Recent advance in treatment of atherosclerosis: Key targets and plaque-positioned delivery strategies

Abstract

Atherosclerosis, a chronic inflammatory disease of vascular wall, is a progressive pathophysiological process with lipids oxidation/depositing initiation and innate/adaptive immune responses. The coordination of multi systems covering oxidative stress, dysfunctional endothelium, diseased lipid uptake, cell apoptosis, thrombotic and pro-inflammatory responding as well as switched SMCs contributes to plaque growth. In this circumstance, inevitably, targeting these processes is considered to be effective for treating atherosclerosis. Arriving, retention and working of payload candidates mediated by targets in lesion direct ultimate therapeutic outcomes. Accumulating a series of scientific studies and clinical practice in the past decades, lesion homing delivery strategies including stent/balloon/nanoparticle-based transportation worked as the potent promotor to ensure a therapeutic effect. The objective of this review is to achieve a very brief summary about the effective therapeutic methods cooperating specifical targets and positioning-delivery strategies in atherosclerosis for better outcomes.

Keywords: Atherosclerosis; balloon; nanoparticle; site-homing delivery; stent; targets.

Figure 1.

The main progresses of atheromatous plaques.

Figure 2.

The stenosis severity-guided delivery strategies.

Figure 3.

The main external stimulus-mediated phenotypic modulation of SMCs.

Figure 4.

Apoptosis and efferocytosis of vascular wall cells (endothelial cells, smooth muscle cells and macrophages) in atherosclerosis.

Figure 5.

The key pro-atherogenic role of NLRP3 inflammasome and IL-1β in initiation and development in atheroma plaque.

Figure 6.

The effect of PCSK9 on atherosclerotic progression.^,, Covered by inflammatory conditions, oxLDL and ROS at the plaque site, response cells (ECs, SMCs, and MAs) synthesize PCSK9, elevating SR (LOX-1, SRA, CD36) expression for more oxLDL intake, lowering ABCA1 and ABCG1 with decrease cholesterol outflow. Under this modulation, lipid-laden cells emerge as foam cells. Concomitantly, PCSK9 upregulates adhesion molecules VCAM-1 expression (more monocytes trafficking), and provokes macrophages to liberate inflammatory molecules (TNFα and IL-1β) based on TLR4/NF-κB pathway activation.

Figure 7.

The major portion of platelets in growing atherosclerotic plaques and prothrombotic events. There are abundant membrane-anchored receptors for adhering to injured/inflamed endothelial layer (GPIbα for P-selectin and vWF, PSGL-1 binding to P-selectin, CD40L-CD40 interaction, CX3CR1 for CX3CL1), ruptured lesion (GPVIα and α2β1 for collagen, GPIb for vWF), monocytes/macrophages (P-selectin for PSGL-1, CX3CR1 for CX3CL1), and active platelets (GPIbα and αIIbβ3 grasp additional platelets). PAR1/PAR4 coupling thrombin and P2Y1/P2Y12 binding ADP quietly potentiate platelet activation. Thrombin binding PAR promotes TXA2 and ADP producing, in addition to this, more ADP generating has a lot to do with TXA2-bound TP receptors.

Figure 8.

The extrinsic and intrinsic clotting pathway. Ample TF combining coagulation factor FVIIa transforms FIX into FIXa, and FX into FXa, is closely linked to extrinsic and intrinsic coagulation pathway, finally meeting at bio-synthesizing thrombin and stable fibrin clot formation imbued with platelets and erythrocytes. More than TF-FVIIa pathway, FXII interacts with negatively charged surface or molecules, followed by forming FIXa and FXIa resulting from activated FXII (FXIIa), which means intrinsic pathway starts.

Figure 9.

The NOX-derived ROS pathway and important renin-angiotensin system. The mediators of NOX activity and expression are involved in excessive proatherogenic factors, such as pathological shear stress, TNFα, PDGF, oxLDL, and important angiotensin II (Ang II). By renin-angiotensin pathway, generated Ang II linking to angiotensin type 1 receptor (AT1R) activates membrane-bound NADPH oxidase in ECs, SMCs, and macrophages, and it also traffics to AT1R on outer mitochondria membranes, inducing mitochondria-derived ROS. Importantly, NOX-derived ROS aggravates ROS overproduction by acting on eNOS and xanthine dehydrogenase.

Figure 10.

The schematic representation of the main lesion-specific delivery formulations.

Figure 11.

The promising treatment of atherosclerosis in development and the trends.