In Vivo PET Imaging of HDL in Multiple Atherosclerosis Models

Carlos Pérez-Medina; Tina Binderup; Mark E Lobatto; Jun Tang; Claudia Calcagno; Luuk Giesen; Chang Ho Wessel; Julia Witjes; Seigo Ishino; Samantha Baxter; Yiming Zhao; Sarayu Ramachandran; Mootaz Eldib; Brenda L Sánchez-Gaytán; Philip M Robson; Jason Bini; Juan F Granada; Kenneth M Fish; Erik S G Stroes; Raphaël Duivenvoorden; Sotirios Tsimikas; Jason S Lewis; Thomas Reiner; Valentín Fuster; Andreas Kjær; Edward A Fisher; Zahi A Fayad; Willem J M Mulder

doi:10.1016/j.jcmg.2016.01.020

In Vivo PET Imaging of HDL in Multiple Atherosclerosis Models

Carlos Pérez-Medina, Tina Binderup, Mark E Lobatto, Jun Tang, Claudia Calcagno, Luuk Giesen, Chang Ho Wessel, Julia Witjes, Seigo Ishino, Samantha Baxter, Yiming Zhao, Sarayu Ramachandran, Mootaz Eldib, Brenda L Sánchez-Gaytán, Philip M Robson, Jason Bini, Juan F Granada, Kenneth M Fish, Erik S G Stroes, Raphaël DuivenvoordenSotirios Tsimikas, Jason S Lewis, Thomas Reiner, Valentín Fuster, Andreas Kjær, Edward A Fisher, Zahi A Fayad, Willem J M Mulder

54 Citationer (Scopus)

Abstract

OBJECTIVES: The goal of this study was to develop and validate a noninvasive imaging tool to visualize the in vivo behavior of high-density lipoprotein (HDL) by using positron emission tomography (PET), with an emphasis on its plaque-targeting abilities.

BACKGROUND: HDL is a natural nanoparticle that interacts with atherosclerotic plaque macrophages to facilitate reverse cholesterol transport. HDL-cholesterol concentration in blood is inversely associated with risk of coronary heart disease and remains one of the strongest independent predictors of incident cardiovascular events.

METHODS: Discoidal HDL nanoparticles were prepared by reconstitution of its components apolipoprotein A-I (apo A-I) and the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine. For radiolabeling with zirconium-89 ((89)Zr), the chelator deferoxamine B was introduced by conjugation to apo A-I or as a phospholipid-chelator (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-deferoxamine B). Biodistribution and plaque targeting of radiolabeled HDL were studied in established murine, rabbit, and porcine atherosclerosis models by using PET combined with computed tomography (PET/CT) imaging or PET combined with magnetic resonance imaging. Ex vivo validation was conducted by radioactivity counting, autoradiography, and near-infrared fluorescence imaging. Flow cytometric assessment of cellular specificity in different tissues was performed in the murine model.

RESULTS: We observed distinct pharmacokinetic profiles for the two (89)Zr-HDL nanoparticles. Both apo A-I- and phospholipid-labeled HDL mainly accumulated in the kidneys, liver, and spleen, with some marked quantitative differences in radioactivity uptake values. Radioactivity concentrations in rabbit atherosclerotic aortas were 3- to 4-fold higher than in control animals at 5 days' post-injection for both (89)Zr-HDL nanoparticles. In the porcine model, increased accumulation of radioactivity was observed in lesions by using in vivo PET imaging. Irrespective of the radiolabel's location, HDL nanoparticles were able to preferentially target plaque macrophages and monocytes.

CONCLUSIONS: (89)Zr labeling of HDL allows study of its in vivo behavior by using noninvasive PET imaging, including visualization of its accumulation in advanced atherosclerotic lesions. The different labeling strategies provide insight on the pharmacokinetics and biodistribution of HDL's main components (i.e., phospholipids, apo A-I).

Originalsprog	Engelsk
Tidsskrift	J A C C: Cardiovascular Imaging
Vol/bind	9
Udgave nummer	8
Sider (fra-til)	950-961
Antal sider	12
ISSN	1936-878X
DOI	https://doi.org/10.1016/j.jcmg.2016.01.020
Status	Udgivet - 1 aug. 2016

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10.1016/j.jcmg.2016.01.020

Citationsformater

Pérez-Medina, C., Binderup, T., Lobatto, M. E., Tang, J., Calcagno, C., Giesen, L., Wessel, C. H., Witjes, J., Ishino, S., Baxter, S., Zhao, Y., Ramachandran, S., Eldib, M., Sánchez-Gaytán, B. L., Robson, P. M., Bini, J., Granada, J. F., Fish, K. M., Stroes, E. S. G., ... Mulder, W. J. M. (2016). In Vivo PET Imaging of HDL in Multiple Atherosclerosis Models. J A C C: Cardiovascular Imaging, 9(8), 950-961. https://doi.org/10.1016/j.jcmg.2016.01.020

Pérez-Medina, C, Binderup, T, Lobatto, ME, Tang, J, Calcagno, C, Giesen, L, Wessel, CH, Witjes, J, Ishino, S, Baxter, S, Zhao, Y, Ramachandran, S, Eldib, M, Sánchez-Gaytán, BL, Robson, PM, Bini, J, Granada, JF, Fish, KM, Stroes, ESG, Duivenvoorden, R, Tsimikas, S, Lewis, JS, Reiner, T, Fuster, V, Kjær, A, Fisher, EA, Fayad, ZA & Mulder, WJM 2016, 'In Vivo PET Imaging of HDL in Multiple Atherosclerosis Models', J A C C: Cardiovascular Imaging, bind 9, nr. 8, s. 950-961. https://doi.org/10.1016/j.jcmg.2016.01.020

@article{7647387b7d2a4c0fa99f78c2dc693d1b,

title = "In Vivo PET Imaging of HDL in Multiple Atherosclerosis Models",

abstract = "OBJECTIVES: The goal of this study was to develop and validate a noninvasive imaging tool to visualize the in vivo behavior of high-density lipoprotein (HDL) by using positron emission tomography (PET), with an emphasis on its plaque-targeting abilities.BACKGROUND: HDL is a natural nanoparticle that interacts with atherosclerotic plaque macrophages to facilitate reverse cholesterol transport. HDL-cholesterol concentration in blood is inversely associated with risk of coronary heart disease and remains one of the strongest independent predictors of incident cardiovascular events.METHODS: Discoidal HDL nanoparticles were prepared by reconstitution of its components apolipoprotein A-I (apo A-I) and the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine. For radiolabeling with zirconium-89 ((89)Zr), the chelator deferoxamine B was introduced by conjugation to apo A-I or as a phospholipid-chelator (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-deferoxamine B). Biodistribution and plaque targeting of radiolabeled HDL were studied in established murine, rabbit, and porcine atherosclerosis models by using PET combined with computed tomography (PET/CT) imaging or PET combined with magnetic resonance imaging. Ex vivo validation was conducted by radioactivity counting, autoradiography, and near-infrared fluorescence imaging. Flow cytometric assessment of cellular specificity in different tissues was performed in the murine model.RESULTS: We observed distinct pharmacokinetic profiles for the two (89)Zr-HDL nanoparticles. Both apo A-I- and phospholipid-labeled HDL mainly accumulated in the kidneys, liver, and spleen, with some marked quantitative differences in radioactivity uptake values. Radioactivity concentrations in rabbit atherosclerotic aortas were 3- to 4-fold higher than in control animals at 5 days' post-injection for both (89)Zr-HDL nanoparticles. In the porcine model, increased accumulation of radioactivity was observed in lesions by using in vivo PET imaging. Irrespective of the radiolabel's location, HDL nanoparticles were able to preferentially target plaque macrophages and monocytes.CONCLUSIONS: (89)Zr labeling of HDL allows study of its in vivo behavior by using noninvasive PET imaging, including visualization of its accumulation in advanced atherosclerotic lesions. The different labeling strategies provide insight on the pharmacokinetics and biodistribution of HDL's main components (i.e., phospholipids, apo A-I).",

author = "Carlos P{\'e}rez-Medina and Tina Binderup and Lobatto, {Mark E} and Jun Tang and Claudia Calcagno and Luuk Giesen and Wessel, {Chang Ho} and Julia Witjes and Seigo Ishino and Samantha Baxter and Yiming Zhao and Sarayu Ramachandran and Mootaz Eldib and S{\'a}nchez-Gayt{\'a}n, {Brenda L} and Robson, {Philip M} and Jason Bini and Granada, {Juan F} and Fish, {Kenneth M} and Stroes, {Erik S G} and Rapha{\"e}l Duivenvoorden and Sotirios Tsimikas and Lewis, {Jason S} and Thomas Reiner and Valent{\'i}n Fuster and Andreas Kj{\ae}r and Fisher, {Edward A} and Fayad, {Zahi A} and Mulder, {Willem J M}",

year = "2016",

month = aug,

day = "1",

doi = "10.1016/j.jcmg.2016.01.020",

language = "English",

volume = "9",

pages = "950--961",

journal = "J A C C: Cardiovascular Imaging",

issn = "1936-878X",

publisher = "Elsevier",

number = "8",

}

TY - JOUR

T1 - In Vivo PET Imaging of HDL in Multiple Atherosclerosis Models

AU - Pérez-Medina, Carlos

AU - Binderup, Tina

AU - Lobatto, Mark E

AU - Tang, Jun

AU - Calcagno, Claudia

AU - Giesen, Luuk

AU - Wessel, Chang Ho

AU - Witjes, Julia

AU - Ishino, Seigo

AU - Baxter, Samantha

AU - Zhao, Yiming

AU - Ramachandran, Sarayu

AU - Eldib, Mootaz

AU - Sánchez-Gaytán, Brenda L

AU - Robson, Philip M

AU - Bini, Jason

AU - Granada, Juan F

AU - Fish, Kenneth M

AU - Stroes, Erik S G

AU - Duivenvoorden, Raphaël

AU - Tsimikas, Sotirios

AU - Lewis, Jason S

AU - Reiner, Thomas

AU - Fuster, Valentín

AU - Kjær, Andreas

AU - Fisher, Edward A

AU - Fayad, Zahi A

AU - Mulder, Willem J M

PY - 2016/8/1

Y1 - 2016/8/1

N2 - OBJECTIVES: The goal of this study was to develop and validate a noninvasive imaging tool to visualize the in vivo behavior of high-density lipoprotein (HDL) by using positron emission tomography (PET), with an emphasis on its plaque-targeting abilities.BACKGROUND: HDL is a natural nanoparticle that interacts with atherosclerotic plaque macrophages to facilitate reverse cholesterol transport. HDL-cholesterol concentration in blood is inversely associated with risk of coronary heart disease and remains one of the strongest independent predictors of incident cardiovascular events.METHODS: Discoidal HDL nanoparticles were prepared by reconstitution of its components apolipoprotein A-I (apo A-I) and the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine. For radiolabeling with zirconium-89 ((89)Zr), the chelator deferoxamine B was introduced by conjugation to apo A-I or as a phospholipid-chelator (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-deferoxamine B). Biodistribution and plaque targeting of radiolabeled HDL were studied in established murine, rabbit, and porcine atherosclerosis models by using PET combined with computed tomography (PET/CT) imaging or PET combined with magnetic resonance imaging. Ex vivo validation was conducted by radioactivity counting, autoradiography, and near-infrared fluorescence imaging. Flow cytometric assessment of cellular specificity in different tissues was performed in the murine model.RESULTS: We observed distinct pharmacokinetic profiles for the two (89)Zr-HDL nanoparticles. Both apo A-I- and phospholipid-labeled HDL mainly accumulated in the kidneys, liver, and spleen, with some marked quantitative differences in radioactivity uptake values. Radioactivity concentrations in rabbit atherosclerotic aortas were 3- to 4-fold higher than in control animals at 5 days' post-injection for both (89)Zr-HDL nanoparticles. In the porcine model, increased accumulation of radioactivity was observed in lesions by using in vivo PET imaging. Irrespective of the radiolabel's location, HDL nanoparticles were able to preferentially target plaque macrophages and monocytes.CONCLUSIONS: (89)Zr labeling of HDL allows study of its in vivo behavior by using noninvasive PET imaging, including visualization of its accumulation in advanced atherosclerotic lesions. The different labeling strategies provide insight on the pharmacokinetics and biodistribution of HDL's main components (i.e., phospholipids, apo A-I).

AB - OBJECTIVES: The goal of this study was to develop and validate a noninvasive imaging tool to visualize the in vivo behavior of high-density lipoprotein (HDL) by using positron emission tomography (PET), with an emphasis on its plaque-targeting abilities.BACKGROUND: HDL is a natural nanoparticle that interacts with atherosclerotic plaque macrophages to facilitate reverse cholesterol transport. HDL-cholesterol concentration in blood is inversely associated with risk of coronary heart disease and remains one of the strongest independent predictors of incident cardiovascular events.METHODS: Discoidal HDL nanoparticles were prepared by reconstitution of its components apolipoprotein A-I (apo A-I) and the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine. For radiolabeling with zirconium-89 ((89)Zr), the chelator deferoxamine B was introduced by conjugation to apo A-I or as a phospholipid-chelator (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-deferoxamine B). Biodistribution and plaque targeting of radiolabeled HDL were studied in established murine, rabbit, and porcine atherosclerosis models by using PET combined with computed tomography (PET/CT) imaging or PET combined with magnetic resonance imaging. Ex vivo validation was conducted by radioactivity counting, autoradiography, and near-infrared fluorescence imaging. Flow cytometric assessment of cellular specificity in different tissues was performed in the murine model.RESULTS: We observed distinct pharmacokinetic profiles for the two (89)Zr-HDL nanoparticles. Both apo A-I- and phospholipid-labeled HDL mainly accumulated in the kidneys, liver, and spleen, with some marked quantitative differences in radioactivity uptake values. Radioactivity concentrations in rabbit atherosclerotic aortas were 3- to 4-fold higher than in control animals at 5 days' post-injection for both (89)Zr-HDL nanoparticles. In the porcine model, increased accumulation of radioactivity was observed in lesions by using in vivo PET imaging. Irrespective of the radiolabel's location, HDL nanoparticles were able to preferentially target plaque macrophages and monocytes.CONCLUSIONS: (89)Zr labeling of HDL allows study of its in vivo behavior by using noninvasive PET imaging, including visualization of its accumulation in advanced atherosclerotic lesions. The different labeling strategies provide insight on the pharmacokinetics and biodistribution of HDL's main components (i.e., phospholipids, apo A-I).

U2 - 10.1016/j.jcmg.2016.01.020

DO - 10.1016/j.jcmg.2016.01.020

M3 - Journal article

C2 - 27236528

SN - 1936-878X

VL - 9

SP - 950

EP - 961

JO - J A C C: Cardiovascular Imaging

JF - J A C C: Cardiovascular Imaging

IS - 8

ER -

In Vivo PET Imaging of HDL in Multiple Atherosclerosis Models

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