CC Chemokine Receptor 5 Targeted Nanoparticles Imaging the Progression and Regression of Atherosclerosis Using Positron Emission Tomography/Computed Tomography

Lisa Detering; Allison Abdilla; Hannah P. Luehmann; Jesse W. Williams; Li Hao Huang; Deborah Sultan; Andrew Elvington; Gyu Seong Heo; Pamela K. Woodard; Robert J. Gropler; Gwendalyn J. Randolph; Craig J. Hawker; Yongjian Liu

doi:10.1021/acs.molpharmaceut.0c01183

CC Chemokine Receptor 5 Targeted Nanoparticles Imaging the Progression and Regression of Atherosclerosis Using Positron Emission Tomography/Computed Tomography

Lisa Detering, Allison Abdilla, Hannah P. Luehmann, Jesse W. Williams, Li Hao Huang, Deborah Sultan, Andrew Elvington, Gyu Seong Heo, Pamela K. Woodard, Robert J. Gropler, Gwendalyn J. Randolph, Craig J. Hawker, Yongjian Liu

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Chemokines and chemokine receptors play an important role in the initiation and progression of atherosclerosis by mediating the trafficking of inflammatory cells. Chemokine receptor 5 (CCR5) has major implications in promoting the development of plaques to advanced stage and related vulnerability. CCR5 antagonist has demonstrated the effective inhibition of atherosclerotic progression in mice, making it a potential biomarker for atherosclerosis management. To accurately determine CCR5 in vivo, we synthesized CCR5 targeted Comb nanoparticles through a modular design and construction strategy with control over the physiochemical properties and functionalization of CCR5 targeting peptide d-Ala-peptide T-amide (DAPTA-Comb). In vivo pharmacokinetic evaluation through 64Cu radiolabeling showed extended blood circulation of 64Cu-DAPTA-Combs conjugated with 10%, 25%, and 40% DAPTA. The different organ distribution profiles of the three nanoparticles demonstrated the effect of DAPTA on not only physicochemical properties but also targeting efficiency. In vivo positron emission tomography/computed tomography (PET/CT) imaging in an apolipoprotein E knockout mouse atherosclerosis model (ApoE-/-) showed that the three 64Cu-DAPTA-Combs could sensitively and specifically detect CCR5 along the progression of atherosclerotic lesions. In an ApoE-encoding adenoviral vector (AAV) induced plaque regression ApoE-/- mouse model, decreased monocyte recruitment, CD68+ macrophages, CCR5 expression, and plaque size were all associated with reduced PET signals, which not only further confirmed the targeting efficiency of 64Cu-DAPTA-Combs but also highlighted the potential of these targeted nanoparticles for atherosclerosis imaging. Moreover, the up-regulation of CCR5 and colocalization with CD68+ macrophages in the necrotic core of ex vivo human plaque specimens warrant further investigation for atherosclerosis prognosis.

Original language	English (US)
Pages (from-to)	1386-1396
Number of pages	11
Journal	Molecular pharmaceutics
Volume	18
Issue number	3
DOIs	https://doi.org/10.1021/acs.molpharmaceut.0c01183
State	Published - Mar 1 2021
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by Grants 1R35HL145212 and R01HL138163 from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The characterization of nanoparticles was performed in the Shared Facilities of the National Science Foundation (NSF) Materials Research and Engineering Center at UC Santa Barbara, Grant DMR-1720256. We thank Nicole Fettig, Margaret Morris, Amanda Klaas, and Lori Strong for their assistance with the biodistribution and imaging studies in animals, Alaina McGrath for synthesis help, and Thomas Voller, Evelyn Madrid, and Paul Eisenbeis for Cu production. 64

Publisher Copyright:
© 2021 American Chemical Society.

Keywords

CCR5
atherosclerosis
macrophage
nanoparticle
positron emission tomography

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acs.molpharmaceut.0c01183

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Detering, L., Abdilla, A., Luehmann, H. P., Williams, J. W., Huang, L. H., Sultan, D., Elvington, A., Heo, G. S., Woodard, P. K., Gropler, R. J., Randolph, G. J., Hawker, C. J., & Liu, Y. (2021). CC Chemokine Receptor 5 Targeted Nanoparticles Imaging the Progression and Regression of Atherosclerosis Using Positron Emission Tomography/Computed Tomography. Molecular pharmaceutics, 18(3), 1386-1396. https://doi.org/10.1021/acs.molpharmaceut.0c01183

Detering, L, Abdilla, A, Luehmann, HP, Williams, JW, Huang, LH, Sultan, D, Elvington, A, Heo, GS, Woodard, PK, Gropler, RJ, Randolph, GJ, Hawker, CJ & Liu, Y 2021, 'CC Chemokine Receptor 5 Targeted Nanoparticles Imaging the Progression and Regression of Atherosclerosis Using Positron Emission Tomography/Computed Tomography', Molecular pharmaceutics, vol. 18, no. 3, pp. 1386-1396. https://doi.org/10.1021/acs.molpharmaceut.0c01183

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title = "CC Chemokine Receptor 5 Targeted Nanoparticles Imaging the Progression and Regression of Atherosclerosis Using Positron Emission Tomography/Computed Tomography",

abstract = "Chemokines and chemokine receptors play an important role in the initiation and progression of atherosclerosis by mediating the trafficking of inflammatory cells. Chemokine receptor 5 (CCR5) has major implications in promoting the development of plaques to advanced stage and related vulnerability. CCR5 antagonist has demonstrated the effective inhibition of atherosclerotic progression in mice, making it a potential biomarker for atherosclerosis management. To accurately determine CCR5 in vivo, we synthesized CCR5 targeted Comb nanoparticles through a modular design and construction strategy with control over the physiochemical properties and functionalization of CCR5 targeting peptide d-Ala-peptide T-amide (DAPTA-Comb). In vivo pharmacokinetic evaluation through 64Cu radiolabeling showed extended blood circulation of 64Cu-DAPTA-Combs conjugated with 10%, 25%, and 40% DAPTA. The different organ distribution profiles of the three nanoparticles demonstrated the effect of DAPTA on not only physicochemical properties but also targeting efficiency. In vivo positron emission tomography/computed tomography (PET/CT) imaging in an apolipoprotein E knockout mouse atherosclerosis model (ApoE-/-) showed that the three 64Cu-DAPTA-Combs could sensitively and specifically detect CCR5 along the progression of atherosclerotic lesions. In an ApoE-encoding adenoviral vector (AAV) induced plaque regression ApoE-/- mouse model, decreased monocyte recruitment, CD68+ macrophages, CCR5 expression, and plaque size were all associated with reduced PET signals, which not only further confirmed the targeting efficiency of 64Cu-DAPTA-Combs but also highlighted the potential of these targeted nanoparticles for atherosclerosis imaging. Moreover, the up-regulation of CCR5 and colocalization with CD68+ macrophages in the necrotic core of ex vivo human plaque specimens warrant further investigation for atherosclerosis prognosis.",

keywords = "CCR5, atherosclerosis, macrophage, nanoparticle, positron emission tomography",

author = "Lisa Detering and Allison Abdilla and Luehmann, {Hannah P.} and Williams, {Jesse W.} and Huang, {Li Hao} and Deborah Sultan and Andrew Elvington and Heo, {Gyu Seong} and Woodard, {Pamela K.} and Gropler, {Robert J.} and Randolph, {Gwendalyn J.} and Hawker, {Craig J.} and Yongjian Liu",

note = "Funding Information: This work was supported by Grants 1R35HL145212 and R01HL138163 from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The characterization of nanoparticles was performed in the Shared Facilities of the National Science Foundation (NSF) Materials Research and Engineering Center at UC Santa Barbara, Grant DMR-1720256. We thank Nicole Fettig, Margaret Morris, Amanda Klaas, and Lori Strong for their assistance with the biodistribution and imaging studies in animals, Alaina McGrath for synthesis help, and Thomas Voller, Evelyn Madrid, and Paul Eisenbeis for Cu production. 64 Publisher Copyright: {\textcopyright} 2021 American Chemical Society.",

year = "2021",

month = mar,

day = "1",

doi = "10.1021/acs.molpharmaceut.0c01183",

language = "English (US)",

volume = "18",

pages = "1386--1396",

journal = "Molecular pharmaceutics",

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AU - Detering, Lisa

AU - Abdilla, Allison

AU - Luehmann, Hannah P.

AU - Williams, Jesse W.

AU - Huang, Li Hao

AU - Sultan, Deborah

AU - Elvington, Andrew

AU - Heo, Gyu Seong

AU - Woodard, Pamela K.

AU - Gropler, Robert J.

AU - Randolph, Gwendalyn J.

AU - Hawker, Craig J.

AU - Liu, Yongjian

N1 - Funding Information: This work was supported by Grants 1R35HL145212 and R01HL138163 from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The characterization of nanoparticles was performed in the Shared Facilities of the National Science Foundation (NSF) Materials Research and Engineering Center at UC Santa Barbara, Grant DMR-1720256. We thank Nicole Fettig, Margaret Morris, Amanda Klaas, and Lori Strong for their assistance with the biodistribution and imaging studies in animals, Alaina McGrath for synthesis help, and Thomas Voller, Evelyn Madrid, and Paul Eisenbeis for Cu production. 64 Publisher Copyright: © 2021 American Chemical Society.

PY - 2021/3/1

Y1 - 2021/3/1

N2 - Chemokines and chemokine receptors play an important role in the initiation and progression of atherosclerosis by mediating the trafficking of inflammatory cells. Chemokine receptor 5 (CCR5) has major implications in promoting the development of plaques to advanced stage and related vulnerability. CCR5 antagonist has demonstrated the effective inhibition of atherosclerotic progression in mice, making it a potential biomarker for atherosclerosis management. To accurately determine CCR5 in vivo, we synthesized CCR5 targeted Comb nanoparticles through a modular design and construction strategy with control over the physiochemical properties and functionalization of CCR5 targeting peptide d-Ala-peptide T-amide (DAPTA-Comb). In vivo pharmacokinetic evaluation through 64Cu radiolabeling showed extended blood circulation of 64Cu-DAPTA-Combs conjugated with 10%, 25%, and 40% DAPTA. The different organ distribution profiles of the three nanoparticles demonstrated the effect of DAPTA on not only physicochemical properties but also targeting efficiency. In vivo positron emission tomography/computed tomography (PET/CT) imaging in an apolipoprotein E knockout mouse atherosclerosis model (ApoE-/-) showed that the three 64Cu-DAPTA-Combs could sensitively and specifically detect CCR5 along the progression of atherosclerotic lesions. In an ApoE-encoding adenoviral vector (AAV) induced plaque regression ApoE-/- mouse model, decreased monocyte recruitment, CD68+ macrophages, CCR5 expression, and plaque size were all associated with reduced PET signals, which not only further confirmed the targeting efficiency of 64Cu-DAPTA-Combs but also highlighted the potential of these targeted nanoparticles for atherosclerosis imaging. Moreover, the up-regulation of CCR5 and colocalization with CD68+ macrophages in the necrotic core of ex vivo human plaque specimens warrant further investigation for atherosclerosis prognosis.

AB - Chemokines and chemokine receptors play an important role in the initiation and progression of atherosclerosis by mediating the trafficking of inflammatory cells. Chemokine receptor 5 (CCR5) has major implications in promoting the development of plaques to advanced stage and related vulnerability. CCR5 antagonist has demonstrated the effective inhibition of atherosclerotic progression in mice, making it a potential biomarker for atherosclerosis management. To accurately determine CCR5 in vivo, we synthesized CCR5 targeted Comb nanoparticles through a modular design and construction strategy with control over the physiochemical properties and functionalization of CCR5 targeting peptide d-Ala-peptide T-amide (DAPTA-Comb). In vivo pharmacokinetic evaluation through 64Cu radiolabeling showed extended blood circulation of 64Cu-DAPTA-Combs conjugated with 10%, 25%, and 40% DAPTA. The different organ distribution profiles of the three nanoparticles demonstrated the effect of DAPTA on not only physicochemical properties but also targeting efficiency. In vivo positron emission tomography/computed tomography (PET/CT) imaging in an apolipoprotein E knockout mouse atherosclerosis model (ApoE-/-) showed that the three 64Cu-DAPTA-Combs could sensitively and specifically detect CCR5 along the progression of atherosclerotic lesions. In an ApoE-encoding adenoviral vector (AAV) induced plaque regression ApoE-/- mouse model, decreased monocyte recruitment, CD68+ macrophages, CCR5 expression, and plaque size were all associated with reduced PET signals, which not only further confirmed the targeting efficiency of 64Cu-DAPTA-Combs but also highlighted the potential of these targeted nanoparticles for atherosclerosis imaging. Moreover, the up-regulation of CCR5 and colocalization with CD68+ macrophages in the necrotic core of ex vivo human plaque specimens warrant further investigation for atherosclerosis prognosis.

KW - CCR5

KW - atherosclerosis

KW - macrophage

KW - nanoparticle

KW - positron emission tomography

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CC Chemokine Receptor 5 Targeted Nanoparticles Imaging the Progression and Regression of Atherosclerosis Using Positron Emission Tomography/Computed Tomography

Abstract

Bibliographical note

Keywords

UN SDGs

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