Recent progress in the detection and treatment of atherosclerosis by nanoparticles

Highlights

• The detailed mechanism of the development of atherosclerosis plaque, including the latest discoveries on lipid deposition that are different from traditional views.

• A comprehensive table which collected the most up-to-date literature on the application of nanoparticles in the diagnosis and treatment of atherosclerosis.

• The targets of nanoparticles in plaque can be divided into cellular targets and non-cellular targets.

• The method and progress of detecting plaque with its advantages and disadvantages.

• AS treatment methods can be divided into five categories.

Abstract

Cardiovascular diseases (CVDs) have high mortality and morbidity in the US and presently rank as one of the leading causes of death. Atherosclerosis (AS) acts as one of the CVDs, playing an important role in mortality because of many lethal complications. The common cause of AS is that low-density lipoprotein (LDL) in the blood circulation enters the intima through endothelial cells that have been broken for various reasons. Under the action of inflammatory factors secreted by damaged endothelial cells, monocytes also enter the inner membrane and differentiate into macrophages. Macrophages engulf the oxidized LDL and become foam cells which eventually become apoptotic. However, recent studies have shown that LDL entry into the intima, an important step in AS, may be associated with endothelial cells actively inhaling LDL through the receptor. Nanotechnology is a promising technology that can be applied in the noninvasive imaging and therapy of AS. Nanoparticles (NPs) have the ability to passively target AS because of their inherent small diameter. They can also be loaded with chemicals for targeting lesions, contrast agents for imaging, and drugs for treatment to achieve accurate diagnosis and treatment of AS. This review consequently highlights the recent progress in the detection and treatment of AS by NPs.

Introduction

According to the Heart and Stroke Statistics Report of the American Heart Association, the number of patients with cardiovascular diseases (CVDs) is 121.5 million overall, claiming that approximately 17.6 million deaths are attributed to CVD globally [1], and many vascular conditions begin with atherosclerosis (AS).

AS is an inflammatory disease of the arteries, the initial phase of which usually involves the pathological damage of endothelial cells exposed to luminal blood flow and the metabolic disorders of lipid molecules. The endothelial cells have both sensorial and executive functions and can produce effector molecules that adjust inflammation, thrombosis, and vascular remodeling, like a selectively permeable barrier between tissues and blood [2]. Unhealthy diet, smoking habits, high blood pressure, or acute shock in the lumen wall may result in early endothelial damage. It is traditionally believed that under normal conditions, low-density lipoprotein (LDL) in the bloodstream is cleared in the liver. When endothelial cells are damaged, LDL deposits in the intima, and accumulates more with the increase of circulating LDL level. However, it was recently reported that LDL in blood is deposited in the endothelium through active absorption of scavenger receptor class B type 1 (SR-B1) receptor on endothelial cells. As a cholesterol-transporting receptor, although SR-B1 can prevent atherosclerosis by binding high-density lipoprotenin (HDL) and transporting cholesterol back into the liver, Huang et al. found that with the help of the intracellular transporter dedicator of cytokinesis 4 (DOCK4), the SR-B1 allows LDL to enter the vessel wall and promote the development of plaque [3,4].

Oxidized LDL (ox-LDL), which is obtained by oxidizing LDL accumulated in the inner membrane, inhibits the production of NO with various anti-atherosclerotic properties and stimulates endothelial cells to secrete pro-inflammatory molecules such as growth factors and the adhesion molecules. Different adhesion molecules upregulated by endothelial cells include vascular cell adhesion protein 1 (VCAM-1), selectin, and intercellular adhesion molecule 1 (ICAM-1) [5]. In the blood, monocytes adhere to endothelial cells through highly expressed adhesion molecules and migrate to the intimal layer. Monocytes in intimal layers differentiate into macrophages and recruit more monocytes by secreting monocyte chemoattractant protein 1 (MCP-1) and other inflammatory factors [2]. In addition, chemokines and cytokines secreted by macrophages promote the transfer of smooth muscle cells (SMC) from the media to the intimal layers. The phagocytosis of LDL by macrophages and SMC promotes the formation of foam cells, which are representative cells of AS. After the necrotic apoptosis of the foam cells, the released lipids and necrotic cells collectively form the lipid core, resulting in the development of “lipid streaks” [6]. The general mechanism of AS is summarized in Fig. 1.

Maintenance of the fibrous cap involves both synthesis of collagen by SMC and degradation of the extracellular matrix. The formation of new blood vessels in the plaque helps the entry of more inflammatory cells, products of which are likely to affect these two processes, such as IFN-γ restraining the creation of extracellular matrix by SMC. Macrophages secrete proteases that degrade extracellular matrices such as matrix metalloproteinases (MMPs), gelatinases, and stromelysin [7]. When the collagen is generated faster than the speed of the matrix degradation, the plaque becomes more stable and gradually forms a fibrous collagen cap. Conversely, when the fibrous collagen cap is thinned to some degree, the risk of plaque rupture simultaneously increases [8]. Based on the tendency of rupture, the plaque is divided into stable and vulnerable plaques. Stable plaques are often rich in SMC and extracellular matrices. Occlusive levels of stable plaques can lead to the reduction of antegrade blood flow, stenosis, and ischemia that may eventually cause tissue death. Rupture of vulnerable plaques followed by thrombus emergence causes fatal myocardial infarction or ischemic stroke complications [9]. Vulnerable plaques usually have dense macrophages, larger lipid cores, thinner fibrous collagen caps, more neovascularization, and stronger inflammatory responses [10].

Based on the foregoing, there is an urgent demand for novel approaches for the detection and treatment of AS. Targeted drug or diagnostic agent delivery by NPs is a heartening way to address these matters. Due to their nanoscale particle size, smaller than the smallest blood vessels of the human body, NPs can display microcirculation perfusion better than micron-sized particles. Different proteins and peptides can be modified on the NPs according to the microenvironment of the disease, to target the lesions. The contrast agent can be loaded on the targeted NPs to obtain more detailed and accurate information on the development of specific lesions, and the loaded drugs can be given more accurately to reduce the side effects associated with such drugs. In Table 1, Table 2, various research on NPs for the diagnosis and treatment of AS in recent years according to different targets are provided, respectively.