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Design and Modular Construction of a Polymeric Nanoparticle for Targeted Atherosclerosis Positron Emission Tomography Imaging: A Story of 25% 64Cu-CANF-Comb

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ABSTRACT

Purpose

To assess the physicochemical properties, pharmacokinetic profiles, and in vivo positron emission tomography (PET) imaging of natriuretic peptide clearance receptors (NPRC) expressed on atherosclerotic plaque of a series of targeted, polymeric nanoparticles.

Methods

To control their structure, non-targeted and targeted polymeric (comb) nanoparticles, conjugated with various amounts of c-atrial natriuretic peptide (CANF, 0, 5, 10 and 25%), were synthesized by controlled and modular chemistry. In vivo pharmacokinetic evaluation of these nanoparticles was performed in wildtype (WT) C57BL/6 mice after 64Cu radiolabeling. PET imaging was performed on an apolipoprotein E–deficient (ApoE−/−) mouse atherosclerosis model to assess the NPRC targeting efficiency. For comparison, an in vivo blood metabolism study was carried out in WT mice.

Results

All three 64Cu-CANF-comb nanoparticles showed improved biodistribution profiles, including significantly reduced accumulation in both liver and spleen, compared to the non-targeted 64Cu-comb. Of the three nanoparticles, the 25% 64Cu-CANF-comb demonstrated the best NPRC targeting specificity and sensitivity in ApoE−/− mice. Metabolism studies showed that the radiolabeled CANF-comb was stable in blood up to 9 days. Histopathological analyses confirmed the up-regulation of NPRC along the progression of atherosclerosis.

Conclusion

The 25% 64Cu-CANF-comb demonstrated its potential as a PET imaging agent to detect atherosclerosis progression and status.

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Abbreviations

%ID/g:

Percent injected dose per gram of tissue

%ID/organ:

Percent injected dose per organ of tissue

°C:

Degree celsius

AIBN:

Azobisisobutyronitrile

ApoE−/− :

Apolipoprotein E-deficient

CANF:

C-type atrial natriuretic factor

DLS:

Dynamic light scattering

DMF:

N, N-Dimethylformamide

DOTA:

1,4,7,10-tetraazacyclododecane-1,4,7-tris(t-butyl acetate)

EDTA:

Ethylenediaminetetraacetic acid

F-FDG:

2-deoxy-2-[18F]-fluoro-D-glucose

FIG:

Figure

FPLC:

Fast performance liquid chromatography

GPC:

Gel permeation chromatography

H&E:

Hematoxyline and eosin

HCD:

High cholesterol diet

HPLC:

High pressure liquid chromatography

I.V.:

Intravenous

ITLC:

Instant thin layer chromatography

MPS:

Mononuclear phagocyte system

NPRC:

Natriuretic peptide clearance receptor

NPRs:

Natriuretic peptide receptors

PDI:

Polydispersity index

PEGMA:

Polyethylene glycol methacrylate

PET/CT:

Positron emission tomography/Computed tomography

PI:

Post injection

PMMA:

Poly(methyl methacrylate)

RAFT:

Reversible addition-fragmentation chain-transfer

RCP:

Radiochemical purity

SPECT:

Single photon emission computed tomography

WT:

Wildtype

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ACKNOWLEDGMENTS AND DISCLOSURES

This work is supported by the National Heart, Lung and Blood Institute of the National Institutes of Health as a Program of Excellence in Nanotechnology (HHSN268201000046C). The characterization of nanoparticles was performed in the Central Facilities of the UCSB Materials Research Laboratory supported by the MRSEC Program of the National Science Foundation under award no. DMR1121053. No other potential conflict of interest relevant to this article was reported.

We thank Nicole Fettig, Margaret Morris, Amanda Roth, Lori Strong, and Ann Stroncek for their assistance with animals and imaging studies and Tom Voller, Evelyn Madrid, Paul Eisenbies, Efrem Mebrahtu, and Suzanne Lapi for 64Cu production. We thank the helpful discussion and comments from Dr. Richard Pierce.

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    Authors and Affiliations

    1. Department of Radiology, Washington University, St. Louis, Missouri, USA

      Pamela K. Woodard, Yongjian Liu, Hannah P. Luehmann, Lisa Detering, Deborah E. Sultan, Richard Laforest & Robert J. Gropler

    2. Materials Research Laboratory, University of California, Santa Barbara, California,, USA

      Eric D. Pressly, Alaina J. McGrath & Craig J. Hawker

    3. Department of Chemistry and Biochemistry, University of California, Santa Barbara, California,, USA

      Craig J. Hawker

    4. Materials Department, University of California, Santa Barbara, California, USA

      Craig J. Hawker

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    1. Pamela K. Woodard
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    Correspondence to Craig J. Hawker.

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    Pamela K. Woodard, Yongjian Liu and Eric D. Pressly contributed equally to this work.

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    Woodard, P.K., Liu, Y., Pressly, E.D. et al. Design and Modular Construction of a Polymeric Nanoparticle for Targeted Atherosclerosis Positron Emission Tomography Imaging: A Story of 25% 64Cu-CANF-Comb. Pharm Res 33, 2400–2410 (2016). https://doi.org/10.1007/s11095-016-1963-8

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    • DOI: https://doi.org/10.1007/s11095-016-1963-8

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