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Cited by 423Nanoparticle-Based Drug DeliveryAtherosclerosis and Cardiovascular DiseasesNanotechnology research and applications

Perspectives and opportunities for nanomedicine in the management of atherosclerosis

Open access
Lobatto, Mark E., Fuster, Valentin, Fayad, Zahi A., Mulder, Willem J. M.·2011·Nature Reviews Drug Discovery
DOI 10.1038/nrd3578PMC PMC3623275
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Abstract

The use of nanotechnology for medical purposes — nanomedicine — has grown exponentially over the past few decades. This is exemplified by the US Food and Drug Administration's approval of several nanotherapies for various conditions, as well as the funding of nanomedical programmes worldwide. Although originally the domain of anticancer therapy, recent advances have illustrated the considerable potential of nanomedicine in the diagnosis and treatment of atherosclerosis. This Review elaborates on nanoparticle-targeting concepts in atherosclerotic disease, provides an overview of the use of nanomedicine in atherosclerosis, and discusses potential future applications and clinical benefits.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that nanomedicine has considerable potential for targeted therapy and in vivo imaging of atherosclerosis, building on nanoparticle-targeting lessons from cancer. It surveys preclinical and early clinical applications while emphasizing that translation is limited by animal-model differences, nanoparticle toxicity/retention, and the impracticality of chronic injectable nanotherapy.

Key findings

  • Nanoparticle targeting in atherosclerosis can exploit nonspecific permeability/retention and active targeting to adhesion molecules such as VCAM1, selectins, and αVβ3 integrin, as well as plaque macrophages, lipoproteins, and thrombus components. The review notes that cancer is commonly focal whereas atherosclerosis is a systemic vascular disease developing simultaneously at multiple sites.
  • HDL-based approaches are prominent: HDL is an endogenous lipidic nanoparticle 7–13 nm in size, and a small randomized clinical trial of ETC-216 (APOA1Milano) given as five weekly doses produced statistically significant regression of coronary atherosclerosis by serial intravascular ultrasound.
  • USPIO-enhanced MRI was reported in patients: in the first clinical study, 11 patients scheduled for carotid endarterectomy had a 24% decrease in carotid signal intensity after USPIO injection; in the ATHEROMA study, 20 patients per group received high-dose (80 mg/day) or low-dose (10 mg/day) atorvastatin, with substantial reduction in plaque inflammation at 6 and 12 weeks in the high-dose group and no reduction in the low-dose group.
  • Other reported applications include a single intravenous dose of glucocorticoid-encapsulated PEG liposomes in atherosclerotic rabbits reducing the 18F-FDG–PET signal 2 days after treatment; iodinated nanoparticles showing marked CT signal enhancement 2 hours after injection in a rabbit model; and 64Cu-labeled iron oxide nanoparticles accumulating in atherosclerotic arteries of APOE-knockout mice by PET–CT. In-stent restenosis is cited as still occurring in 3–20% of patients.

Methods

  • Narrative review focusing mainly on targeted therapy and in vivo imaging of atherosclerosis with injectable nanoparticulate agents and microparticles with diameters up to ~300 nm, noting that structures up to 500 nm have also been classified as nanomedical.
  • Synthesizes preclinical animal-model studies and clinical trials, including rabbit, mouse, rat, porcine, and non-human primate models, plus human imaging and intervention studies.
  • No primary experiments or systematic quantitative synthesis are reported; the paper organizes evidence around targeting concepts, therapeutic strategies, and imaging modalities.

Limitations

  • The paper states that many exciting preclinical nanoparticle findings in atherosclerosis have not progressed from development, partly because animal models develop accelerated atherosclerosis with lesion properties different from humans, and because of variability between animal models, diets, and induction methods, illustrating a need for standardization.
  • It also states that nanoparticulate agents can have limited diffusibility, toxic, immunostimulatory, and immunosuppressive properties, and extended body retention requiring extensive toxicological studies; most applications are limited to acute phases, while prolonged nanoparticle injection for chronic prevention is unrealistic and impractical.
  • Evident from the text: as a narrative review, it does not provide a systematic search strategy, risk-of-bias assessment, or meta-analysis, and combined therapeutic/diagnostic nanoprobes are expected to remain mostly limited to preclinical models.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nrd3578

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 148 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Subendothelial retention of lipoproteins and immune cells in the vessel wall comprises the first stage of atherosclerosis.

    “Subendothelial retention of lipoproteins and immune cells in the vessel wall comprises the first stage of atherosclerosis.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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      Not checked in the free run.

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  • Premisecitation

    Most occlusions that cause acute coronary syndromes arise from non-stenotic vulnerable plaques rather than lesions with severe stenosis.

    “Most occlusions that cause acute coronary syndromes do not result from lesions with severe stenosis; rather, they arise from non-stenotic lesions that are also referred to as vulnerable plaques29.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

  • Premisecitation

    Many processes in atherosclerosis also occur in cancer, including hypoxia-induced neovascularization, endothelial dysfunction, permeability of the microvasculature, and upregulation of adhesion molecules.

    “many of these processes also occur in cancer as most of them are inflammation-related, including hypoxia-induced neovascularization, endothelial dysfunction, permeability of the microvasculature and the upregulation of adhesion molecules to facilitate the recruitment of cells30,31.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [30] Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002). source

      Not checked in the free run.

    • cites [31] Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008). source

      Not checked in the free run.

  • Interpretationreasoning

    Identification and treatment of rupture-prone plaques before clinical events occur would result in substantial health benefits.

    “The identification and treatment of such rupture-prone plaques in patients before clinical events occur would result in substantial health benefits.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    The molecular and cellular processes in atherosclerosis create numerous opportunities for targeting the atherosclerotic plaque using nanoparticles.

    “The processes described above and their accompanying molecular and cellular events create numerous opportunities for targeting the atherosclerotic plaque using nanoparticles.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 15
  • May combine two claims. 50

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Atherosclerosis remains the major cause of morbidity and mortality in cardiovascular disease and represents a substantial economic burden.

    “atherosclerosis remains the major cause of morbidity and mortality in the field of cardiovascular disease, and represents a substantial economic burden18.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Roger, V. L. et al. Heart disease and stroke statistics —2011 update: a report from the American Heart Association. Circulation 123, e18–e209 (2011). source

      Not checked in the free run.

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    Premisecitation

    Dysfunctional endothelium is a crucial pathophysiological factor in atherosclerosis, causing increased permeation of macromolecules, increased expression of chemotactic and adhesion molecules, and enhanced recruitment and accumulation of monocytes.

    “Dysfunctional endothelium is a crucial pathophysiological factor in atherosclerosis, causing increased permeation of macromolecules such as lipoproteins, increased expression of chemotactic molecules (for example, monocyte chemotactic protein 1) and adhesion molecules (for example, intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1), as well as E-selectin and P-”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Chiu, J. J. & Chien, S. Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. Physiol. Rev. 91, 327–387 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ruptured atherosclerotic plaques in coronary arteries account for ~70% of fatal acute myocardial infarctions and/or sudden coronary deaths, and plaque rupture in carotid arteries causes ischaemic stroke.

    “the most severe complications arise from ruptured atherosclerotic plaques in coronary arteries, which account for ~70% of fatal acute myocardial infarctions and/or sudden coronary deaths, and plaque rupture in carotid arteries, which causes ischaemic stroke19.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Naghavi, M. et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 108, 1664–1672 (2003). source

      Not checked in the free run.

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    Premisecitation

    The enhanced permeability and retention effect allows macromolecules and nanoparticles to extravasate from the bloodstream at local sites and remain retained locally owing to impaired lymphatic drainage, whereas normal vascular physiology restricts nanoparticle distribution.

    “Normal vascular physiology results in tight (<2 nm) endothelial junctions, which will restrict nanoparticle distribution, whereas a dysfunctional endothelium leads to large gaps that allow macromolecules and nanoparticles to extravasate from the bloodstream at local sites and remain retained locally owing to impaired lymphatic drainage35,36.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Fang, J., Nakamura, H. & Maeda, H. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv. Drug Deliv. Rev. 63, 136–151 (2011). source

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    • cites [36] Tarbell, J. M. Shear stress and the endothelial transport barrier. Cardiovasc. Res. 87, 320–330 (2010). source

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    Premisecitation

    Lesions most susceptible to rupture are characterized by active inflammation, thin fibrous caps with large lipid cores, endothelial denudation with superficial platelet aggregation, fissured plaques, or luminal stenosis exceeding 90%.

    “Lesions that are most susceptible to rupture are characterized by active inflammation, thin fibrous caps with large lipid cores, endothelial denudation with superficial platelet aggregation, fissured plaques or luminal stenosis exceeding 90%19.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Naghavi, M. et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 108, 1664–1672 (2003). source

      Not checked in the free run.

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    Premisecitation

    Plaque neovessels are fragile structures prone to leakage and rupture, probably because of lack of mural cells and poorly formed endothelial cell junctions.

    “Plaque neovessels are fragile structures that are also prone to leakage and rupture, probably because of the lack of mural cells and poorly formed endothelial cell junctions26.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Kolodgie, F. D. et al. Elimination of neoangiogenesis for plaque stabilization: is there a role for local drug therapy? J. Am. Coll. Cardiol. 49, 2093–2101 (2007). source

      Not checked in the free run.

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    Premisecitation

    Plaque neovascularization is correlated with inflammation, promoting plaque progression, and may contribute to plaque rupture by facilitating cellular trafficking and immune cell recruitment through the vasa vasorum.

    “Plaque neovascularization has been correlated with inflammation, thereby promoting plaque progression, and it may even contribute to plaque rupture as it facilitates cellular trafficking and the recruitment of immune cells through the vasa vasorum25.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Moreno, P. R., Sanz, J. & Fuster, V. Promoting mechanisms of vascular health: circulating progenitor cells, angiogenesis, and reverse cholesterol transport. J. Am. Coll. Cardiol. 53, 2315–2323 (2009). source

      Not checked in the free run.

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    Premisecitation

    APOA1 mimetics can be orally administered and may be beneficial in high-risk patients with cardiovascular disease taking statins.

    “APOA1 mimetics have been created for chronic treatment; these mimetics can be orally administered and may be beneficial in high-risk patients with cardiovascular disease who are taking statins as standard of care64,65.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [64] Bloedon, L. T. et al. Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients. J. Lipid Res. 49, 1344–1352 (2008). source

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    • cites [65] Navab, M. et al. Structure and function of HDL mimetics. Arterioscler. Thromb. Vasc. Biol. 30, 164–168 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    This glucocorticoid liposome formulation may provide a rapid anti-inflammatory response in patients needing short-term therapy after an acute coronary event or in patients with severe atherosclerotic risk factors who have not received long-term risk-reduction therapy.

    “As with HDL, this formulation may provide a rapid anti-inflammatory response in patients who are in need of short-term therapy after an acute coronary event or in patients with severe atherosclerotic risk factors who have not received long-term risk-reduction therapy.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Results from animal models of atherosclerosis are predictive of effects in humans.

  • May combine two claims.

    Premisecitation

    The recognition of the role of inflammation in atherosclerosis has led to the formulation of anti-inflammatory drugs tailored to atherosclerosis, several of which are currently under investigation in clinical trials.

    “The recognition of the role of inflammation in atherosclerosis has led to the formulation of anti-inflammatory drugs tailored to atherosclerosis, several of which are currently under investigation in clinical trials79,80.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [79] Libby, P., Ridker, P. M. & Hansson, G. K. Inflammation in atherosclerosis: from pathophysiology to practice. J. Am. Coll. Cardiol. 54, 2129–2138 (2009). source

      Not checked in the free run.

    • cites [80] Charo, I. F. & Taub, R. Anti-inflammatory therapeutics for the treatment of atherosclerosis. Nature Rev. Drug Discov. 10, 365–376 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Although nonspecific targeting has never been thoroughly investigated in atherosclerosis, it can be exploited owing to permeability of the luminal endothelium and microvascular permeability and leakiness of neovessels of the vasa vasorum.

    “Although it has never been thoroughly investigated in atherosclerosis, nonspecific targeting can be exploited owing to the previously mentioned permeability of the luminal endothelium, as well as the microvascular permeability and leakiness of the neovessels of the vasa vasorum37.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] van Bochove, G. S. et al. Contrast enhancement by differently sized paramagnetic MRI contrast agents in mice with two phenotypes of atherosclerotic plaque. Contrast Media Mol. Imaging 6, 35–45 (2011). source

      Not checked in the free run.

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    Premisecitation

    In-stent restenosis can still occur in 3-20% of patients after drug-eluting stent implantation, and not all coronary lesions are suited for revascularization with drug-eluting stents.

    “in-stent restenosis can still occur in 3–20% of patients, and not all coronary lesions are suited for revascularization with drug-eluting stents85.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Dangas, G. D. et al. In-stent restenosis in the drug-eluting stent era. J. Am. Coll. Cardiol. 56, 1897–1907 (2010). source

      Not checked in the free run.

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    Premisecitation

    A single injection of liposome-encapsulated siRNA silences APOB mRNA expression in the liver and reduces APOB protein, serum cholesterol, and LDL in the bloodstream as early as 24 hours after treatment in non-human primates.

    “In non-human primates, a single injection of liposome-encapsulated siRNA silences APOB mRNA expression in the liver and reduces levels of the APOB protein, serum cholesterol and LDL in the bloodstream as early as 24 hours after treatment76 (FIG. 2b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Zimmermann, T. S. et al. RNAi-mediated gene silencing in non-human primates. Nature 441, 111–114 (2006). This study demonstrates the potential of systemic lipid-lowering by liposome-encapsulated siRNA. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intravenously injected nanoparticles may associate with circulating cells or cells in the spleen that subsequently migrate to areas of inflammation, as reported in stroke and myocardial infarction, and may also occur in atherosclerosis.

    “intravenously injected nanoparticles may associate with circulating cells or cells in the spleen that subsequently migrate to areas of inflammation. This observation has been reported in the setting of inflammation related to stroke and myocardial infarction, and may also occur in atherosclerosis38.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Flogel, U. et al. In vivo monitoring of inflammation after cardiac and cerebral ischemia by fluorine magnetic resonance imaging. Circulation 118, 140–148 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intravascular infusion of rHDL containing APOA1Milano reduces lipid and macrophage content of plaques, reverses endothelial dysfunction, inhibits progression, and induces rapid regression of atherosclerosis in animal models.

    “Intravascular infusion of rHDL containing a genetic variant of APOA1, APOA1Milano (also known as ETC-216), has resulted in a multitude of beneficial effects by reducing the lipid and macrophage content of plaques, reversing endothelial dysfunction, inhibiting the progression of atherosclerosis and inducing rapid regression of atherosclerosis in animal models57–61.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [57] Shah, P. K. et al. Effects of recombinant apolipoprotein A-IMilano on aortic atherosclerosis in apolipoprotein E-deficient mice. Circulation 97, 780–785 (1998). source

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      Not checked in the free run.

    • cites [59] Chiesa, G. et al. Recombinant apolipoprotein A-IMilano infusion into rabbit carotid artery rapidly removes lipid from fatty streaks. Circ. Res. 90, 974–980 (2002). source

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    • cites [60] Ibanez, B. et al. Rapid change in plaque size, composition, and molecular footprint after recombinant apolipoprotein A-IMilano (ETC-216) administration: magnetic resonance imaging study in an experimental model of atherosclerosis. J. Am. Coll. Cardiol. 51, 1104–1109 (2008). source

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    • cites [61] Kaul, S. et al. Rapid reversal of endothelial dysfunction in hypercholesterolemic apolipoprotein E-null mice by recombinant apolipoprotein A-IMilano-phospholipid complex. J. Am. Coll. Cardiol. 44, 1311–1319 (2004). source

      Not checked in the free run.

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    Premisecitation

    The function and cholesterol efflux capacity of HDL are the crucial factors associated with its atheroprotective effects, as simply increasing serum HDL levels does not necessarily reduce cardiovascular event risk.

    “The function and cholesterol efflux capacity of HDL are the crucial factors associated with its atheroprotective effects52, as indicated in a meta-analysis that showed that simply increasing serum HDL levels does not necessarily reduce the risk of cardiovascular events53.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [52] Khera, A. V. et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N. Engl. J. Med. 364, 127–135 (2011). source

      Not checked in the free run.

    • cites [53] Briel, M. et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ 338, b92 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Corticosteroids have anti-inflammatory effects in atherosclerosis but are not considered for long-term administration owing to poor pharmacokinetic profile and adverse side effects.

    “Corticosteroids have anti-inflammatory effects in atherosclerosis, although they are not considered for long-term administration owing to a poor pharmacokinetic profile and adverse side effects79,81.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [79] Libby, P., Ridker, P. M. & Hansson, G. K. Inflammation in atherosclerosis: from pathophysiology to practice. J. Am. Coll. Cardiol. 54, 2129–2138 (2009). source

      Not checked in the free run.

    • cites [81] Poon, M. et al. Dexamethasone inhibits macrophage accumulation after balloon arterial injury in cholesterol fed rabbits. Atherosclerosis 155, 371–380 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HDL is believed to protect against cardiovascular disease primarily through reverse cholesterol transport and additionally through modulation of inflammation.

    “HDL is believed to protect against cardiovascular disease primarily through reverse cholesterol transport, moving cholesterol from peripheral cells (particularly lipid-laden plaque macrophages) to the liver, and additionally through the modulation of inflammation51.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Navab, M., Reddy, S. T., Van Lenten, B. J. & Fogelman, A. M. HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms. Nature Rev. Cardiol. 8, 222–232 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The physicochemical properties of nanoparticles largely determine their biodistribution, although targeting ligands can substantially enhance intracellular uptake, which can increase therapeutic activity.

    “Therefore, it can be concluded that the physicochemical properties of nanoparticles will largely determine their biodistribution (BOX 1), although the presence of targeting ligands can substantially enhance intracellular uptake, which can increase therapeutic activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Functionalized nanoparticles do not enhance the percentage of injected dose reaching the specific lesion, but they allow better distribution among pathological lesions and increase internalization by targeted cells.

    “Various research groups have established that using functionalized nanoparticles does not enhance the percentage of the injected dose of the nanoparticle that reaches the specific lesion, but it does allow for better distribution of the nanoparticle among pathological lesions and increases its internalization by targeted cells44,45.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [44] Kirpotin, D. B. et al. Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models. Cancer Res. 66, 6732–6740 (2006). This study demonstrates that ligand-directed targeting can increase cell internalization. source

      Not checked in the free run.

    • cites [45] Bartlett, D. W., Su, H., Hildebrandt, I. J., Weber, W. A. & Davis, M. E. Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc. Natl Acad. Sci. USA 104, 15549–15554 (2007). source

      Not checked in the free run.

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    Premisecitation

    HDL infusions administered weekly inhibit aortic fatty streaks and lipid deposition or regress atherosclerotic plaques in rabbit models.

    “HDL infusions administered on a weekly basis have shown compelling results in rabbit models, resulting in the inhibition of aortic fatty streaks and lipid deposition in the atherosclerotic wall or the regression of atherosclerotic plaques55,56.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [55] Badimon, J. J., Badimon, L., Galvez, A., Dische, R. & Fuster, V. High density lipoprotein plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits. Lab. Invest. 60, 455–461 (1989).

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    • cites [56] Badimon, J. J., Badimon, L. & Fuster, V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J. Clin. Invest. 85, 1234–1241 (1990). source

      Not checked in the free run.

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    Premisecitation

    Clinical trials of therapeutic angiogenesis with adenoviral or lipid-based VEGF transfection have not shown clinically relevant positive effects, mainly attributed to low gene transfer efficiency.

    “Several clinical trials have addressed the efficacy of therapeutic angiogenesis with adenoviral or lipid-based transfection of VEGF, but have not yet shown any clinically relevant positive effects — this has been mainly attributed to a low efficiency of gene transfer109,110.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [109] Hedman, M. et al. Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: Phase II results of the Kuopio Angiogenesis Trial (KAT). Circulation 107, 2677–2683 (2003). source

      Not checked in the free run.

    • cites [110] Yla-Herttuala, S., Rissanen, T. T., Vajanto, I. & Hartikainen, J. Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine. J. Am. Coll. Cardiol. 49, 1015–1026 (2007). source

      Not checked in the free run.

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    Premisecitation

    Molecular imaging allows study of subclinical plaque inflammation, other cellular processes, neovascularization and enzymatic activity in atherosclerosis.

    “Molecular imaging allows the study of subclinical plaque inflammation and other cellular processes in atherosclerosis, as well as neovascularization and enzymatic activity118,119.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [118] Chen, I. Y. & Wu, J. C. Cardiovascular molecular imaging: focus on clinical translation. Circulation 123, 425–443 (2011). source

      Not checked in the free run.

    • cites [119] Leuschner, F. & Nahrendorf, M. Molecular imaging of coronary atherosclerosis and myocardial infarction: considerations for the bench and perspectives for the clinic. Circ. Res. 108, 593–606 (2011). This is a review on the processes that can be targeted to enable the detection of coronary atherosclerosis by molecular imaging. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The micelles concentrated at the rupture-prone region of the plaque and showed considerable antithrombin activity.

    “The micelles were mainly concentrated at the rupture-prone region of the plaque and showed considerable antithrombin activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] Peters, D. et al. Targeting atherosclerosis by using modular, multifunctional micelles. Proc. Natl Acad. Sci. USA 106, 9815–9819 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rats with stainless steel stents in carotid arteries, intra-arterial injection of superparamagnetic nanoparticles preloaded into endothelial cells and exposure to a homogenous magnetic field showed high uptake of cells within the stent area, representing a novel strategy for site-specific delivery of cell-based therapy.

    “Polyak et al.102 used an alternative method to address delayed endothelial healing. Rats with stainless steel stents in their carotid arteries were intra-arterially injected with superparamagnetic nanoparticles that were preloaded into endothelial cells, making these cells magnetically responsive. The rats were subsequently exposed to a homogenous magnetic field that showed a high uptake of cells”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Polyak, B. et al. High field gradient targeting of magnetic nanoparticle-loaded endothelial cells to the surfaces of steel stents. Proc. Natl Acad. Sci. USA 105, 698–703 (2008). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Prednisolone phosphate encapsulated in PEG-conjugated liposomes designed to target the vascular subendothelial matrix was used by Joner et al.

    “Joner et al.91 used a different approach, whereby prednisolone phosphate was encapsulated in PEG-conjugated liposomes that were specifically designed to target the vascular subendothelial matrix.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Joner, M. et al. Site-specific targeting of nanoparticle prednisolone reduces in-stent restenosis in a rabbit model of established atheroma. Arterioscler. Thromb. Vasc. Biol. 28, 1960–1966 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Various other nanoparticle formulations have been proposed to prevent restenosis after stent implantation, including albumin-stabilized paclitaxel nanoparticles, micellar doxorubicin, virus-mediated siRNA, lysine-based siRNA nanoparticles, perfluorocarbon nanoparticles containing doxorubicin or paclitaxel targeting vascular smooth muscle cells, αVβ3 integrin-targeted perfluorocarbon nanoparticles,

    “Other nanoparticle formulations that have been proposed to prevent restenosis after stent implantation include: albumin-stabilized nanoparticles containing paclitaxel93; micellar doxorubicin94; virus-mediated transfer of siRNA95; lysine-based nanoparticles delivering siRNA96; perfluorocarbon nanoparticles containing doxorubicin or paclitaxel that target vascular smooth muscle cells97; αVβ3 integr”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [93] Kolodgie, F. D. et al. Sustained reduction of in-stent neointimal growth with the use of a novel systemic nanoparticle paclitaxel. Circulation 106, 1195–1198 (2002). source

      Not checked in the free run.

    • cites [94] Uwatoku, T. et al. Application of nanoparticle technology for the prevention of restenosis after balloon injury in rats. Circ. Res. 92, e62–e69 (2003). source

      Not checked in the free run.

    • cites [95] Abid, M. R. et al. Forkhead transcription factors inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia. J. Biol. Chem. 280, 29864–29873 (2005). source

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  • May combine two claims.

    Premisecitation

    A liposomal formulation containing clodronate depleted monocyte levels, thereby reducing neointimal proliferation after balloon injury in rats and rabbits.

    “a liposomal formulation containing the bisphosphonate clodronate was used to deplete monocyte levels, thereby reducing neointimal proliferation after balloon injury in rats and rabbits89.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Danenberg, H. D. et al. Macrophage depletion by clodronate-containing liposomes reduces neointimal formation after balloon injury in rats and rabbits. Circulation 106, 599–605 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autopsy cases show that atherosclerotic changes occur in both drug-eluting stent and bare-metal stent implantation, which may contribute to late-stage thrombotic events.

    “Autopsy cases show that atherosclerotic changes occur in both drug-eluting stent and bare-metal stent implantation, which may also contribute to these late-stage thrombotic events88.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] Nakazawa, G. et al. The pathology of neoatherosclerosis in human coronary implants: bare-metal and drug-eluting stents. J. Am. Coll. Cardiol. 57, 1314–1322 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Macrophages in atherosclerotic plaques account for the majority of leukocytes and inflammation and are implicated in plaque rupture, representing an important target.

    “Macrophages in atherosclerotic plaques account for the majority of leukocytes and inflammation in plaques, and are implicated in plaque rupture, thereby representing an important target127.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] Woollard, K. J. & Geissmann, F. Monocytes in atherosclerosis: subsets and functions. Nature Rev. Cardiol. 7, 77–86 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    MRI excels in visualizing plaque components including fibrous cap and lipid core, whereas CT allows visualization of calcifications.

    “MRI is recognized as a technique that excels in visualizing different components of the plaque, including the fibrous cap and lipid core, whereas CT allows the visualization of calcifications.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    PET and SPECT lack anatomical information, so they are commonly used with CT and recently MRI.

    “However, a major disadvantage of these imaging modalities is the lack of anatomical information, so they are commonly used in combination with CT and, recently, MRI.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    CT coronary angiography is widely used clinically and acquires images in seconds, but is less sensitive for contrast-generating material than MRI.

    “On the contrary, CT coronary angiography is widely used in the clinical setting and can be used to acquire images within a matter of seconds; however, it is less sensitive for the visualization of contrast-generating material than MRI.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Blood-pool nanoparticle agents with long circulatory half-life remain visible in the vasculature for prolonged periods and can suffice for multiple imaging acquisitions.

    “Because of their long circulatory half-life, these agents remain visible within the vasculature for prolonged periods of time and can therefore suffice for multiple imaging acquisitions139,140.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [139] Torchilin, V. P., Frank-Kamenetsky, M. D. & Wolf, G. L. CT visualization of blood pool in rats by using long-circulating, iodine-containing micelles. Acad. Radiol. 6, 61–65 (1999). source

      Not checked in the free run.

    • cites [140] Rabin, O., Manuel Perez, J., Grimm, J., Wojtkiewicz, G. & Weissleder, R. An X-ray computed tomography imaging agent based on long-circulating bismuth sulphide nanoparticles. Nature Mater. 5, 118–122 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    USPIO-enhanced MRI can identify plaque inflammatory status and plaque stability in carotid arteries.

    “Another study demonstrated that USPIO-enhanced MRI can identify plaque inflammatory status and plaque stability in carotid arteries (FIG. 5c).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [129] Tang, T. Y. et al. The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) Study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease. J. Am. Coll. Cardiol. 53, 2039–2050 (2009). source

      Not checked in the free run.

    • cites [130] Fayad, Z. A., Razzouk, L., Briley-Saebo, K. C. & Mani, V. Iron oxide magnetic resonance imaging for atherosclerosis therapeutic evaluation: still “rusty?” J. Am. Coll. Cardiol. 53, 2051–2052 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a randomized study, high-dose atorvastatin (80 mg/day) reduced plaque inflammation at 6 and 12 weeks, while low-dose (10 mg/day) did not.

    “A substantial reduction in plaque inflammation from the baseline was observed at both time points in the high-dose group; by constrast, there was no reduction from the baseline in the low-dose group129,130.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [129] Tang, T. Y. et al. The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) Study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease. J. Am. Coll. Cardiol. 53, 2039–2050 (2009). source

      Not checked in the free run.

    • cites [130] Fayad, Z. A., Razzouk, L., Briley-Saebo, K. C. & Mani, V. Iron oxide magnetic resonance imaging for atherosclerosis therapeutic evaluation: still “rusty?” J. Am. Coll. Cardiol. 53, 2051–2052 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    PET and SPECT are much more sensitive than MRI/CT and can detect molecular targets within the picomolar range.

    “Nuclear imaging techniques such as PET and SPECT, however, are much more sensitive and can detect molecular targets within the picomolar range.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    MRI and CT are excellent for macroscopically depicting atherosclerotic plaques non-invasively and are being improved for assessing plaque size and composition.

    “MRI and CT are excellent techniques for macroscopically depicting atherosclerotic plaques in a non-invasive manner, and are continually being improved for the purpose of accurately assessing plaque size and composition123,124.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [123] Underhill, H. R., Hatsukami, T. S., Fayad, Z. A., Fuster, V. & Yuan, C. MRI of carotid atherosclerosis: clinical implications and future directions. Nature Rev. Cardiol. 7, 165–173 (2010). source

      Not checked in the free run.

    • cites [124] Voros, S. et al. Coronary atherosclerosis imaging by Coronary CT angiography: current status, correlation with intravascular interrogation and meta-analysis. JACC Cardiovasc. Imaging 4, 537–548 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    A disadvantage of CT molecular imaging with iodinated nanoparticles is the necessity of a baseline scan, causing a double radiation dose and requiring pre- and post-scan comparison.

    “A disadvantage of this approach, however, is the necessity of a baseline scan, subjecting the patient to a double dose of radiation and requiring pre- and post-scan image comparison.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Use of nanoparticles for X-ray contrast-enhanced imaging is largely unexplored but has increased considerably in the past 5 years.

    “The use of nanoparticles for X-ray contrast-enhanced imaging is largely unexplored but has seen a considerable increase in the past 5 years.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Hyafil et al. published the first example of CT-based molecular imaging using iodinated nanoparticles for detection of macrophages in a rabbit model, showing marked signal enhancement 2 hours after injection.

    “Hyafil et al.141 published the first example of CT-based molecular imaging using iodinated nanoparticles for the detection of macrophages in a rabbit model of atherosclerotic plaques, showing a marked signal enhancement 2 hours after injection of the iodinated nanoparticles (FIG. 5f).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] Hyafil, F. et al. Noninvasive detection of macrophages using a nanoparticulate contrast agent for computed tomography. Nature Med. 13, 636–641 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Nanoparticles carrying contrast-generating material can be used to track drug delivery or quantify expression of cellular markers after treatment.

    “Besides diagnosing subclinical atherosclerosis, nanoparticles carrying contrast-generating material can be used to track drug delivery or enable the quantification of expression of cellular markers after treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    USPIOs are phagocytosed by macrophages in atherosclerotic plaques, causing iron oxide-associated MRI signal loss, first reported in a rabbit model.

    “USPIOs are phagocytosed by macrophages in atherosclerotic plaques, thereby causing iron oxide-associated MRI signal loss, which was first reported in a rabbit model126 (FIG. 5b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Ruehm, S. G., Corot, C., Vogt, P., Kolb, S. & Debatin, J. F. Magnetic resonance imaging of atherosclerotic plaque with ultrasmall superparamagnetic particles of iron oxide in hyperlipidemic rabbits. Circulation 103, 415–422 (2001). This was the first study to use USPIO-enhanced MRI of atherosclerotic plaques in a rabbit model. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Nanoparticles can exhibit favourable pharmacokinetics and plaque targeting, and may serve as valuable tracers for nuclear imaging.

    “However, nanoparticles can exhibit favourable pharmacokinetics and plaque targeting, and therefore may serve as valuable tracers for nuclear imaging.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Apoptosis has been studied using annexin A5-functionalized nanoparticles.

    “and apoptosis has been studied using annexin A5-functionalized nanoparticles135.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [135] van Tilborg, G. A. et al. Annexin A5-functionalized bimodal nanoparticles for MRI and fluorescence imaging of atherosclerotic plaques. Bioconjug. Chem. 21, 1794–1803 (2010). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisereasoning

    X-ray contrast agents in clinical use are iodinated small molecules requiring short imaging times due to rapid renal clearance.

    “The X-ray contrast agents in clinical use are iodinated small molecules, which require very short imaging times owing to their rapid clearance by the kidney.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Including nanocrystals in the core of HDL enables its detection by multiple imaging techniques without compromising the important biophysical features of HDL.

    “This paper reports the effect of including nanocrystals in the core of HDL to enable its detection by multiple imaging techniques without compromising the important biophysical features of HDL.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] Cormode, D. P. et al. Nanocrystal core high-density lipoproteins: a multimodality contrast agent platform. Nano Lett. 8, 3715–3723 (2008). This paper reports the effect of including nanocrystals in the core of HDL to enable its detection by multiple imaging techniques without compromising the important biophysical features of HDL. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Continuous discovery of new molecular targets, improved understanding of pathophysiology, and ongoing developments in nanoparticle synthesis and imaging technologies will aid in prevention and treatment of atherosclerosis.

    “The continuous discovery of new molecular targets, our improved understanding of the pathophysiology of atherosclerosis, as well as ongoing developments in nanoparticle synthesis methods and imaging technologies will aid in the prevention and treatment of this disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Nanotechnology can have a role in stent design, tissue engineering and early-detection techniques, and may have additional applications in myocardial infarction, aortic aneurysms, thrombolytic therapy, ablation therapy for atrial fibrillation and other cardiovascular disorders.

    “Nanotechnology can have a role in stent design165, tissue engineering166 and early-detection techniques167, but it may also have additional applications in myocardial infarction168, aortic aneurysms169, thrombolytic therapy170, ablation therapy for atrial fibrillation171 and other cardiovascular disorders.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [165] Martinez, A. W. & Chaikof, E. L. Microfabrication and nanotechnology in stent design. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 3, 256–268 (2011). source

      Not checked in the free run.

    • cites [166] Dvir, T., Timko, B. P., Kohane, D. S. & Langer, R. Nanotechnological strategies for engineering complex tissues. Nature Nanotechnol. 6, 13–22 (2011). source

      Not checked in the free run.

    • cites [167] Park, J. S. et al. A highly sensitive and selective diagnostic assay based on virus nanoparticles. Nature Nanotechnol. 4, 259–264 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Use of nanoparticles in cardiovascular disease has led to better understanding of atherosclerosis, the role of imaging and evaluation of pharmacotherapy.

    “Nevertheless, the use of nanoparticles in cardiovascular disease has led to a better understanding of atherosclerosis, the role of imaging and the evaluation of pharmacotherapy163.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163] Lindsay, A. C. & Choudhury, R. P. Form to function: current and future roles for atherosclerosis imaging in drug development. Nature Rev. Drug Discov. 7, 517–529 (2008). This review describes the role of atherosclerosis imaging on drug development. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Certain nanoparticulate agents can exhibit limited diffusibility, toxic, immunostimulatory and immunosuppressive properties, and can be retained in the body for extended periods, requiring extensive toxicological studies before clinical translation.

    “However, the properties that enable these advantages create limitations, as certain nanoparticulate agents can exhibit limited diffusibility in addition to toxic, immunostimulatory and immunosuppressive properties. They can also be retained in the body for an extended period of time, requiring extensive toxicological studies before their successful translation into the clinical setting157.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [157] Dobrovolskaia, M. A. & McNeil, S. E. Immunological properties of engineered nanomaterials. Nature Nanotechnol. 2, 469–478 (2007). This review describes the immunotoxicological aspects of nanotechnology-based therapeutic or diagnostic nanoparticles. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Nanomedicine holds promise as personalized medicine for management of cardiovascular disease, particularly target-specific treatment and imaging of atherosclerotic disease.

    “Nanomedicine holds promise as a type of personalized medicine for the management of cardiovascular disease in general, particularly the target-specific treatment and imaging of atherosclerotic disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    When the peptide encounters an active protease it is cleaved, emitting fluorescence signals that allow detection of the probe.

    “When encountering an active protease the peptide is cleaved, thereby emitting fluorescence signals that allow the detection of the probe151.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [151] Nahrendorf, M. et al. Hybrid in vivo FMT-CT imaging of protease activity in atherosclerosis with customized nanosensors. Arterioscler. Thromb. Vasc. Biol. 29, 1444–1451 (2009). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The long circulating half-life of radiolabelled nanoparticles warrants extensive toxicity studies before clinical translation due to risks of prolonged radioactive exposure.

    “The long circulating half-life of radiolabelled nanoparticles warrants extensive toxicity studies before their translation into clinical medicine owing to the risks associated with prolonged exposure to radioactive material.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Dextran-coated iron oxide nanoparticles have favourable targeting properties for plaque imaging by PET-CT.

    “This study reports the effects of exploiting the favourable targeting properties of dextran-coated iron oxide nanoparticles for plaque imaging by PET–CT.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148] Nahrendorf, M. et al. Nanoparticle PET-CT imaging of macrophages in inflammatory atherosclerosis. Circulation 117, 379–387 (2008). This study reports the effects of exploiting the favourable targeting properties of dextran-coated iron oxide nanoparticles for plaque imaging by PET–CT. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Various other optical imaging techniques for molecular imaging of atherosclerosis are being explored, including photo-acoustic imaging, fluorescence, absorption and Raman spectroscopy, optical coherence tomography, and bioluminescence.

    “Various other optical imaging techniques for the molecular imaging of atherosclerosis are being explored, such as photo-acoustic imaging, fluorescence, absorption and Raman spectroscopy, optical coherence tomography, and bioluminescence152.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Jaffer, F. A., Libby, P. & Weissleder, R. Optical and multimodality molecular imaging: insights into atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 29, 1017–1024 (2009). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Imaging of drug delivery can be useful but it is not necessary to administer diagnostic labels each time a patient receives treatment.

    “Imaging of drug delivery can be useful but it is not necessary to administer diagnostic labels each time a patient receives treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Agents most likely to be developed for clinical use in the future are either completely biodegradable or have small hydrodynamic diameters to facilitate fast renal clearance.

    “and the agents that are most likely to be developed for clinical use in the future are either completely biodegradable or they have small hydrodynamic diameters to facilitate fast renal clearance158.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158] Choi, H. S. & Frangioni, J. V. Nanoparticles for biomedical imaging: fundamentals of clinical translation. Mol. Imaging 9, 291–310 (2010).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    USPIO-enhanced MRI can image atherosclerotic plaques in a rabbit model.

    “This was the first study to use USPIO-enhanced MRI of atherosclerotic plaques in a rabbit model.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Ruehm, S. G., Corot, C., Vogt, P., Kolb, S. & Debatin, J. F. Magnetic resonance imaging of atherosclerotic plaque with ultrasmall superparamagnetic particles of iron oxide in hyperlipidemic rabbits. Circulation 103, 415–422 (2001). This was the first study to use USPIO-enhanced MRI of atherosclerotic plaques in a rabbit model. source

      Not checked in the free run.

59 of 59

  • The paper relies on this without support.

    Elevated APOB and LDL levels are associated with an increased risk of coronary artery disease.

    “Elevated APOB and LDL levels are associated with an increased risk of coronary artery disease.”

  • The paper relies on this without support.

    Cancer is commonly a focal disease, whereas atherosclerosis is a systemic vascular disease that develops at various sites throughout the body simultaneously.

    “cancer is commonly a focal disease, whereas atherosclerosis is a systemic vascular disease that develops at various sites throughout the body simultaneously.”

  • The paper relies on this without support.

    Results from animal models of atherosclerosis are predictive of effects in humans.

    “As with HDL, this formulation may provide a rapid anti-inflammatory response in patients who are in need of short-term therapy after an acute coronary event or in patients with severe atherosclerotic risk factors who have not received long-term risk-reduction therapy.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Macrophage infiltration can serve as a biomarker for the stage and progression of cardiovascular disorders such as atherosclerosis.

    “Macrophage infiltration can be used as a biomarker in several pathological conditions. It can for instance provide information on the stage and progression of cardiovascular disorders, such as atherosclerosis [169, 170].”

    From Iron oxide nanoparticles: Diagnostic, therapeutic and theranostic applications (2019) · cites this paper as [170]

The citation lists haven’t been fetched yet

References 190 · Cited by 423

Authors
Lobatto, M. E., Fuster, V., Fayad, Z. A., & Mulder, W. J. M.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • Amsterdam UMC Location University of Amsterdam (NL)
Corresponding author
Mulder, Willem J. M.
ORCID
Venue
Nature Reviews Drug Discovery
Publisher
Springer Science and Business Media LLC
Published
2011-10-21
Volume
10
Issue
11
Pages
835-852
ISSN
  • 1474-1776 (ISSN-L)
  • 1474-1784
DOI
10.1038/nrd3578
PMC
PMC3623275
OpenAlex
W2096485414
Semantic Scholar
2c2b32d2fa86fcf0a80b7b870ce779ef657e6fca
Cited by
423
References
190
Citations by year
2026: 14 · 2025: 19 · 2024: 23 · 2023: 27 · 2022: 34 · 2021: 28 · 2020: 32 · 2019: 31 · 2018: 29 · 2017: 28 · 2016: 33 · 2015: 32 · 2014: 37 · 2013: 34 · 2012: 20
FWCI
1.78
Type
journal article
Language
en
Update notices
erratum (2011-10-31)
Open access
Licence
Locations
  • Nature Reviews Drug Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • International Atherosclerosis Society
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (HHSN268201000045C)
  • National Cancer Institute (R01CA155432)
  • National Institute of Biomedical Imaging and Bioengineering (R01EB009638)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Physical Sciences › Engineering › Biomedical Engineering › Nanotechnology research and applications
Keywords
nanomedicine, atherosclerosis, nanoparticle targeting, atherosclerosis diagnosis, atherosclerosis treatment, nanotherapy, drug delivery
MeSH terms
Animals, Humans, Drug Delivery Systems, Disease Management, Atherosclerosis, Nanomedicine, Nanoparticles

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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