Application of Nanomaterials in Early Imaging and Advanced Treatment of Atherosclerosis

Abstract

Atherosclerosis (AS) is a serious disease that poses a significant threat to the global population. In this review, we analyze the development of AS from multiple perspectives, aiming to elucidate its molecular mechanisms. We also focus on imaging techniques and therapeutic approaches, highlighting the crucial role of nanomaterials in both imaging and therapy for AS. By leveraging their compatibility and targeting capabilities, nanomaterials can be integrated with traditional medical imaging and therapeutic agents to achieve targeted drug delivery, controlled release, and precise localization and imaging of atherosclerotic plaques.

Figure 1

Endothelial Dysfunction in Atherosclerosis. The cross-sectional and longitudinal views of the vessel demonstrate that as plaque forms and expands, the lumen narrows, reducing the space available for blood flow.

Figure 2

Atherosclerotic Plaque Formation. Low-density lipoprotein (LDL) enters the subendothelial space and is oxidized to oxidized LDL. The accumulation of oxidized LDL stimulates endothelial cells to produce inflammatory factors. Monocytes are recruited and accumulate in the subendothelium, where they are activated by inflammatory cells to become macrophages. These macrophages phagocytose surrounding lipid molecules, transforming into foam cells. These foam cells accumulate in the vascular wall to form fibrous plaques. Smooth muscle cells then migrate to form a fibrous cap, enhancing the stability of the plaque.

Figure 3

Mechanisms of Lipid Handling in Macrophages. When excess ox-LDL damages the endothelium and enters the subendothelial space, it is phagocytized by macrophages via receptors such as LOX-1, CD36, and SR-A1, which are highly expressed on macrophages. In lysosomes, cholesteryl esters in LDL are broken down into free cholesterol by lysosomal acid lipase (LAL). At this point, cholesteryl ester accumulation predominates due to high expression of acetyl coenzyme A acetyltransferase 1 (ACAT1) and low levels of NCEH. Increased scavenger receptor expression leads to enhanced ox-LDL uptake by macrophages, while the expression of cholesterol transporters such as ABCA1, ABCG1, and SR-BI is relatively low. This imbalance results in the accumulation of cholesteryl esters in macrophages, further promoting their transformation into foam cells.

Figure 4

(a) The mechanism of Pt(IV)/CQ/PFH NPs-DPPA-1. (b) In vitro and in vivo imaging maps, showing the negative control, positive control, and experimental group from left to right. Reproduced with permission from reference (106). Copyright 2022 American Chemical Society.

Figure 5

(a) Schematic drawing of the atherosclerosis plaque model establishment. (b) Representative PAA-Gd-enhanced 3D MR angiography at 5 min postcontrast, for showing the vascular stenosis site (yellow dotted circle). (c) Representative T₁-weighted images of plaque section acquired pre- and at different time points postinjection of PAA-Gd. Triplicates were performed independently with similar results. (d) H&E and α-SMA staining of tissue slices from external carotid arteries. Triplicates were performed independently with similar results. (e) Schematic drawing of the thrombosis and thrombolytic therapy. (f) PAA-Gd-enhanced 3D angiography of mouse carotid thrombosis pretreatment (obtained at 5 min after PAA-Gd injection), and the real-time monitoring of thrombolytic therapy post-treatment of urokinase (uPA). (The carotid thrombosis was identified by yellow dotted circle). (g) Representative 2D time-of-flight (TOF) angiography of thrombus section acquired pre- and 40 min post-treatment of uPA. Triplicates were performed independently with similar results. (h) H&E staining of bilateral common carotid arteries. Triplicates were performed independently with similar results. The embedded scale bar of frame (c), (c) inset, (d), (g), and (h), corresponded to 2 mm, 0.5 mm, 50 μm, 2 mm, and 100 μm. Reproduced with permission from reference (114). Copyright 2023 PubMed Central.

Figure 6

Imaging effect after Gd addition. (a) T1 images obtained after coincubation of cells with the nanoparticle at different Gd concentrations. (b) Linear plot of 1/T1 versus Gd concentration. (c) MR imaging of the nanoparticles applied to C57 and ApoE^–/– mice, respectively. Reproduced with permission from reference (122). Copyright 2023 American Chemical Society.

Figure 7

Schematic diagram of the synthesis and principle of action of BNTs. (a) Schematic illustration of the formation of BNTs. (b) Schematic illustration of tumor-homing of elongated BNTs, CT imaging-guided radio-/chemotherapy mediated by the BNTs/drug, and subsequent BNTs disassembly and renal clearance. Reproduced with permission from reference (124). Copyright 2018 American Chemical Society.

Figure 8

(a) The mechanism of MMP2cNPs. (b) The representative in vivo PET, CT, and PET/CT images of mice models with carotid atherosclerotic plaques at 4 h after injection of MMP2cNPs. (c) Coronal PET images of mice models with carotid atherosclerotic plaques at 1 h, 2 h, 4 h, 12 and 24 h after injection of MMP2cNPs or MMP2ncNPs. (d) In vivo CL57/BL6 mice with carotid atherosclerotic plaque MRIs obtained before and 24 h after administration of MMP2cNPs or MMP2ncNPs at a dose of 10 mg iron/kg (red arrow, cross section of the carotid artery). International Journal of Nanomedicine2022, 17, 6773–6789. Originally published by and used with permission from Dove Medical Press Ltd. Reproduced with permission from reference (130). Copyright 2022 PubMed Central.

Figure 9

Mechanisms of nanomaterials. Common and desirable nanomaterials generally function as carriers while also providing targeting and imaging capabilities for precision therapy. Besides drug delivery, nanoparticles often encapsulate fluorescent or contrast agents. To avoid phagocytosis and prolong their half-life, nanoparticles may incorporate components with high biocompatibility, such as macrophage membranes. Additionally, bioactive substances on the surface of nanoparticles can enhance precision therapy through high affinity to the target. In animal experiments, nanoparticles reach the plaque site following tail vein injection and release various components that influence inflammatory factors in the plaque environment. Some nanoparticles can even promote macrophage polarization to the M2 phenotype, contributing to disease treatment. For imaging, the inclusion of contrast agents enhances MRI efficiency, while fluorescent agents significantly improve fluorescence imaging, resulting in clearer visualization of diseases.

Figure 10

Preparation route and targeted delivery process of SIM from SHPEMs. SIM: simvastatin; HA: hyaluronic acid; SHPEMs: SIM-loaded amino-PEG-Ptyr-EO micelles; SHPEMs: SIM-loaded HA-coated amino-PEG-Ptyr-EO micelles. Reproduced with permission from ref (150). Copyright 2020 PubMed Central.

Figure 11

Results of pathological experiments in mice. (a) Ratio of plaque area to total area. (b) H&E staining of the heart, liver, spleen, lung, and kidney from mice in each group. (c) SIM: simvastatin; SPEMs: SIM-loaded amino-PEG-Ptyr-EO micelles; SHPEMs: SIM-loaded HA-coated amino-PEG-Ptyr-EO micelles. Reproduced with permission from ref (150). Copyright 2020 PubMed Central.

Figure 12

Rate of intracellular ROS production with different treatments over time. (a) Representative fluorescent images of LPS-activated Raw264.7 macrophages incubated with TA, HD-Fe³⁺, and HFTNPs for 15, 30, and 60 min, respectively. Raw264.7 macrophages were treated with PBS as control. TA: 29.4 μM, iron: 117.6 μM. Scale bars: 100 nm. (b) Quantitative analysis of LPS-activated Raw264.7 cells incubated with PBS, TA, HD-Fe³⁺, and HFTNPs for 15, 30, and 60 min by flow cytometry. LPS + HFTNPs vs LPS: **p < 0.01; LPS + TA vs LPS: ^#p <0.05 and ^##p < 0.01. Reproduced with permission from ref (172). Copyright 2021 American Chemical Society.

Figure 13

Schematic representation of Nrg4’s protective role in atherosclerosis via the ErbB4-Akt-NF-κB signaling pathway. Reproduced with permission from ref (181). Copyright 2022 PubMed Central.