Surface-modified nanotherapeutics targeting atherosclerosis

Abstract

Atherosclerosis is a chronic and metabolic-related disease that is a serious threat to human health. Currently available diagnostic and therapeutic measures for atherosclerosis lack adequate efficiency which requires promising alternative approaches. Nanotechnology-based nano-delivery systems allow for new perspectives for atherosclerosis therapy. Surface-modified nanoparticles could achieve highly effective therapeutic effects by binding to specific receptors that are abnormally overexpressed in atherosclerosis, with less adverse effects on non-target tissues. The main purpose of this review is to summarize the research progress and design ideas to target atherosclerosis using a variety of ligand-modified nanoparticle systems, discuss the shortcomings of current vector design, and look at future development directions. We hope that this review will provide novel research strategies for the design and development of nanotherapeutics targeting atherosclerosis.

Figure 1.

AP-Lipo in situ upregulates anti-inflammatory macrophages for atherosclerosis regression. (A) AP-Lipo selectively targeted to the activated vascular endothelial cells by the interaction between cRGDfK and ανβ3 integrin. (B) AP-Lipo entered atherosclerotic plaques through enhanced permeability and retention effect and would be recognized and uptake by M1 macrophages due to the “eat‑me” signal of PtdSer. (C) AP-Lipo generated anti-inflammatory response by increasing M2 macrophages polarization or increasing the M2 macrophages number in atherosclerotic plaques. Adapted with permission from ref . Copyright (2019) Elsevier.

Figure 2.

Targeted anti-inflammatory NP design and application to the resolution of inflammation in atherosclerotic plaques. (a) Col-IV IL-10 NP (NP22) identified from screening 24 formulations was fabricated by nanoprecipitation using a glass microfluidic rapid-mixing chip. The NPs were formed in a single self-assembly step and consisted of a blend of NH2-PLGA-NH2, PDLA-PEG-OMe, PLGA-PEG-Col IV, and IL-10 in addition to d-(+)-glucosamine hydrochloride as an IL-10-stabilizing additive and cryoprotectant. (b) The targeted NPs can enter plaques via leaky endothelial junctions and bind to exposed collagen IV (Col IV) and release their therapeutic inflammation-resolving IL-10 payload within the plaque over time, resulting in increased efferocytosis, an increase in cap size, and a decrease in necrotic core size (orange arrows). Adapted with permission from ref . Copyright (2016) American Chemical Society.

Figure 3.

Construction of modular multifunctional micelles. (A) Individual lipopeptide monomers are made up of a DSPE tail, a poly (ethylene glycol) (PEG2000) spacer, and a variable polar head group (X) of CREKA, FAM-CREKA, FAM, N-acetylcysteine, Cy7, or hirulog. The monomers were combined to form various mixed micelles. (B) The 3D structure of FAM-CREKA/Cy7/hirulog mixed micelle. Adapted with permission from ref . Copyright (2009) PNAS.

Figure 4.

Design and structure of MCP-1 PAMs. (A) Schematic depicting PAM self-assembly. PAs consist of a di-stearoyl hydrophobic tail (two 18-carbon chains) and a PEG spacer that was conjugated to the MCP-1 peptide that corresponds to the CCR2-binding motif (residues 13–35), scrambled peptide, or the Cy7 fluorophore. Fluorescently labeled, mixed micelles consisted of peptide-containing and Cy7-labeled amphiphiles in a 90:10 molar ratio. (B) Representative TEM images of MCP-1 PAMs (L) and scrambled PAMs (R). Both micelles are spherical in shape with a diameter on the order of 10 nm. Adapted with permission from ref . Copyright (2015) Wiley.

Figure 5.

Schematic representations of the nanoparticle formulations and in vitro efficacy data (a) Schematic representation of dual gadolinium and fluorescent dye (Cy5.5, DiO, DiR) labeled statin containing reconstituted high-density lipoprotein ([Gd-dye-S]-rHDL), statin containing rHDL ([S]-rHDL), and rHDL. Negative staining transmission electron microscopy (TEM) images of each of the aforementioned particles showed the typical disk-like morphology. The circular shapes are nanoparticles viewed enface, while the striped configurations are rouleaux of nanoparticles viewed from the side. Adapted with permission from ref . Copyright (2014) Springer Nature.

Figure 6.

Schematic diagram on preparation methods and atherosclerotic lesion targeting property of HA-LT-rHDL. Adapted with permission from ref . Copyright (2014) Elsevier.