Willem J M Mulder

University of Amsterdam, Amsterdamo, North Holland, Netherlands

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Publications (127)798.4 Total impact

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    ABSTRACT: Rationale: Local plaque macrophage proliferation and monocyte production in hematopoietic organs promote progression of atherosclerosis. Therefore, non-invasive imaging of proliferation could serve as a biomarker and monitor therapeutic intervention. Objective: To explore (18)F-fluorothymidine ((18)F-FLT) PET-CT imaging of cell proliferation in atherosclerosis. Methods and results: (18)F-FLT PET-CT was performed in mice, rabbits and humans with atherosclerosis. In ApoE(-/-) mice, increased (18)F-FLT signal was observed in atherosclerotic lesions, spleen and bone marrow (SUV wild-type versus ApoE(-/-) mice, 0.05±0.01 versus 0.17±0.01, P<0.05 in aorta; 0.13±0.01 versus 0.28±0.02, P<0.05 in bone marrow; 0.06±0.01 versus 0.22±0.01, P<0.05 in spleen), corroborated by ex vivo scintillation counting and autoradiography. Flow cytometry confirmed significantly higher proliferation of macrophages in aortic lesions and hematopoietic stem and progenitor cells in the spleen and bone marrow in these mice. In addition, (18)F-FLT plaque signal correlated with the duration of high cholesterol diet (r2=0.33, p<0.05). Aortic 18F-FLT uptake was reduced when cell proliferation was suppressed with 5-FU in ApoE(-/-) mice (p<0.05). In rabbits, inflamed atherosclerotic vasculature with the highest (18)F-fluorodeoxyglucose uptake enriched (18)F-FLT. In patients with atherosclerosis, (18)F-FLT signal significantly increased in the inflamed carotid artery and in the aorta. Conclusions: (18)F-FLT PET imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis.
    Circulation Research 09/2015; DOI:10.1161/CIRCRESAHA.115.307024 · 11.02 Impact Factor
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    ABSTRACT: Atherosclerotic plaques that cause stroke and myocardial infarction are characterized by increased microvascular permeability and inflammation. Dynamic contrast-enhanced MRI (DCE-MRI) has been proposed as a method to quantify vessel wall microvascular permeability in vivo. Until now, most DCE-MRI studies of atherosclerosis have been limited to two-dimensional (2D) multi-slice imaging. Although providing the high spatial resolution required to image the arterial vessel wall, these approaches do not allow the quantification of plaque permeability with extensive anatomical coverage, an essential feature when imaging heterogeneous diseases, such as atherosclerosis. To our knowledge, we present the first systematic evaluation of three-dimensional (3D), high-resolution, DCE-MRI for the extensive quantification of plaque permeability along an entire vascular bed, with validation in atherosclerotic rabbits. We compare two acquisitions: 3D turbo field echo (TFE) with motion-sensitized-driven equilibrium (MSDE) preparation and 3D turbo spin echo (TSE). We find 3D TFE DCE-MRI to be superior to 3D TSE DCE-MRI in terms of temporal stability metrics. Both sequences show good intra- and inter-observer reliability, and significant correlation with ex vivo permeability measurements by Evans Blue near-infrared fluorescence (NIRF). In addition, we explore the feasibility of using compressed sensing to accelerate 3D DCE-MRI of atherosclerosis, to improve its temporal resolution and therefore the accuracy of permeability quantification. Using retrospective under-sampling and reconstructions, we show that compressed sensing alone may allow the acceleration of 3D DCE-MRI by up to four-fold. We anticipate that the development of high-spatial-resolution 3D DCE-MRI with prospective compressed sensing acceleration may allow for the more accurate and extensive quantification of atherosclerotic plaque permeability along an entire vascular bed. We foresee that this approach may allow for the comprehensive and accurate evaluation of plaque permeability in patients, and may be a useful tool to assess the therapeutic response to approved and novel drugs for cardiovascular disease. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    NMR in Biomedicine 08/2015; 28(10):n/a-n/a. DOI:10.1002/nbm.3369 · 3.04 Impact Factor

  • Atherosclerosis 07/2015; 241(1):e87. DOI:10.1016/j.atherosclerosis.2015.04.306 · 3.99 Impact Factor
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    ABSTRACT: Tumor-associated macrophages (TAMs) are increasingly investigated in cancer immunology, and are considered a promising target for better and tailored treatment of malignant growth. Although TAMs also have high diagnostic and prognostic value, TAM imaging still remains largely unexplored. Here, we describe the development of reconstituted high-density lipoprotein (rHDL)-facilitated TAM positron emission tomography (PET) imaging in a breast cancer model. Radiolabeled rHDL nanoparticles incorporating the long-lived positron-emitting nuclide (89)Zr were developed using two different approaches. The nanoparticles were composed of phospholipids and apolipoprotein A-I (ApoA-I) in a 2.5:1 weight ratio. (89)Zr was complexed with DFO, conjugated to either a phospholipid or ApoA-I protein to generate (89)Zr-PL-HDL and (89)Zr-AI-HDL, respectively. In vivo evaluation was carried out in an orthotopic mouse model of breast cancer and included pharmacokinetic analysis, biodistribution studies, and PET imaging. Ex vivo histological analysis of tumor tissues to assess regional distribution of (89)Zr radioactivity was also performed. Fluorescent analogs of the radiolabeled agents were used to determine cell-targeting specificity using flow cytometry. The phospholipid- and apoA-I-labeled rHDL were produced at 79 ± 13 % (n = 6) and 94 ± 6 % (n = 6) radiochemical yield, respectively, with excellent radiochemical purity (> 99 %). Intravenous administration of both probes resulted in high tumor radioactivity accumulation (16.5 ± 2.8 and 8.6 ± 1.3 %ID/g for ApoA-I- and phospholipid-labeled rHDL, respectively) at 24 hours post injection. Histological analysis showed good co-localization of radioactivity with TAM-rich areas in tumor sections. Flow cytometry revealed high specificity of rHDL for TAMs, which had the highest uptake per cell (6.8-fold higher than tumor cells for both DiO@Zr-PL-HDL and DiO@Zr-AI-HDL) and accounted for 40.7 % and 39.5% of the total cellular DiO@Zr-PL-HDL and DiO@Zr-AI-HDL in tumors, respectively. We have developed (89)Zr-labeled TAM imaging agents based on the natural nanoparticle rHDL. In an orthotopic mouse model of breast cancer, we have demonstrated their specificity for macrophages, a result that was corroborated by flow cytometry. Quantitative macrophage PET imaging with our (89)Zr-rHDL imaging agents could be valuable for non-invasive monitoring of TAM immunology and targeted treatment. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Journal of Nuclear Medicine 06/2015; 56(8). DOI:10.2967/jnumed.115.158956 · 6.16 Impact Factor
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    ABSTRACT: While acute myocardial infarction mortality declines, patients continue to face reinfarction and/or heart failure. The immune system, which intimately interacts with healthy and diseased tissues through resident and recruited leukocytes, is a central interface for a global host response to ischemia. Pathways that enhance the systemic leukocyte supply may be potential therapeutic targets. Pre-clinically, imaging helps to identify immunity's decision nodes, which may serve as such targets. In translating the rapidly-expanding pre-clinical data on immune activity, the difficulty of obtaining multiple clinical tissue samples from involved organs is an obstacle that whole-body imaging can help overcome. In patients, molecular and cellular imaging can be integrated with blood-based diagnostics to assess the translatability of discoveries, including the activation of hematopoietic tissues after myocardial infarction, and serve as an endpoint in clinical trials. In this review, we discuss these concepts while focusing on imaging immune activity in organs involved in ischemic heart disease. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
    Journal of the American College of Cardiology 04/2015; 65(15):1583-1591. DOI:10.1016/j.jacc.2015.02.034 · 16.50 Impact Factor
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    ABSTRACT: Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking blood monocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Because macrophage proliferation was recently shown to dominate macrophage accumulation in advanced plaques, locally inhibiting macrophage proliferation may reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E deficient mice (Apoe(-/-) ) with advanced atherosclerotic plaques. This resulted in rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an eight-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting local macrophage proliferation can effectively treat inflammation in atherosclerosis.
    Science Advances 04/2015; 1(3):e1400223-e1400223. DOI:10.1126/sciadv.1400223
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    ABSTRACT: The present study describes the development of a good manufacturing practice (GMP)-grade liposomal nanotherapy containing prednisolone phosphate for the treatment of inflammatory diseases. After formulation design, GMP production was commenced which yielded consistent, stable liposomes sized 100 nm ± 10 nm, with a prednisolone phosphate (PLP) incorporation efficiency of 3-5%. Pharmacokinetics and toxicokinetics of GMP-grade liposomal nanoparticles were evaluated in healthy rats, which was compared to daily and weekly administration of free prednisolone phosphate, revealing a long circulatory half-life with minimal side effects. Subsequently, non-invasive multimodal clinical after liposomal nanotherapy's intravenous administration revealed anti-inflammatory effects on the vessel wall of atherosclerotic rabbits. The present program led to institutional review board approval for two clinical trials with patients with atherosclerosis. Copyright © 2015. Published by Elsevier Inc.
    Nanomedicine: nanotechnology, biology, and medicine 03/2015; 11(5). DOI:10.1016/j.nano.2015.02.020 · 6.16 Impact Factor
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    ABSTRACT: Drug delivery to atherosclerotic plaques via liposomal nanoparticles may improve therapeutic agents' risk-benefit ratios. Our paper details the first clinical studies of a liposomal nanoparticle encapsulating prednisolone (LN-PLP) in atherosclerosis. First, PLP's liposomal encapsulation improved its pharmacokinetic profile in humans (n=13) as attested by an increased plasma half-life of 63 hours (LN-PLP 1.5 mg/kg). Second, intravenously infused LN-PLP appeared in 75% of the macrophages isolated from iliofemoral plaques of patients (n=14) referred for vascular surgery in a randomized, placebo-controlled trial. LN-PLP treatment did however not reduce arterial wall permeability or inflammation in patients with atherosclerotic disease (n=30), as assessed by multimodal imaging in a subsequent randomized, placebo-controlled study. In conclusion, we successfully delivered a long-circulating nanoparticle to atherosclerotic plaque macrophages in patients, whereas prednisolone accumulation in atherosclerotic lesions had no anti-inflammatory effect. Nonetheless, the present study provides guidance for development and imaging-assisted evaluation of future nanomedicine in atherosclerosis. Copyright © 2015. Published by Elsevier Inc.
    Nanomedicine: nanotechnology, biology, and medicine 03/2015; 11(5). DOI:10.1016/j.nano.2015.02.021 · 6.16 Impact Factor
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    ABSTRACT: High-density lipoprotein (HDL) is a natural nanoparticle that exhibits an intrinsic affinity for atherosclerotic plaque macrophages. Its natural targeting capability as well as the option to incorporate lipophilic payloads, e.g., imaging or therapeutic components, in both the hydrophobic core and the phospholipid corona make the HDL platform an attractive nanocarrier. To realize controlled release properties, we developed a hybrid polymer/HDL nanoparticle comprised of a lipid/apolipoprotein coating that encapsulates a poly(lactic-co-glycolic acid) (PLGA) core. This novel HDL-like nanoparticle (PLGA-HDL) displayed natural HDL characteristics, including preferential uptake by macrophages and a good cholesterol efflux capacity, combined with a typical PLGA nanoparticle slow release profile. In vivo studies carried out with an ApoE knockout mouse model of atherosclerosis showed clear accumulation of PLGA-HDL nanoparticles in atherosclerotic plaques, which co-localized with plaque macrophages. This bio-mimetic platform integrates the targeting capacity of HDL bio-mimetic nanoparticles with the characteristic versatility of PLGA based nanocarriers.
    Bioconjugate Chemistry 02/2015; 26(3). DOI:10.1021/bc500517k · 4.51 Impact Factor
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    ABSTRACT: Atherosclerosis is a major cause of global morbidity and mortality that could benefit from novel targeted therapeutics. Recent studies have shown efficient and local drug delivery with nanoparticles, although the nanoparticle targeting mechanism for atherosclerosis has not yet been fully elucidated. Here we used in vivo and ex vivo multimodal imaging to examine permeability of the vessel wall and atherosclerotic plaque accumulation of fluorescently labeled liposomal nanoparticles in a rabbit model. We found a strong correlation between permeability as established by in vivo DCE-MRI and nanoparticle plaque accumulation with subsequent nanoparticle distribution throughout the vessel wall. These key observations will enable the development of nanotherapeutic strategies for atherosclerosis.
    ACS Nano 01/2015; 9(2). DOI:10.1021/nn506750r · 12.88 Impact Factor
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    ABSTRACT: Reverse cholesterol transport (RCT) contributes to the anti-atherogenic effects of HDL. Patients with the orphan disease familial hypoalphalipoproteinemia (FHA) are characterized by decreased tissue cholesterol removal and an increased atherogenic burden. We performed an open-label, uncontrolled proof-of-concept study to evaluate the effect of infusions with an apolipoprotein-AI containing HDL-mimetic particle (CER-001) on RCT and the arterial wall in FHA. Subjects received 20 infusions of CER-001 (8mg/kg) during 6 months. Efficacy was assessed by measuring (apo)lipoproteins, plasma-mediated cellular cholesterol efflux, fecal sterol excretion (FSE) and carotid artery wall dimension by MRI and artery wall inflammation by FDG-PET/CT scan. We included seven FHA patients (HDLc 13.8 [1.8 - 29.1] mg/dl; apoA-I 28.7 [7.9 - 59.1] mg/dl). Following 9 infusions in 1 month, apoA-I and HDL-c increased directly after infusion by 27.0 mg/dl and 16.1 mg/dl (p=0.018). CER-001 induced a 44% increase (p=0.018) in in vitro cellular cholesterol efflux with a trend towards increased FSE (p=0.068). After nine infusions of CER-001, carotid mean vessel wall area decreased compared to baseline from 25.0 to 22.8 mm2 (p=0.043) and target-to-background ratio from 2.04 to 1.81 (p=0.046). In FHA-subjects, CER-001 stimulates cholesterol mobilisation and reduces artery wall dimension and inflammation, supporting further evaluation of CER-001 in FHA patients. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    The Journal of Lipid Research 01/2015; 56(3). DOI:10.1194/jlr.M055665 · 4.42 Impact Factor
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    ABSTRACT: Background: Patients with familial hypercholesterolemia (FH) are characterized by elevated atherogenic lipoprotein particles, predominantly low-density lipoprotein cholesterol (LDL-C), which is associated with accelerated atherogenesis and increased cardiovascular risk. Objectives: This study used (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) to investigate whether arterial inflammation is higher in patients with FH and, moreover, whether lipoprotein apheresis attenuates arterial wall inflammation in FH patients. Methods: In total, 38 subjects were recruited: 24 FH patients and 14 normolipidemic controls. All subjects underwent FDG-PET imaging at baseline. Twelve FH patients who met the criteria for lipoprotein apheresis underwent apheresis procedures followed by a second FDG-PET imaging 3 days (range 1 to 4 days) after apheresis. Subsequently, the target-to-background ratio (TBR) of FDG uptake within the arterial wall was assessed. Results: In FH patients, the mean arterial TBR was higher compared with healthy controls (2.12 ± 0.27 vs. 1.92 ± 0.19; p = 0.03). A significant correlation was observed between baseline arterial TBR and LDL-C (R = 0.37; p = 0.03) that remained significant after adjusting for statin use (β = 0.001; p = 0.02) and atherosclerosis risk factors (β = 0.001; p = 0.03). LDL-C levels were significantly reduced after lipoprotein apheresis (284 ± 118 mg/dl vs. 127 ± 50 mg/dl; p < 0.001). There was a significant reduction of arterial inflammation after lipoprotein apheresis (TBR: 2.05 ± 0.31 vs. 1.91 ± 0.33; p < 0.02). Conclusions: The arterial wall of FH patients is characterized by increased inflammation, which is markedly reduced after lipoprotein apheresis. This lends support to a causal role of apoprotein B-containing lipoproteins in arterial wall inflammation and supports the concept that lipoprotein-lowering therapies may impart anti-inflammatory effects by reducing atherogenic lipoproteins.
    Journal of the American College of Cardiology 10/2014; 64(14):1418-26. DOI:10.1016/j.jacc.2014.01.088 · 16.50 Impact Factor
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    ABSTRACT: Background Understanding how leukocytes impact atherogenesis contributes critically to our concept of atherosclerosis development and the identification of potential therapeutic targets. Objectives The study evaluates an in vivo imaging approach to visualize peripheral blood mononuclear cell (PBMC) accumulation in atherosclerotic lesions of cardiovascular (CV) patients using hybrid single-photon emission computed tomography/computed tomography (SPECT/CT). Methods At baseline, CV patients and healthy controls underwent 18fluorodeoxyglucose positron emission tomography-computed tomography and magnetic resonance imaging to assess arterial wall inflammation and dimensions, respectively. For in vivo trafficking, autologous PBMCs were isolated, labeled with technetium-99m, and visualized 3, 4.5, and 6 h post-infusion with SPECT/CT. Results Ten CV patients and 5 healthy controls were included. Patients had an increased arterial wall inflammation (target-to-background ratio [TBR] right carotid 2.00 ± 0.26 in patients vs. 1.51 ± 0.12 in controls; p = 0.022) and atherosclerotic burden (normalized wall index 0.52 ± 0.09 in patients vs. 0.33 ± 0.02 in controls; p = 0.026). Elevated PBMC accumulation in the arterial wall was observed in patients; for the right carotid, the arterial-wall-to-blood ratio (ABR) 4.5 h post-infusion was 2.13 ± 0.35 in patients versus 1.49 ± 0.40 in controls (p = 0.038). In patients, the ABR correlated with the TBR of the corresponding vessel (for the right carotid: r = 0.88; p < 0.001). Conclusions PBMC accumulation is markedly enhanced in patients with advanced atherosclerotic lesions and correlates with disease severity. This study provides a noninvasive imaging tool to validate the development and implementation of interventions targeting leukocytes in atherosclerosis.
    Journal of the American College of Cardiology 09/2014; 64(10):1019–1029. DOI:10.1016/j.jacc.2014.06.1171 · 16.50 Impact Factor

  • Atherosclerosis 08/2014; 235(2):e137. DOI:10.1016/j.atherosclerosis.2014.05.383 · 3.99 Impact Factor

  • Atherosclerosis 08/2014; 235(2):e20. DOI:10.1016/j.atherosclerosis.2014.05.026 · 3.99 Impact Factor
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    ABSTRACT: Unlabelled: Advances in preclinical molecular imaging have generated new opportunities to noninvasively visualize the biodistribution and tumor targeting of nanoparticle therapeutics. Capitalizing on recent achievements in this area, we sought to develop an (89)Zr-based labeling strategy for liposomal nanoparticles that accumulate in tumors via passive targeting mechanisms. Methods: (89)Zr-labeled liposomes were prepared using 2 different approaches: click labeling and surface chelation. Pharmacokinetic and biodistribution studies, as well as PET/CT imaging of the radiolabeled nanoparticles, were performed on a mouse model of breast cancer. In addition, a dual PET/optical probe was prepared by incorporation of a near-infrared fluorophore and tested in vivo by PET and near-infrared fluorescence imaging. Results: The surface chelation approach proved to be superior in terms of radiochemical yield and stability, as well as in vivo performance. Accumulation of these liposomes in tumor peaked at 24 h after injection and was measured to be 13.7 ± 1.8 percentage injected dose per gram. The in vivo performance of this probe was not essentially perturbed by the incorporation of a near-infrared fluorophore. Conclusion: We have developed a highly modular and efficient strategy for the labeling of liposomal nanoparticles with (89)Zr. In xenograft and orthotopic mouse models of breast cancer, we demonstrated that the biodistribution of these nanoparticles can be visualized by PET imaging. In combination with a near-infrared dye, these liposomal nanoparticles can serve as bimodal PET/optical imaging agents. The liposomes target malignant growth, and their bimodal features may be useful for simultaneous PET and intraoperative imaging.
    Journal of Nuclear Medicine 07/2014; 55(10). DOI:10.2967/jnumed.114.141861 · 6.16 Impact Factor
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    Willem J M Mulder · Farouc A Jaffer · Zahi A Fayad · Matthias Nahrendorf ·
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    ABSTRACT: Bioengineering provides unique opportunities to better understand and manage atherosclerotic disease. The field is entering a new era that merges the latest biological insights into inflammatory disease processes with targeted imaging and nanomedicine. Preclinical cardiovascular molecular imaging allows the in vivo study of targeted nanotherapeutics specifically directed toward immune system components that drive atherosclerotic plaque development and complication. The first multicenter trials highlight the potential contribution of multimodality imaging to more efficient drug development. This review describes how the integration of engineering, nanotechnology, and cardiovascular immunology may yield precision diagnostics and efficient therapeutics for atherosclerosis and its ischemic complications.
    Science translational medicine 06/2014; 6(239):239sr1. DOI:10.1126/scitranslmed.3005101 · 15.84 Impact Factor
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    ABSTRACT: Lipid coated nanocrystal assemblies are among the most extensively investigated nanoparticle platforms for biomedical imaging and therapeutic purposes. However, very few efforts have been addressed to the lipid coating exchange dynamics in such systems, which is key to our understanding of the nanoparticles' coating stability and their interactions with the environment. Here, we apply the Förster resonance energy transfer (FRET) from quantum dot (QD) core to Cy5.5 dye labeled lipids at the surface to monitor the lipid exchange dynamics in situ and to study its dependence on concentration, temperature and solvent. A kinetic model is developed to describe the experimental data, allowing the rate constants and the activation energy for lipid exchange to be determined. The activation energy for lipid exchange on QD micelles is 155 kJ/mol in saline environment and 130 kJ/mol in pure water. The findings presented here provide basic knowledge on these self-assembled structures and contribute to understanding their performance and to further design of nanomedicine.
    Small 03/2014; 10(6). DOI:10.1002/smll.201301962 · 8.37 Impact Factor
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    ABSTRACT: Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.
    Nature Communications 01/2014; 5:3065. DOI:10.1038/ncomms4065 · 11.47 Impact Factor
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    ABSTRACT: Therapeutic and diagnostic nanomaterials are being intensely studied for several diseases, including cancer and atherosclerosis. However, the exact mechanism by which nanomedicines accumulate at targeted sites remains a topic of investigation, especially in the context of atherosclerotic disease. Models to accurately predict transvascular permeation of nanomedicines are needed to aid in design optimization. Here we show that an endothelialized microchip with controllable permeability can be used to probe nanoparticle translocation across an endothelial cell layer. To validate our in vitro model, we studied nanoparticle translocation in an in vivo rabbit model of atherosclerosis using a variety of preclinical and clinical imaging methods. Our results reveal that the translocation of lipid-polymer hybrid nanoparticles across the atherosclerotic endothelium is dependent on microvascular permeability. These results were mimicked with our microfluidic chip, demonstrating the potential utility of the model system.
    Proceedings of the National Academy of Sciences 01/2014; 111(3). DOI:10.1073/pnas.1322725111 · 9.67 Impact Factor

Publication Stats

5k Citations
798.40 Total Impact Points


  • 2013-2015
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands
    • Leibniz-Institut für Molekulare Pharmakologie
      Berlín, Berlin, Germany
    • Carnegie Mellon University
      • Pittsburgh NMR Center for Biomedical Research
      Pittsburgh, PA, United States
    • Massachusetts General Hospital
      • Center for Systems Biology
      Boston, MA, United States
  • 2007-2015
    • Icahn School of Medicine at Mount Sinai
      • Department of Radiology
      Borough of Manhattan, New York, United States
  • 2004-2012
    • Utrecht University
      • Centre for Biomembranes and Lipid Enzymology
      Utrecht, Utrecht, Netherlands
  • 2005-2009
    • Technische Universiteit Eindhoven
      • Department of Biomedical Engineering
      Eindhoven, North Brabant, Netherlands
  • 2004-2007
    • Delft University of Technology
      • Faculty of Applied Sciences (AS)
      Delft, South Holland, Netherlands