Combined Therapeutics for Atherosclerosis Treatment Using Polymeric Nanovectors.

Baltazar Hiram Leal,Lilia Arellano,Víctor X Mosquera,Alberto Bouzas,Adriana Cambón,Brenda Velasco,Silvia Barbosa,Gerardo Prieto,Javier Fernandez-Vega,Abeer Al-Modlej,Pablo Taboada,Alberto Pardo

doi:10.3390/pharmaceutics14020258

Abstract

Atherosclerosis is an underlying risk factor in cardiovascular diseases (CVDs). The combination of drugs with microRNAs (miRNA) inside a single nanocarrier has emerged as a promising anti-atherosclerosis strategy to achieve the exploitation of their complementary mechanisms of action to achieve synergistic therapeutic effects while avoiding some of the drawbacks associated with current systemic statin therapies. We report the development of nanometer-sized polymeric PLGA nanoparticles (NPs) capable of simultaneously encapsulating and delivering miRNA-124a and the statin atorvastatin (ATOR). The polymeric NPs were functionalized with an antibody able to bind to the vascular adhesion molecule-1 (VCAM1) overexpressed in the inflamed arterial endothelium. The dual-loaded NPs were non-toxic to cells in a large range of concentrations, successfully attached overexpressed VCAM receptors and released the cargoes in a sustainable manner inside cells. The combination of both ATOR and miRNA drastically reduced the levels of proinflammatory cytokines such as IL-6 and TNF-α and of reactive oxygen species (ROS) in LPS-activated macrophages and vessel endothelial cells. In addition, dual-loaded NPs precluded the accumulation of low-density lipoproteins (LdL) inside macrophages as well as morphology changes to a greater extent than in single-loaded NPs. The reported findings validate the present NPs as suitable delivery vectors capable of simultaneously targeting inflamed cells in atherosclerosis and providing an efficient approach to combination nanomedicines.

Highlights

Cardiovascular diseases (CVDs) are the main cause of death worldwide, with 17.6 M deaths in 2019, which is projected to increase to 23.6 M by 2030 due to the increase in the population of elderly people and the average lifestyle of society, with atherosclerosis being the main underlying factor [1,2]
MiRNA-124a is produced in the cytoplasm, where the precursor micro RNAs (miRNAs) hairpin is cleaved by endoribonuclease Dicer, forming the miRNA duplex
Conclusions miRNAs simultaneously regulate several inflammation-related genes, and their combination with statins opens the door to afford the treatment of inflamed endothelial vascular tissue, making use of complementary pathways to achieve synergistic therapeutic outcomes

Summary

Introduction

Cardiovascular diseases (CVDs) are the main cause of death worldwide, with 17.6 M deaths in 2019, which is projected to increase to 23.6 M by 2030 due to the increase in the population of elderly people and the average lifestyle of society, with atherosclerosis being the main underlying factor [1,2]. Pharmaceutics 2022, 14, 258 the dysfunction of the endothelial layer that can arise as early as adolescence and leads to the accumulation and retention of cholesterol-containing, low-density lipoproteins (LdLs) in the sub-endothelial space due to a complex interplay between activated leukocytes (monocytes, macrophages, and T cells) and the inflamed endothelium This phenomenon progresses through the formation of atheromatous plaques in the intima of arteries, which often significantly compromise the residual lumen. Atherosclerotic lesions do not form randomly; rather, they preferentially occur at vascular niches proximal to vessel branches and bends including several locations in the aortic arch, ascending and descending aorta, and coronary and carotid arteries [4] At these locations, the local flow behavior is characterized as “disturbed” and is associated with low shear stress recirculation (average < 0.4 Pa) in comparison with straight regions of arteries with “normal” high shear stress, which show laminar pulsatile flow (average > 1 Pa; maximum < 10 Pa). Prolonged exposure to excessive cyclic circumferential stretch derived from heart beating resulted in the enhanced generation of vasoactive mediators, pro-inflammatory markers and matrix metalloproteinases [5–8], which favor vessel endothelial inflammation and atherogenesis

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Conclusion