A review of molecular imaging of atherosclerosis and the potential application of dendrimer in imaging of plaque

Figures & data

Table 1 Commonly used imaging techniques for AS diagnosis

Types	Principles of imaging	References
US	Ultrasound is a kind of sound wave with a frequency greater than the upper limit of human hearing (>22 kHz) and ultrasound devices operate with frequencies from 20 kHz up to several gigahertz to detect objects and measure distances	^Citation5
Nuclear medicine	Nuclear medicine records radiation emitting from within the body, and for such reason, it is called a physiological imaging modality	^Citation5
PET	The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide (tracer), which has been introduced into the body on a biologically active molecule	^Citation6^–^Citation8
SPECT	It is similar to conventional nuclear medicine planar imaging using a gamma camera. However, it is able to provide true 3D information	^Citation9, ^Citation10
Radiography	It uses electromagnetic radiation other than visible light, especially X-rays, to view the internal structure of a nonuniformly composed and opaque object	^Citation5
CT	A CT scan use computer-processed combinations of many X-ray images taken from various angles to produce cross-sectional (tomographic) images (virtual “slices”) of specific areas of a scanned object, allowing the user to see inside the object without cutting	^Citation5
MRI	MRI scanners use strong magnetic fields, radio waves, and field gradients to generate images of the inside of the body. And, it includes T1/T2-weighted MR	^Citation11 ^Citation12^–^Citation14 ^Citation15
Molecular imaging	It originated from the field of radiopharmacology due to the need to better understand fundamental molecular pathways inside organisms in a noninvasive manner, which visualizes cellular function and the follow-up of the molecular process in living organisms without perturbing them	^Citation22, ^Citation24
Other optical imaging	Fluorescence imaging (fluorescence labeling and staining combined with imaging instruments) and bioluminescence imaging (utilizes native light emission from in living organisms)	^Citation16, ^Citation17

Abbreviations: AS, atherosclerosis; CT, computed tomography; 3D, three-dimensional; MR, magnetic resonance; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single photon emission CT; US, ultrasound.

Figure 1 Dendrimer-facilitated molecular imaging of atherosclerosis plaque.

Note: Dendrimer modified with multi-signal elements or therapeutic agents can target at a series of molecules that are upregulated in plaque area during AS, and can function as contrast agents or therapeutic agents there.

Abbreviations: AS, atherosclerosis; US, ultrasound; CT, computed tomography; SPECT, single photon emission CT; PET, positron emission tomography; MRI, magnetic resonance imaging; MMP, matrix metalloproteinase; VEGF, vascular endothelial growth factor; PS, phosphatidylserine.

Table 2 AS biomarkers used in molecular imaging

Biomarkers	Molecular imaging probes	Imaging technique	Author	References
VCAM-1	Validate an (18)F-labeled small VCAM-1 affinity ligand and demonstrate the feasibility of imaging VCAM-1 expression by PET–CT	PET–CT MRI	Nahrendorf et al	^Citation11, ^Citation28^–^Citation30, ^Citation114
Lipids	sIVPA imaging identifies lipids in human coronary AS plaque by relying on contrast in the near-infrared absorption spectra of the arterial wall components	sIVPA	Jansen et al	^Citation31
OSEs	Manganese (Mn(II)) molecular imaging probes targeting to OSEs with oxidation-specific antibodies MDA2 and IK17	MR	Briley-Saebo et al	^Citation35
Macrophages CD204	Using anti-CD204 monoclonal IgG	MRI	Amirbekian et al	^Citation40^–^Citation44
LOX-1	Imaging probe consisting of liposomes loaded with LOX-1 antibody or nonspecific immunoglobulin G	SPECT/CT and MR	Li et al	^Citation47
	LOX-1 antibody conjugated to USPIO nanoparticles could take the probe to vulnerable plaques, which will be verified by colocalization with vulnerable plaque biomarker	MRI	Wen et al	^Citation50
Stable plaque	Using the novel CD80-specific probe discriminated the stable ones from vulnerable atherosclerotic plaques	PET	Muller et al	^Citation51
MMP	Synthesized radiolabeled MPIs	Radionuclide imaging	Hartung et al	^Citation58
	A kind of MPI labeled with ^99mTc could be used as an MMP-targeted tracer	Micro-SPECT	Razavian M et al	^Citation59
	Using broad-spectrum MMP inhibitor HO-CGS 27023A, labeled with ^123I or ^125I image MMP activity	Scintigraphy	Schafers et al	^Citation60
PS	Utilizing Annexin A5 (like ^99mTc-annexin A5) to target PS, which was highly taken up in plaque rich in macrophages	SPECT/CT	Zhao et al	^Citation68^–^Citation70
Apoptosis (liposomes contained PS)	Utility of paramagnetic Gd-PS	Fluorescence plate reader and MRI	Maiseyeu et al	^Citation74
Caspase activity	Utilizing a peptide-based caspase inhibitor for quantification of caspase activity	PET	Hight et al	^Citation75
Matrix remodeling	Using an elastin-specific contrast agent to assess vascular remodeling for the prediction of vulnerable plaques	MRI	Phinikaridou et al	^Citation77
αvβ3 integrina	Expression of αvβ3 integrin by vasa vasorum was imaged at 1.5 T in cholesterol-fed rabbit aortas using integrin-targeted paramagnetic nanoparticles that incorporated fumagillin at 0 or 30 µg/kg	MRI	Winter et al	^Citation76
NGALa	It is highly expressed in plaques and associated with increased MMP-9 activity. Thus, enhancement of MR images on the abdominal aorta of ApoE(−/−)/eNOS(−/−) mice and colocalization of micelles, macrophages, and NGAL/24p3 were observed at 72 h after injection of NGAL/24p3-targeted micelles	MRI	te Boekhorst et al	^Citation52
VEGFa	Molecular near-infrared fluorescent imaging with an engineered Cy5.5-labeled single-chain VEGF tracer (scVEGF/Cy) to detect VEGF receptors and vascular remodeling in human coronary artery grafts by molecular imaging	Near-infrared fluorescent imaging	Zhang et al	^Citation78
CD40a	A synthetic peptide corresponding with the phage insert NP31 displayed nanomolar affinity for CD40 and this design of a novel, selective peptide ligand for CD40 by phage display examined	Truncation and alanine scan studies	Yu et al	^Citation55

Notes:

a The biomarker of AS, which has brighter future as potential targets for molecular imaging. Gd-PS, gadolinium liposomes enriched with PS.

Abbreviations: AS, atherosclerosis; CT, computed tomography; LOX-1, Lectin-like oxidized low-density lipoprotein receptor-1; MMP, matrix metalloproteinase; MPIs, MMP inhibitors; MR, magnetic resonance; MRI, magnetic resonance imaging; NGAL, neutrophil gelatinase-associated lipocalin; OSEs, oxidation-specific epitopes; PET, positron emission tomography; PS, phosphatidylserine; sIVPA, spectroscopic intravascular photoacoustics; SPECT, single photon emission CT; USPIO, ultrasmall superparamagnetic iron oxide; VCAM-1, vascular cell adhesion molecule-1; VEGF, vascular endothelial growth factor.

Table 3 Dendrimers based molecular imaging agents

Contrast agents	Disease	Modality	Author	References
Mn(II) or Gd(III) chelating dendrimers	Soft tissues	MRI	Klemm et al	^Citation88, ^Citation91, ^Citation94
Dye-conjugated dendrimers	Single proteins and biomolecules in cells	Fluorescence imaging	Kim et al	^Citation95, ^Citation96
Dendrimer-entrapped AuNPs	Blood pool and tumor	CT	Peng et al	^Citation97^–^Citation100
Dendrimers conjugated to iodinated-compounds	Human hepatocellular carcinoma	CT	Liu et al	^Citation97^–^Citation100
Dendrimers conjugated with FA and Cu^2+	Cancers	Synchrotron X-ray fluorescence analysis	Zhang et al	^Citation93
Folate-receptor targeted dendrimer nanoclusters labeled with Gd	Cancers	MR	Cheng et al	^Citation26
Dendrimer-based contrast agents modified on an atom-by-atom scale	Organs and other target-specific locations	Hybrid modality imaging	Longmire et al	^Citation79
Au DENPs loaded with Gd chelator/Gd(III) complexes modified with RGD peptide	Tumors	CT and MR	Chen et al	^Citation101, ^Citation102
Gd-loaded dendrimer-entrapped AuNPs	Major organs of rats or mice	CT/MR	Wen et al	^Citation25
Dendrimer modified with AuNP followed by Gd(III) chelation and acetylation of the remaining dendrimer terminal amine groups (Gd-Au DENPs)	Breast cancer	CT/MR	Li et al	^Citation103
FA-modified multifunctional Au DENPs loaded with Gd	Tumors	CT/MR	Chen et al	^Citation104
A probe consisting of the fourth generation (G(4)-PAMAM) dendrimer nanoparticles labeled with high-affinity conjugating ligands and an organic fluorescent dye fluorescein	Mitochondria	CAT microscopy	Denora et al	^Citation95
PEG modified Au DENPsa	As plaques	CT	Ye et al	^Citation107
Labeling Au DENPs with PEG and FIa	AS	CT	Qin et al	^Citation108
Dendrimers with ^64Cu modified with LyP-1a	p32 proteins on activated macrophages	PET–CT	Seo et al	^Citation109
G8 dendrimers modified by Mn and antibody MDA2a	As lesions	MRI	Nguyen et al	^Citation110

Note:

a The usage of dendrimers based contrast agents in imagining of AS plaques.

Abbreviations: AS, atherosclerosis; Au DENPs, dendrimer-entrapped gold nanoparticles; AuNP, gold nanoparticle; CAT, confocal–atomic force microscopy–total internal reflectance fluorescence; CT, computed tomography; FA, folic acid; FI, fluorescein isothiocyanate; Gd, gadolinium; MR, magnetic resonance; MRI, magnetic resonance imaging; PEG, polyethylene glycol; RGD, arginylglycylaspartic acid; PET, positron emission tomography.

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