of liraglutide) or chronically (1 µg/kg, 6 weeks, 2x/week) with GlpNP, liraglutide or control NPs, followed by assessment of metabolic parameters, atheroma burden, inflammation and vascular function. Humal plaque specimens expressed high levels of GLP-1R within the locus of de-differentiated smooth muscle cells that also expressed myeloid marker CD68. However, innate immune cells under a variety of conditions expressed very low levels of , as seen in lineage tracing and Southern blotting experiments examining full-length open reading frame mRNA transcripts. Importantly, de-differentiated vascular smooth muscle cells demonstrated significant expression levels, suggesting that these could represent the cells with predominant positivity in atherosclerosis. GlpNP resisted proteolysis and demonstrated biological activity including glycemia lowering at 30 µg/kg and cholesterol efflux. Activatable properties of GlpNP were confirmed by imaging cytometry and using whole organ imaging. GlpNP targeted CD11b/CD11c cells in circulation and smooth muscle cells in aortic plaque in Apoe mice when assessed by MRI and fluorescence imaging. At a very low dose of 1 µg/kg, previously known to have little effect on glycemia and weight loss, GlpNP delivered i.v. for six weeks reduced triglyceride-rich lipoproteins in plasma, plaque burden and plaque cholesterol without significant effects on weight, glycemia and plasma cholesterol levels. : GlpNP improves atherosclerosis at weight-neutral doses as low as 1 µg/kg with the effects independent from the pancreas or the central nervous system. Our study underlines the importance of direct actions of GLP-1 analogs on atherosclerosis, involving cholesterol efflux and inflammation. Our findings are the first to suggest the therapeutic modulation of vascular targets by GlpNP, especially in the context of smooth muscle cell inflammation.
10.7150/thno.66456
Recent advances in micro- and nano-bubbles for atherosclerosis applications.
Wijaya Andy,Maruf Ali,Wu Wei,Wang Guixue
Biomaterials science
Atherosclerosis is the most prevalent cause of cardiovascular disease-induced deaths worldwide. Micro- and nano-bubbles (MNBs) have been developed as the vehicles for detection, investigation, and drug delivery, specifically targeting atherosclerotic sites. MNBs have been clinically applied and commercialized as contrast agents because they typically respond to ultrasound for guiding and stimulating imaging. The assembly process involves some specific substrates (proteins, lipids, and polymers) to adjust their characteristics and depends upon rational designs for combined therapeutic-diagnostic (theranostic) applications. Ancillary surface modifications of MNBs enable the unification of MNBs with antibody, inflammatory markers, or genes to more specifically deliver cargos to the oxidized lipid-rich quarry area and release the payloads on demand to the lesion site. This review provides brief information on the process of fabricating MNBs and their applications in bio-nanomedicine for diagnosing and remodeling atherosclerosis.
10.1039/d0bm00762e
Nano-sponge-like liposomes remove cholesterol crystals for antiatherosclerosis.
Journal of controlled release : official journal of the Controlled Release Society
Atherosclerotic cardiovascular diseases remain the leading causes of morbidity and mortality worldwide. Cholesterol crystals in atherosclerotic plaques play an essential role in atherosclerosis progression. However, no clinical drugs have been used for removing cholesterol crystals from plaque to counter atherosclerosis. Previous studies identified the hydrophobic domain of lipid bilayer in liposomes acted as sinks for solubilizing hydrophobic cholesterol. Moreover, adjusting the composition of the lipid bilayer in liposomes can enhance its hydrophobic molecule loading capacity. Therefore, in this study, ginsenosides Rb1 (Rb1), one of main active components of ginseng which has a similar structure to cholesterol, is anchored into soy phospholipids bilayer with its hydrophobic region to prepare nano-sponge-like liposomes (Rb1-LPs), aiming to amplify the solubilization of cholesterol in lipid bilayer. For targeting delivery to atherosclerotic plaques, Annexin V (AnxV), a protein that can specifically recognize phosphatidylserine upregulated in atherosclerotic plaques, is applied to decorate the surface of Rb1-LPs by click reaction to obtain the final preparation of AnxV-Rb1-LPs. The in vitro studies showed that incorporating Rb1 into lipid bilayer remarkably increased the affinity of the lipid bilayer to free cholesterol and the solubilization of cholesterol crystals. Additionally, nano-sponge-like liposomes could efficiently reduce the accumulation of cholesterol crystals and improve cholesterol efflux, finally inhibiting inflammation and apoptosis in cholesterol-laden cells. Furthermore, AnxV-Rb1-LPs could efficiently accumulate in atherosclerotic plaques after intravenous injection, exert nano-sponge-like functions to remove intra- and extracellular cholesterol crystals, ultimately alleviating inflammation and apoptosis in atherosclerotic plaques for antiatherosclerosis. Therefore, AnxV-Rb1-LPs provide a potential strategy for removing cholesterol crystals in atherosclerotic plaques and can be further utilized in other diseases with excessive cholesterol accumulation.
10.1016/j.jconrel.2022.07.021
Nanotechnological approach to delivering nutraceuticals as promising drug candidates for the treatment of atherosclerosis.
Drug delivery
Atherosclerosis is Caesar's sword, which poses a huge risk to the present generation. Understanding the atherosclerotic disease cycle would allow ensuring improved diagnosis, better care, and treatment. Unfortunately, a highly effective and safe way of treating atherosclerosis in the medical community remains a continuous challenge. Conventional treatments have shown considerable success, but have some adverse effects on the human body. Natural derived medications or nutraceuticals have gained immense popularity in the treatment of atherosclerosis due to their decreased side effects and toxicity-related issues. In hindsight, the contribution of nutraceuticals in imparting enhanced clinical efficacy against atherosclerosis warrants more experimental evidence. On the other hand, nanotechnology and drug delivery systems (DDS) have revolutionized the way therapeutics are performed and researchers have been constantly exploring the positive effects that DDS brings to the field of therapeutic techniques. It could be as exciting as ever to apply nano-mediated delivery of nutraceuticals as an additional strategy to target the atherosclerotic sites boasting high therapeutic efficiency of the nutraceuticals and fewer side effects.
10.1080/10717544.2021.1892241
Targeted delivery of anti-inflammatory cytokine by nanocarrier reduces atherosclerosis in Apo E mice.
Biomaterials
Unresolved inflammation is a hallmark of many deadly diseases including atherosclerosis, a silent pathological condition behind majority of cardiovascular diseases. Yet, anti-inflammatory drugs are not clinically used in the treatment of patients with atherosclerosis. The currently approved treatment regimen against atherosclerosis is mainly focused on lowering the cholesterol/lipid levels in blood and has little to do with controlling inflammation, the underlying cause. Recent preclinical and clinical data suggest that effective alleviation of inflammation in the atherosclerosis plaque could reduce the risk of cardiovascular disease. In this work, we have encapsulated interleukin-10 (IL10), a multipotent anti-inflammatory cytokine into cRGD conjugated pluronic based nano-carriers (NC) for targeted delivery to atherosclerotic plaques. The NC could encapsulate the therapeutic protein with a high loading efficiency in a mild condition and showed sustained release capabilities. The efficacy of cytokine encapsulated NC was analyzed in vitro using the lipopolysaccharide stimulated macrophage cells and in vivo using an established apolipoprotein E-knockout (ApoE) C57BL/6 mouse model. Compared to free IL10, intravenous administration of NC encapsulated IL10 resulted in vastly improved pharmacokinetic profile and profoundly high accumulation of the cytokine in the atherosclerosis lesions. IL10 delivered by NC was bioactive and reduced the production of pro-inflammatory cytokine IL-1β in the lesion and led to significant regression in the plaque size. These results signify the prospect of nanoparticle based cytokine delivery for preventing atherosclerotic through inflammation modulation in near future.
10.1016/j.biomaterials.2019.119550
Surface-modified nanotherapeutics targeting atherosclerosis.
Biomaterials science
Atherosclerosis is a chronic and metabolic-related disease that is a serious threat to human health. Currently available diagnostic and therapeutic measures for atherosclerosis lack adequate efficiency which requires promising alternative approaches. Nanotechnology-based nano-delivery systems allow for new perspectives for atherosclerosis therapy. Surface-modified nanoparticles could achieve highly effective therapeutic effects by binding to specific receptors that are abnormally overexpressed in atherosclerosis, with less adverse effects on non-target tissues. The main purpose of this review is to summarize the research progress and design ideas to target atherosclerosis using a variety of ligand-modified nanoparticle systems, discuss the shortcomings of current vector design, and look at future development directions. We hope that this review will provide novel research strategies for the design and development of nanotherapeutics targeting atherosclerosis.
10.1039/d2bm00660j
Targeting and clearance of senescent foamy macrophages and senescent endothelial cells by antibody-functionalized mesoporous silica nanoparticles for alleviating aorta atherosclerosis.
Biomaterials
Senescent cells drive atherosclerosis at all stages and contribute to cardiovascular disease. However, the markers in these senescent aortic plaques have not been well studied, creating a huge obstacle in the exploration of a precise and efficient system for atherosclerosis treatment. Recently, CD9 has been found to induce cellular senescence and aggravated atherosclerotic plaque formation in apolipoprotein E knockout (ApoE) mice. In the present study, this result has been leveraged to develop CD9 antibody-modified, hyaluronic acid-coated mesoporous silica nanoparticles with a hyaluronidase-responsive drug release profile. In invitro models of senescent foamy macrophages and senescent endothelial cells stimulated with oxidized high-density-lipoprotein, the CD9 antibody-modified mesoporous silica nanoparticles exhibit high cellular uptake; reduce the reactive oxygen species level, high-density lipoprotein oxidation, and production of TNF-α and IL-6; and attenuate the senescence process, contributing to improved cell viability. In vivo experiment demonstrated that these nanoparticles can successfully target the senescent lesion areas, deliver the anti-senescence drug rosuvastatin to the senescent atherosclerotic plaques (mainly endothelial cells and macrophages), and alleviate the progression of atherosclerosis in ApoE mice. By providing deep insight regarding the markers in senescent atherosclerotic plaque and developing a nano-system targeting this lesion area, the study proposes a novel and an accurate therapeutic approach for mitigating atherosclerosis through senescent cell clearance.
10.1016/j.biomaterials.2021.120677
Negatively-charged Liposome Nanoparticles Can Prevent Dyslipidemia and Atherosclerosis Progression in the Rabbit Model.
Current vascular pharmacology
BACKGROUND AND AIM:Negatively charged nanoliposomes have a strong attraction towards plasma lipoprotein particles and can thereby regulate lipid metabolism. Here, the impact of such nanoliposomes on dyslipidaemia and progression of atherosclerosis was investigated in a rabbit model. METHODS:Two sets of negatively-charged nanoliposome formulations including [Hydrogenated Soy Phosphatidylcholine (HSPC)/1,2-distearoyl-sn-glycero-3- phosphoglycerol (DSPG)] and [1,2- Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC)/1,2-Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPG)/Cholesterol] were evaluated. Rabbits fed a high-cholesterol diet were randomly divided into 3 groups (n=5/group) intravenously administrated with HSPC/DSPG formulation (DSPG group; 100 mmol/kg), DMPC/DMPG formulation (DMPG group; 100 mmol/kg), or the normal saline (control group; 0.9% NaCl) over a 4-week period. The atherosclerotic lesions of the aortic arch wall were studied using haematoxylin and eosin staining. RESULTS:Both DSPG and DMPG nanoliposome formulations showed a nano-sized range in diameter with a negatively-charged surface and a polydispersity index of <0.1. After 4 weeks administration, the nanoliposome formulations decreased triglycerides (-62±3% [DSPG group] and -58±2% [DMPG group]), total cholesterol (-58±9% [DSPG group] and -37±5% [DMPG group]), and lowdensity lipoprotein cholesterol (-64±6% [DSPG group] and -53±10% [DMPG group]) levels, and increased high-density lipoprotein cholesterol (+67±28% [DSPG group] and +35±19% [DMPG group]) levels compared with the controls. The nanoliposomes showed a significant decrease in the severity of atherosclerotic lesions: mean values of the intima to media ratio in DMPG (0.96±0.1 fold) and DSPG (0.54±0.02 fold) groups were found to be significantly lower than that in the control (1.2±0.2 fold) group (p<0.05). CONCLUSION:Anionic nanoliposomes containing [HSPC/DSPG] and [DMPC/DMPG] correct dyslipidaemia and inhibit the progression of atherosclerosis.
10.2174/1570161119666210820115150
Hyaluronic acid targeted and pH-responsive multifunctional nanoparticles for chemo-photothermal synergistic therapy of atherosclerosis.
Liu Shun,Zhao Yun,Shen Meili,Hao Yujiao,Wu Xiaodong,Yao Yixuan,Li Yapeng,Yang Qingbiao
Journal of materials chemistry. B
Atherosclerosis is a global disease with an extremely high morbidity and fatality rate, so it is necessary to develop effective treatments to reduce its impact. In this work, we successfully prepared a multifunctional drug-loaded nano-delivery system with pH-responsive, CD44-targeted, and chemical-photothermal synergistic treatment. Dendritic mesoporous silica nanoparticles capped with copper sulfide (CuS) were synthesized an oil-water biphase stratification reaction system; these served as the carrier material and encapsulated the anticoagulant drug heparin (Hep). The pH-sensitive Schiff base bond was used as a gatekeeper and targeting agent to modify hyaluronic acid (HA) on the surface of the nanocarrier. HA coating endowed the nanocomposite with the ability to respond to pH and target CD44-positive inflammatory macrophages. Based on this multifunctional nanocomposite, we achieved precise drug delivery, controlled drug release, and chemical-photothermal synergistic treatment of atherosclerosis. The drug release results showed that the nanocarriers exhibited excellent drug-controlled release properties, and could release drugs in the weakly acidic microenvironment of atherosclerotic inflammation. Cytotoxicity and cell uptake experiments indicated that nanocarriers had low cytotoxicity against RAW 264.7 cells. Modification of HA to nanocarriers can be effectively internalized by RAW 264.7 cells stimulated by lipopolysaccharide (LPS). Combining CuS photothermal treatment with anti-atherosclerosis chemotherapy showed better effects than single treatment and . In summary, our research proved that H-CuS@DMSN-NC-HA has broad application prospects in anti-atherosclerosis.
10.1039/d1tb02000e
Novel dual ROS-sensitive and CD44 receptor targeting nanomicelles based on oligomeric hyaluronic acid for the efficient therapy of atherosclerosis.
Hou Xiaoya,Lin Hua,Zhou Xiudi,Cheng Ziting,Li Yi,Liu Xue,Zhao Feng,Zhu Yanping,Zhang Peng,Chen Daquan
Carbohydrate polymers
Although the clinical usage of drugs administration was raising, the application of nanoparticles encapsulating the hydrophobic drugs with plummy efficiency was very scarce for atherosclerosis (AS) treatment. In this work, a novel dual ROS-sensitive and CD44 receptors targeting amphiphilic carrier material, oligomeric hyaluronic acid-2'-[propane-2,2-diyllbls (thio)] diacetic acl-hydroxymethylferrocene (oHA-TKL-Fc), named HASF, was synthesized and characterized by H-NMR spectra. Then, we combined curcumin (Cur) with HASF into nano-micelles (HASF@Cur micelles) by self-assembling method. The resulting HASF@Cur micelles had the average size of 150.8 nm and zeta potential of -35.04 mV to maintain the will-defined spheroidal structure and stability. Importantly, the HASF@Cur micelles had ultrahigh entrapment efficiency (about 51.41 %). Moreover, in vitro release study, Cur release from HASF@Cur micelles was effective in the reactive oxygen species (ROS) condition, and the release rate was interrelated with the concentration of hydrogen peroxide (HO). Further, fluorescence imaging showed that the HASF@Cur micelles could more selective access to Raw 264.7 cells than free Cur via oHA-receptor mediated endocytosis. The MTT assay attested the safety of amphiphilic carrier material HASF. Additionally, the results of in vivo Oil red O lipid staining studies showed that the lesion area of the aorta was reduced to 47.3±3.4 % with HASF@Cur micelles, compared with the lesion area of Cur group (63.2±2.7 %), HASF@Cur micelles had the more remarkable effect in reducing lesion area (*P < 0.05). Consequently, the novel dual ROS-sensitive and CD44 receptors targeting drug delivery system would become a promising strategy for atherosclerosis.
10.1016/j.carbpol.2019.115787
Platelet membrane-cloaked selenium/ginsenoside Rb1 nanosystem as biomimetic reactor for atherosclerosis therapy.
Colloids and surfaces. B, Biointerfaces
Cardiovascular disease remains the dominant contributor to human mortality, and the main etiology of which is atherosclerosis (AS). Enhancing the targeted ability of nanosystem and improving plaque stability are critical challenges for the current management of AS. Herein, we leverage the marked role of platelets in AS to construct a biomimetic nanodrug delivery system (PM@Se/Rb1 NPs), which prepared by cloaking platelet membrane (PM) around Selenium (Se) and ginsenoside Rb1 nanoparticles (Se/Rb1 NPs) core. The core endows the delivery system antioxidant, lipid metabolism and anti-inflammatory effects for AS effective treatment. Moreover, PM-coated nanoparticles reserve platelets' inherent biological elements to deliver drugs to plaques. We further explored the potential effect of PM@Se/Rb1 NPs' combination with the clinical anticoagulant drug warfarin (War) to treat AS and elucidated the possible drug interaction mechanism. As a result, the PM@Se/Rb1 NPs are not only capable of improving inflammatory behaviors such as inhibitory adhesion ability and anti-angiogenesis therapeutic effect in vitro, but also administer efficiently localizing to atherosclerotic plaque explaining by aortic samples from established ApoE mice. Therefore, this study provided a theoretical basis of biomimetic nanodrug in the treatment of AS as well as an effective reference for the combined application of nanodrug and clinical drugs.
10.1016/j.colsurfb.2022.112464
Recent Advances in Managing Atherosclerosis via Nanomedicine.
Chan Cecilia Ka Wing,Zhang Lei,Cheng Chak Kwong,Yang Hongrong,Huang Yu,Tian Xiao Yu,Choi Chung Hang Jonathan
Small (Weinheim an der Bergstrasse, Germany)
Atherosclerosis, driven by chronic inflammation of the arteries and lipid accumulation on the blood vessel wall, underpins many cardiovascular diseases with high mortality rates globally, such as stroke and ischemic heart disease. Engineered bio-nanomaterials are now under active investigation as carriers of therapeutic and/or imaging agents to atherosclerotic plaques. This Review summarizes the latest bio-nanomaterial-based strategies for managing atherosclerosis published over the past five years, a period marked by a rapid surge in preclinical applications of bio-nanomaterials for imaging and/or treating atherosclerosis. To start, the biomarkers exploited by emerging bio-nanomaterials for targeting various components of atherosclerotic plaques are outlined. In addition, recent efforts to rationally design and screen for bio-nanomaterials with the optimal physicochemical properties for targeting plaques are presented. Moreover, the latest preclinical applications of bio-nanomaterials as carriers of imaging, therapeutic, or theranostic agents to atherosclerotic plaques are discussed. Finally, a mechanistic understanding of the interactions between bio-nanomaterials and the plaque ("athero-nano" interactions) is suggested, the opportunities and challenges in the clinical translation of bio-nanomaterials for managing atherosclerosis are discussed, and recent clinical trials for atherosclerotic nanomedicines are introduced.
10.1002/smll.201702793
Hyaluronan Nanoparticles Selectively Target Plaque-Associated Macrophages and Improve Plaque Stability in Atherosclerosis.
Beldman Thijs J,Senders Max L,Alaarg Amr,Pérez-Medina Carlos,Tang Jun,Zhao Yiming,Fay Francois,Deichmöller Jacqueline,Born Benjamin,Desclos Emilie,van der Wel Nicole N,Hoebe Ron A,Kohen Fortune,Kartvelishvily Elena,Neeman Michal,Reiner Thomas,Calcagno Claudia,Fayad Zahi A,de Winther Menno P J,Lutgens Esther,Mulder Willem J M,Kluza Ewelina
ACS nano
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 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 were ca. 90 nm in diameter and displayed very stable morphology under hydrolysis conditions. Flow cytometry revealed a 6- to 40-fold higher uptake of Cy7-HA-NPs by aortic macrophages compared to normal tissue macrophages. Interestingly, both local and systemic HA-NP-immune cell interactions significantly decreased over the disease progression. Zr-HA-NPs-induced radioactivity in atherosclerotic aortas was 30% higher than in wild-type controls. PET imaging of rabbits revealed 6-fold higher standardized uptake values compared to the muscle. The plaques of HA-NP-treated mice contained 30% fewer macrophages compared to control and free HA-treated group. In conclusion, we show favorable targeting properties of HA-NPs, which can be exploited for PET imaging of atherosclerosis-associated inflammation. Furthermore, we demonstrate the anti-inflammatory effects of HA-NPs in atherosclerosis.
10.1021/acsnano.7b01385
Combating atherosclerosis with targeted nanomedicines: recent advances and future prospective.
Nakhlband Ailar,Eskandani Morteza,Omidi Yadollah,Saeedi Nazli,Ghaffari Samad,Barar Jaleh,Garjani Alireza
BioImpacts : BI
Cardiovascular diseases (CVDs) is recognized as the leading cause of mortality worldwide. The increasing prevalence of such disease demands novel therapeutic and diagnostic approaches to overcome associated clinical/social issues. Recent advances in nanotechnology and biological sciences have provided intriguing insights to employ targeted Nanomachines to the desired location as imaging, diagnosis, and therapeutic modalities. Nanomedicines as novel tools for enhanced drug delivery, imaging, and diagnosis strategies have shown great promise to combat cardiovascular diseases. In the current study, we intend to review the most recent studies on the nano-based strategies for improved management of CVDs. A cascade of events results in the formation of atheromatous plaque and arterial stenosis. Furthermore, recent studies have shown that nanomedicines have displayed unique functionalities and provided de novo applications in the diagnosis and treatment of atherosclerosis. Despite some limitations, nanomedicines hold considerable potential in the prevention, diagnosis, and treatment of various ailments including atherosclerosis. Fewer side effects, amenable physicochemical properties and multi-potential application of such nano-systems are recognized through various investigations. Therefore, it is strongly believed that with targeted drug delivery to atherosclerotic lesions and plaque, management of onset and progression of disease would be more efficient than classical treatment modalities.
10.15171/bi.2018.08
Targeted Therapy of Atherosclerosis by a Broad-Spectrum Reactive Oxygen Species Scavenging Nanoparticle with Intrinsic Anti-inflammatory Activity.
Wang Yuquan,Li Lanlan,Zhao Weibo,Dou Yin,An Huijie,Tao Hui,Xu Xiaoqiu,Jia Yi,Lu Shan,Zhang Jianxiang,Hu Houyuan
ACS nano
Atherosclerosis is a leading cause of vascular diseases worldwide. Whereas antioxidative therapy has been considered promising for the treatment of atherosclerosis in view of a critical role of reactive oxygen species (ROS) in the pathogenesis of atherosclerosis, currently available antioxidants showed considerably limited clinical outcomes. Herein, we hypothesize that a broad-spectrum ROS-scavenging nanoparticle can serve as an effective therapy for atherosclerosis, taking advantage of its antioxidative stress activity and targeting effects. As a proof of concept, a broad-spectrum ROS-eliminating material was synthesized by covalently conjugating a superoxide dismutase mimetic agent Tempol and a hydrogen-peroxide-eliminating compound of phenylboronic acid pinacol ester onto a cyclic polysaccharide β-cyclodextrin (abbreviated as TPCD). TPCD could be easily processed into a nanoparticle (TPCD NP). The obtained nanotherapy TPCD NP could be efficiently and rapidly internalized by macrophages and vascular smooth muscle cells (VSMCs). TPCD NPs significantly attenuated ROS-induced inflammation and cell apoptosis in macrophages, by eliminating overproduced intracellular ROS. Also, TPCD NPs effectively inhibited foam cell formation in macrophages and VSMCs by decreasing internalization of oxidized low-density lipoprotein. After intravenous (i.v.) administration, TPCD NPs accumulated in atherosclerotic lesions of apolipoprotein E-deficient (ApoE) mice by passive targeting through the dysfunctional endothelium and translocation via inflammatory cells. TPCD NPs significantly inhibited the development of atherosclerosis in ApoE mice after i.v. delivery. More importantly, therapy with TPCD NPs afforded stabilized plaques with less cholesterol crystals, a smaller necrotic core, thicker fibrous cap, and lower macrophages and matrix metalloproteinase-9, compared with those treated with control drugs previously developed for antiatherosclerosis. The therapeutic benefits of TPCD NPs mainly resulted from reduced systemic and local oxidative stress and inflammation as well as decreased inflammatory cell infiltration in atherosclerotic plaques. Preliminary in vivo tests implied that TPCD NPs were safe after long-term treatment via i.v. injection. Consequently, TPCD NPs can be developed as a potential antiatherosclerotic nanotherapy.
10.1021/acsnano.8b02037
Affinity-Driven Design of Cargo-Switching Nanoparticles to Leverage a Cholesterol-Rich Microenvironment for Atherosclerosis Therapy.
Kim Heegon,Kumar Sandeep,Kang Dong-Won,Jo Hanjoong,Park Ji-Ho
ACS nano
Atherosclerotic plaques exhibit high deposition of cholesterol and macrophages. These are not only the main components of the plaques but also key inflammation-triggering sources. However, no existing therapeutics can achieve effective removal of both components within the plaques. Here, we report cargo-switching nanoparticles (CSNP) that are physicochemically designed to bind to cholesterol and release anti-inflammatory drug in the plaque microenvironment. CSNP have a core-shell structure with a core composed of an inclusion complex of methyl-β-cyclodextrin (cyclodextrin) and simvastatin (statin), and a shell of phospholipids. Upon interaction with cholesterol, which has higher affinity to cyclodextrin than statin, CSNP release statin and scavenge cholesterol instead through cargo-switching. CSNP exhibit cholesterol-sensitive multifaceted antiatherogenic functions attributed to statin release and cholesterol depletion . In mouse models of atherosclerosis, systemically injected CSNP target atherosclerotic plaques and reduce plaque content of cholesterol and macrophages, which synergistically leads to effective prevention of atherogenesis and regression of established plaques. These findings suggest that CSNP provide a therapeutic platform for interfacing with cholesterol-associated inflammatory diseases such as atherosclerosis.
10.1021/acsnano.9b08216
Macrophage membrane functionalized biomimetic nanoparticles for targeted anti-atherosclerosis applications.
Wang Yi,Zhang Kang,Li Tianhan,Maruf Ali,Qin Xian,Luo Li,Zhong Yuan,Qiu Juhui,McGinty Sean,Pontrelli Giuseppe,Liao Xiaoling,Wu Wei,Wang Guixue
Theranostics
Atherosclerosis (AS), the underlying cause of most cardiovascular events, is one of the most common causes of human morbidity and mortality worldwide due to the lack of an efficient strategy for targeted therapy. In this work, we aimed to develop an ideal biomimetic nanoparticle for targeted AS therapy. Based on macrophage "homing" into atherosclerotic lesions and cell membrane coating nanotechnology, biomimetic nanoparticles (MM/RAPNPs) were fabricated with a macrophage membrane (MM) coating on the surface of rapamycin-loaded poly (lactic-co-glycolic acid) copolymer (PLGA) nanoparticles (RAPNPs). Subsequently, the physical properties of the MM/RAPNPs were characterized. The biocompatibility and biological functions of MM/RAPNPs were determined . Finally, in AS mouse models, the targeting characteristics, therapeutic efficacy and safety of the MM/RAPNPs were examined. The advanced MM/RAPNPs demonstrated good biocompatibility. Due to the MM coating, the nanoparticles effectively inhibited the phagocytosis by macrophages and targeted activated endothelial cells . In addition, MM-coated nanoparticles effectively targeted and accumulated in atherosclerotic lesions . After a 4-week treatment program, MM/RAPNPs were shown to significantly delay the progression of AS. Furthermore, MM/RAPNPs displayed favorable safety performance after long-term administration. These results demonstrate that MM/RAPNPs could efficiently and safely inhibit the progression of AS. These biomimetic nanoparticles may be potential drug delivery systems for safe and effective anti-AS applications.
10.7150/thno.47841
Rapamycin-Loaded Polymeric Nanoparticles as an Advanced Formulation for Macrophage Targeting in Atherosclerosis.
Craparo Emanuela Fabiola,Cabibbo Marta,Conigliaro Alice,Barreca Maria Magdalena,Musumeci Teresa,Giammona Gaetano,Cavallaro Gennara
Pharmaceutics
Recently, rapamycin (Rapa) represents a potential drug treatment to induce regression of atherosclerotic plaques; however, its use requires site-specific accumulation in the vessels involved in the formation of the plaques to avoid the systemic effects resulting from its indiscriminate biodistribution. In this work, a stable pharmaceutical formulation for Rapa was realized as a dried powder to be dispersed extemporaneously before administration. The latter was constituted by mannitol (Man) as an excipient and a Rapa-loaded polymeric nanoparticle carrier. These nanoparticles were obtained by nanoprecipitation and using as a starting polymeric material a polycaprolactone (PCL)/α,β-poly(-2-hydroxyethyl)-dl-aspartamide (PHEA) graft copolymer. To obtain nanoparticles targeted to macrophages, an oxidized phospholipid with a high affinity for the CD36 receptor of macrophages, the 1-(palmitoyl)-2-(5-keto-6-octene-dioyl) phosphatidylcholine (KOdia-PC), was added to the starting organic phase. The chemical-physical and technological characterization of the obtained nanoparticles demonstrated that: both the drug loading (DL%) and the entrapment efficiency (EE%) entrapped drug are high; the entrapped drug is in the amorphous state, protected from degradation and slowly released from the polymeric matrix; and the KOdia-PC is on the nanoparticle surface (KP-Nano). The biological characterization demonstrated that both systems are quickly internalized by macrophages while maintaining the activity of the drug. In vitro studies demonstrated that the effect of KP-Nano Rapa-loaded, in reducing the amount of the Phospo-Ser757-ULK1 protein through the inhibition of the mammalian target of rapamycin (mTOR), is comparable to that of the free drug.
10.3390/pharmaceutics13040503
A Nano-Emulsion Platform Functionalized with a Fully Human scFv-Fc Antibody for Atheroma Targeting: Towards a Theranostic Approach to Atherosclerosis.
Bonnet Samuel,Prévot Geoffrey,Mornet Stéphane,Jacobin-Valat Marie-Josée,Mousli Yannick,Hemadou Audrey,Duttine Mathieu,Trotier Aurélien,Sanchez Stéphane,Duonor-Cérutti Martine,Crauste-Manciet Sylvie,Clofent-Sanchez Gisèle
International journal of molecular sciences
Atherosclerosis is at the onset of the cardiovascular diseases that are among the leading causes of death worldwide. Currently, high-risk plaques, also called vulnerable atheromatous plaques, remain often undiagnosed until the occurrence of severe complications, such as stroke or myocardial infarction. Molecular imaging agents that target high-risk atheromatous lesions could greatly improve the diagnosis of atherosclerosis by identifying sites of high disease activity. Moreover, a "theranostic approach" that combines molecular imaging agents (for diagnosis) and therapeutic molecules would be of great value for the local management of atheromatous plaques. The aim of this study was to develop and characterize an innovative theranostic tool for atherosclerosis. We engineered oil-in-water nano-emulsions (NEs) loaded with superparamagnetic iron oxide (SPIO) nanoparticles for magnetic resonance imaging (MRI) purposes. Dynamic MRI showed that NE-SPIO nanoparticles decorated with a polyethylene glycol (PEG) layer reduced their liver uptake and extended their half-life. Next, the NE-SPIO-PEG formulation was functionalized with a fully human scFv-Fc antibody (P3) recognizing galectin 3, an atherosclerosis biomarker. The P3-functionalized formulation targeted atheromatous plaques, as demonstrated in an immunohistochemistry analyses of mouse aorta and human artery sections and in an mouse model of atherosclerosis. Moreover, the formulation was loaded with SPIO nanoparticles and/or alpha-tocopherol to be used as a theranostic tool for atherosclerosis imaging (SPIO) and for delivery of drugs that reduce oxidation (here, alpha-tocopherol) in atheromatous plaques. This study paves the way to non-invasive targeted imaging of atherosclerosis and synergistic therapeutic applications.
10.3390/ijms22105188
Immunomodulatory Nanomedicine for the Treatment of Atherosclerosis.
Journal of clinical medicine
Atherosclerosis is the main underlying cause of cardiovascular diseases (CVDs), which remain the number one contributor to mortality worldwide. Although current therapies can slow down disease progression, no treatment is available that can fully cure or reverse atherosclerosis. Nanomedicine, which is the application of nanotechnology in medicine, is an emerging field in the treatment of many pathologies, including CVDs. It enables the production of drugs that interact with cellular receptors, and allows for controlling cellular processes after entering these cells. Nanomedicine aims to repair, control and monitor biological and physiological systems via nanoparticles (NPs), which have been shown to be efficient drug carriers. In this review we will, after a general introduction, highlight the advantages and limitations of the use of such nano-based medicine, the potential applications and targeting strategies via NPs. For example, we will provide a detailed discussion on NPs that can target relevant cellular receptors, such as integrins, or cellular processes related to atherogenesis, such as vascular smooth muscle cell proliferation. Furthermore, we will underline the (ongoing) clinical trials focusing on NPs in CVDs, which might bring new insights into this research field.
10.3390/jcm10143185