Magnetic mesoporous silica nanoparticles-aided dual MR/NIRF imaging to identify macrophage enrichment in atherosclerotic plaques - ScienceDirect

Nanomedicine: Nanotechnology, Biology and Medicine

Volume 32, February 2021, 102330

Nanomedicine: Nanotechnology, Biology and Medicine

https://doi.org/10.1016/j.nano.2020.102330 Get rights and content

Abstract

Active foamy macrophage enrichment drives atherosclerotic plaque initiation and evolution, and is the prominent target for precisely identifying vulnerable plaque. Precise imaging of high-risk plaque allows promotion of treatment and prevention of vascular pathema. However, current iron oxide (IO) nanoparticles-based magnetic resonance (MR) imaging of plaque is often limited by insufficient perfusion and nonspecific accumulation of peri-aortic lymph nodes. Besides that, intrinsic defects of MR also impede its use for accurately identifying plaque details. Herein, by conjugating with PP1 peptide, a novel magnetic mesoporous silica nanoparticle (PIMI) loaded with near-infrared fluorescence (NIRF) dye (IR820) was fabricated to specifically target and quantify macrophage enrichment of atherosclerotic plaque in ApoE^−/− mice using dual MR/NIRF imaging. Biocompatibility experiments ulteriorly confirmed the high safety of PIMI nanoparticles in vivo, which lays the foundation of next-generation contrast agent for recognizing macrophage-rich plaque in the near future.

Graphical Abstract

Herein, a novel magnetic mesoporous silica nanoparticle loaded with IR820 (PP1-IO@MS-IR820, PIMI) was fabricated to specifically target and quantify macrophage enrichment in atherosclerotic plaque. As illustrated in graphical abstract figure, by conjugating PP1, an overexpressed surface receptor (SR-AI) driven foamy macrophage-targeted peptide, PIMI was designed for conducing efficiently plaque-targeted imaging. Specifically, IO was used as a magnetic core for T2 and T2*-weighted MR imaging; a mesoporous silica layer was prepared to load NIRF dye (IR820) for optical imaging; and the two imaging elements were superimposed to finally achieve dual-mode imaging effect. As a result, the obtained PIMI exhibited improved foamy macrophage deposition and favored atherosclerotic plaque imaging in MR/NIRF dual-modal, which was confirmed by staining of tissue sections.

Unlabelled Image

Section snippets

Synthesis of IO magnetic nanoparticles

1.4 g (4 mmol) of the Fe(acac)₃ was dissolved in 40 mL of dibenzyl ether, followed by addition of oleic acid (4 mL, 12 mmol) and oleylamine (12 mL, 36 mmol) at room temperature. The mixture was heated to 220 °C for 1 h and was heated to 290 °C for 30 min. At room temperature, 80 ml of ethanol was added to the solution, and the IO nanoparticles were precipitated and dispersed in chloroform.

Synthesis of IO@MS nanoparticles

1 g cetyltrimethyl ammonium bromide (CTAB) and 0.01 g triethanolamine (TEA) were dissolved in 20 mL of

Synthesis and characterization of PIMI

This nanoparticle was successfully synthesized by several steps. Firstly, IO was obtained according to the high temperature thermal decomposition approach. To provide loading sites and better biocompatibility for in vivo application, mesoporous silica (MS) was deposited on IO. Then PP1 peptide was subsequently conjugated via the amide condensation reaction, and IR820 was loaded to form the PIMI nanoparticle. TEM images showed the core/shell structure of PIMI nanoparticles with approximately

Discussion

Foamy macrophage plays a key role in atherosclerotic plaque formation, progression and destabilization.31, 32, 33 High content of foamy macrophages in plaque indicates severe inflammation activity, which provides a compelling measurable marker for modern imaging techniques. Clinical imaging approaches, such as CTA and MRA, usually evaluate plaque size based on the degree of luminal stenosis. However, these methods cannot fully picture such active biological components related to high-risk

References (41)

R. Lozano et al.
Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010
Lancet
(2012)
R. Virmani et al.
Pathology of the vulnerable plaque
J Am Coll Cardiol
(2006)
H. Ikeda et al.
Activatable fluorescence imaging of macrophages in atherosclerotic plaques using iron oxide nanoparticles conjugated with indocyanine green
Atherosclerosis
(2018)
B. den Adel et al.
Histological validation of iron-oxide and gadolinium based MRI contrast agents in experimental atherosclerosis: the do's and don't's
Atherosclerosis
(2012)
B.C. te Boekhorst et al.
Negative MR contrast caused by USPIO uptake in lymph nodes may lead to false positive observations with in vivo visualization of murine atherosclerotic plaque
Atherosclerosis
(2010)
M.W. Garbowski et al.
Biopsy-based calibration of T2* magnetic resonance for estimation of liver iron concentration and comparison with R2 Ferriscan
J Cardiovasc Magn Reson
(2014)
N. Chen et al.
Cy5.5 conjugated MnO nanoparticles for magnetic resonance/near-infrared fluorescence dual-modal imaging of brain gliomas
J Colloid Interface Sci
(2015)
J. Wang et al.
Scavenger receptor-AI-targeted ultrasmall gold nanoclusters facilitate in vivo MR and ex vivo fluorescence dual-modality visualization of vulnerable atherosclerotic plaques
Nanomedicine
(2019)
K. Ghassaban et al.
Quantifying iron content in magnetic resonance imaging
Neuroimage
(2019)
I.A. Barbosa et al.
Metalloporphyrins immobilized in Fe3O4@SiO2 mesoporous submicrospheres: reusable biomimetic catalysts for hydrocarbon oxidation
J Colloid Interface Sci
(2016)

J. Li et al.

Size-dependent tissue-specific biological effects of core-shell structured Fe3O4@SiO2-NH2 nanoparticles

J Nanobiotechnology

(2019)

K. Chatterjee et al.

Core/shell nanoparticles in biomedical applications

Adv Colloid Interface Sci

(2014)

M.R. Dweck et al.

Noninvasive molecular imaging of disease activity in atherosclerosis

Circ Res

(2016)

C. Weber et al.

Atherosclerosis: current pathogenesis and therapeutic options

Nat Med

(2011)

R. Virmani et al.

Vulnerable plaque: the pathology of unstable coronary lesions

J Interv Cardiol

(2002)

J.N.E. Redgrave et al.

Histological assessment of 526 symptomatic carotid plaques in relation to the nature and timing of ischemic symptoms: the Oxford Plaque Study

Circulation

(2006)

R. Ji et al.

Identifying macrophage enrichment in atherosclerotic plaques by targeting dual-modal US imaging/MRI based on biodegradable Fe-doped hollow silica nanospheres conjugated with anti-CD68 antibody

Nanoscale

(2018)

C.G. Santos-Gallego et al.

Pathophysiology of acute coronary syndrome

Curr Atheroscler Rep

(2014)

Y. Li et al.

Dual-modality imaging of atherosclerotic plaques using ultrasmall superparamagnetic iron oxide labeled with rhodamine

Nanomedicine (Lond)

(2019)

S. Metz et al.

Characterization of carotid artery plaques with USPIO-enhanced MRI: assessment of inflammation and vascularity as in vivo imaging biomarkers for plaque vulnerability

Int J Cardiovasc Imaging

(2011)

Cited by (22)

Nanotechnology in coronary heart disease
2023, Acta Biomaterialia
Coronary heart disease (CHD) is one of the major causes of death and disability worldwide, especially in low- and middle-income countries and among older populations. Conventional diagnostic and therapeutic approaches have limitations such as low sensitivity, high cost and side effects. Nanotechnology offers promising alternative strategies for the diagnosis and treatment of CHD by exploiting the unique properties of nanomaterials. In this review, we use bibliometric analysis to identify research hotspots in the application of nanotechnology in CHD and provide a comprehensive overview of the current state of the art. Nanomaterials with enhanced imaging and biosensing capabilities can improve the early detection of CHD through advanced contrast agents and high-resolution imaging techniques. Moreover, nanomaterials can facilitate targeted drug delivery, tissue engineering and modulation of inflammation and oxidative stress, thus addressing multiple aspects of CHD pathophysiology. We discuss the application of nanotechnology in CHD diagnosis (imaging and sensors) and treatment (regulation of macrophages, cardiac repair, anti-oxidative stress), and provide insights into future research directions and clinical translation. This review serves as a valuable resource for researchers and clinicians seeking to harness the potential of nanotechnology in the management of CHD.
Coronary heart disease (CHD) is the one of leading cause of death and disability worldwide. Nanotechnology offers new strategies for diagnosing and treating CHD by exploiting the unique properties of nanomaterials. This review uses bibliometric analysis to uncover research trends in the use of nanotechnology for CHD. We discuss the potential of nanomaterials for early CHD detection through advanced imaging and biosensing, targeted drug delivery, tissue engineering, and modulation of inflammation and oxidative stress. We also offer insights into future research directions and potential clinical applications. This work aims to guide researchers and clinicians in leveraging nanotechnology to improve CHD patient outcomes and quality of life.
PSMA1-mediated ultrasmall gold nanoparticles facilitate tumor targeting and MR/CT/NIRF multimodal detection of early-stage prostate cancer
2023, Nanomedicine: Nanotechnology, Biology, and Medicine
Citation Excerpt :
Inspired by Gd-containing nanoparticles that can penetrate defective vascular endothelia and be entrapped within tumor parenchyma via EPR effect, and generate positive MR signals through T1-shortening capacity,37,38 numerous studies have utilized GdIII-based agents to provide biomarker details through MR identification. But as a single modality, it suffered inherent restriction associated with MR equipment including deficient sensitivity, poor time resolution and inevitable motion artifacts.17,39 To circumvent this dilemma, a nano-based multimodal contrast agent (AGGP) was elaborately constructed combining compelling performances and complementary strengths of MR, CT and NIRF techniques, which would provide omnipotent information, capacitate accurate diagnosis and predict prognosis of PCa.
Prostate-specific membrane antigen (PSMA) is a prominent biomarker for prostate cancer (PCa) diagnosis. Safe contrast agents able to render the expression and distribution of PSMA would facilitate early accurate screening and prognostic prediction of PCa. However, current Gd-containing nanoparticles are often limited by nonspecific redistribution in mononuclear phagocyte system (MPS) and inadequate perfusion to target sites. Besides, intrinsic defects of magnetic resonance (MR) equipment also hamper their use for precisely depicting PSMA details. Herein, we devised a novel noninvasive MR/CT/NIRF multimodal contrast agent (AGGP) coordinated to a high-affinity PSMA ligand (PSMA1) to specifically detect and quantify PSMA expression in PCa lesions, which exhibited formidable tripe-modal signal augments, preferential PSMA targeting, effective MPS escaping and profitable renal-clearable behavior in living mice. Biocompatibility and histopathological studies substantiated high security of AGGP in vivo, opening the door to future opportunities for improving early-stage PCa detection and clinical implementation of more effective multifunctional nanotherapeutics.
Multifunctional nanoprobes for macrophage imaging
2022, Biomaterials
Citation Excerpt :
To accurately identify plaque cells and shapes, fluorescence imaging with excitation and emission in the near-infrared region are highly favorable. A magnetic porous silica nanoprobe loaded with IR820 was fabricated to target and image macrophages after conjugation with PP1 peptides [163]. In an atherosclerosis mice model, the targeted nanoprobe revealed significantly decreased MR signals and increased plaque area at 12 h and 24 h compared to the non-targeted nanoprobe during 48 h imaging window, which was further confirmed via ex vivo NIR fluorescence imaging of dissected tissues.
Imaging and tracking macrophage behaviors in vivo are essential to reveal its biological function and fate in various diseases. Small molecular probes suffer from poor macrophage targeting and retention, rapid clearance, and deficient metabolizing stability. To overcome these limitations, a variety of functional nanoprobes have been developed for targeted imaging of macrophages in divergent diseases such as cancer, atherosclerosis and obesity. Generally, nanoprobes are functionalized with targeting peptides, ligands or antibodies to fulfill high macrophage affinity. In this review, the most recent advances of nanoprobes for imaging macrophages in vivo and ex vivo are systematically summarized. The challenges and perspectives of precisely imaging macrophages with improved signal-to-background ratios via nanoprobes are further discussed.
Current advances in the imaging of atherosclerotic vulnerable plaque using nanoparticles
2022, Materials Today Bio
Vulnerable atherosclerotic plaques of the artery wall that pose a significant risk of cardio-cerebral vascular accidents remain the global leading cause of morbidity and mortality. Thus, early delineation of vulnerable atherosclerotic plaques is of clinical importance for prevention and treatment. The currently available imaging technologies mainly focus on the structural assessment of the vascular wall. Unfortunately, several disadvantages in these strategies limit the improvement in imaging effect. Nanoparticle technology is a novel diagnostic strategy for targeting and imaging pathological biomarkers. New functionalized nanoparticles that detect hallmarks of vulnerable plaques are promising for advance further control of this critical illness. The review aims to address the current opportunities and challenges for the use of nanoparticle technology in imagining vulnerable plaques.
Target Functionalized Carbon Dot Nanozymes with Dual-Model Photoacoustic and Fluorescence Imaging for Visual Therapy in Atherosclerosis
2024, Advanced Science
Current targeting strategies and advanced nanoplatforms for atherosclerosis therapy
2024, Journal of Drug Targeting

View all citing articles on Scopus

: Conflict of interest: The authors declare no competing financial interests.

: Funding: This work was supported by the Natural Science Foundation of China (81701826, 81971673), Tianjin Science and Technology Project (19KPHDRC00100), Key Program of the Tianjin Health and Family Planning Commission (16KG115), the Youth Science Foundation of the Second Hospital Center Laboratory of Tianjin Medical University (2018ydey11), and Science Foundation of Tianjin Medical University (2019KJ165).

¹: These authors contributed equally to this work.

²: Mailing address: No. 23, Pingjiang Road, Hexi District, Tianjin 300211, P.R. China.

© 2020 Elsevier Inc. All rights reserved.