A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation

Raphaël Duivenvoorden; Jun Tang; David P. Cormode; Aneta J. Mieszawska; David Izquierdo-Garcia; Canturk Ozcan; Maarten J. Otten; Neeha Zaidi; Mark E. Lobatto; Sarian M. Van Rijs; Bram Priem; Emma L. Kuan; Catherine Martel; Bernd Hewing; Hendrik Sager; Matthias Nahrendorf; Gwendalyn J. Randolph; Erik S.G. Stroes; Valentin Fuster; Edward A. Fisher; Zahi A. Fayad; Willem J.M. Mulder

doi:10.1038/ncomms4065

A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation

Raphaël Duivenvoorden, Jun Tang, David P. Cormode, Aneta J. Mieszawska, David Izquierdo-Garcia, Canturk Ozcan, Maarten J. Otten, Neeha Zaidi, Mark E. Lobatto, Sarian M. Van Rijs, Bram Priem, Emma L. Kuan, Catherine Martel, Bernd Hewing, Hendrik Sager, Matthias Nahrendorf, Gwendalyn J. Randolph, Erik S.G. Stroes, Valentin Fuster, Edward A. FisherZahi A. Fayad, Willem J.M. Mulder

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366 Scopus citations

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.

Original language	English
Article number	3065
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms4065
State	Published - 2014

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Duivenvoorden, R., Tang, J., Cormode, D. P., Mieszawska, A. J., Izquierdo-Garcia, D., Ozcan, C., Otten, M. J., Zaidi, N., Lobatto, M. E., Van Rijs, S. M., Priem, B., Kuan, E. L., Martel, C., Hewing, B., Sager, H., Nahrendorf, M., Randolph, G. J., Stroes, E. S. G., Fuster, V., ... Mulder, W. J. M. (2014). A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation. Nature communications, 5, Article 3065. https://doi.org/10.1038/ncomms4065

@article{1d5dc4a23e4242e993e3659351dd18db,

title = "A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation",

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.",

author = "Rapha{\"e}l Duivenvoorden and Jun Tang and Cormode, {David P.} and Mieszawska, {Aneta J.} and David Izquierdo-Garcia and Canturk Ozcan and Otten, {Maarten J.} and Neeha Zaidi and Lobatto, {Mark E.} and {Van Rijs}, {Sarian M.} and Bram Priem and Kuan, {Emma L.} and Catherine Martel and Bernd Hewing and Hendrik Sager and Matthias Nahrendorf and Randolph, {Gwendalyn J.} and Stroes, {Erik S.G.} and Valentin Fuster and Fisher, {Edward A.} and Fayad, {Zahi A.} and Mulder, {Willem J.M.}",

note = "Funding Information: We would like to thank S. Russell for helping with the FPLC experiments and Wei Chen for his contribution to the flow cytometry experiments. R. Nolasco is gratefully acknowledged for his help in cryosectioning the aorta specimens and CSL (Parkville, Australia) for their kind gift of ApoAI. This work was supported by the NHLBI, NIH, as a Program of Excellence in Nanotechnology (PEN) Award, Contract number HHSN268201000045C as well as the NIH grants R01 EB009638 (Z.A.F.), K99 EB012165 (D.P.C.), R01 CA155432 (W.J.M.M.), P01HL098055 (E.A.F.), R01HL084312 (E.A.F.) and the NWO grant ZonMW Vidi 91713324 (W.J.M.M.). Additional support was provided by the American Heart Association Award number 13PRE14350020-Founders (J.T.), the Deutsche Forschungsgemeinschaft number SA 1668/2-1 (H.S.), the German Research Foundation DFG number HE 6092/1-1 (B.H.) as well as by the International Atherosclerosis Society and by the Foundation {\textquoteleft}De Drie Lichten{\textquoteright} in The Netherlands (M.E.L). Flow cytometry was performed at the MSSM-Flow Cytometry Shared Resource Facility and RT–PCR at the Quantitative PCR Shared Resource Facility. Fluorescence microscopy was performed at the MSSM-Microscopy Shared Resource Facility, supported with funding from NIH-NCI shared resources grant (5R24 CA095823-04), NSF Major Research Instrumentation grant (DBI-9724504) and NIH shared instrumentation grant (1 S10 RR0 9145-01).",

year = "2014",

doi = "10.1038/ncomms4065",

language = "English",

volume = "5",

journal = "Nature communications",

issn = "2041-1723",

}

Duivenvoorden, R, Tang, J, Cormode, DP, Mieszawska, AJ, Izquierdo-Garcia, D, Ozcan, C, Otten, MJ, Zaidi, N, Lobatto, ME, Van Rijs, SM, Priem, B, Kuan, EL, Martel, C, Hewing, B, Sager, H, Nahrendorf, M, Randolph, GJ, Stroes, ESG, Fuster, V, Fisher, EA, Fayad, ZA & Mulder, WJM 2014, 'A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation', Nature communications, vol. 5, 3065. https://doi.org/10.1038/ncomms4065

TY - JOUR

T1 - A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation

AU - Duivenvoorden, Raphaël

AU - Tang, Jun

AU - Cormode, David P.

AU - Mieszawska, Aneta J.

AU - Izquierdo-Garcia, David

AU - Ozcan, Canturk

AU - Otten, Maarten J.

AU - Zaidi, Neeha

AU - Lobatto, Mark E.

AU - Van Rijs, Sarian M.

AU - Priem, Bram

AU - Kuan, Emma L.

AU - Martel, Catherine

AU - Hewing, Bernd

AU - Sager, Hendrik

AU - Nahrendorf, Matthias

AU - Randolph, Gwendalyn J.

AU - Stroes, Erik S.G.

AU - Fuster, Valentin

AU - Fisher, Edward A.

AU - Fayad, Zahi A.

AU - Mulder, Willem J.M.

N1 - Funding Information: We would like to thank S. Russell for helping with the FPLC experiments and Wei Chen for his contribution to the flow cytometry experiments. R. Nolasco is gratefully acknowledged for his help in cryosectioning the aorta specimens and CSL (Parkville, Australia) for their kind gift of ApoAI. This work was supported by the NHLBI, NIH, as a Program of Excellence in Nanotechnology (PEN) Award, Contract number HHSN268201000045C as well as the NIH grants R01 EB009638 (Z.A.F.), K99 EB012165 (D.P.C.), R01 CA155432 (W.J.M.M.), P01HL098055 (E.A.F.), R01HL084312 (E.A.F.) and the NWO grant ZonMW Vidi 91713324 (W.J.M.M.). Additional support was provided by the American Heart Association Award number 13PRE14350020-Founders (J.T.), the Deutsche Forschungsgemeinschaft number SA 1668/2-1 (H.S.), the German Research Foundation DFG number HE 6092/1-1 (B.H.) as well as by the International Atherosclerosis Society and by the Foundation ‘De Drie Lichten’ in The Netherlands (M.E.L). Flow cytometry was performed at the MSSM-Flow Cytometry Shared Resource Facility and RT–PCR at the Quantitative PCR Shared Resource Facility. Fluorescence microscopy was performed at the MSSM-Microscopy Shared Resource Facility, supported with funding from NIH-NCI shared resources grant (5R24 CA095823-04), NSF Major Research Instrumentation grant (DBI-9724504) and NIH shared instrumentation grant (1 S10 RR0 9145-01).

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84892865604&partnerID=8YFLogxK

U2 - 10.1038/ncomms4065

DO - 10.1038/ncomms4065

M3 - Article

C2 - 24445279

AN - SCOPUS:84892865604

SN - 2041-1723

VL - 5

JO - Nature communications

JF - Nature communications

M1 - 3065

ER -

A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation

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