Combined Therapeutics for Atherosclerosis Treatment Using Polymeric Nanovectors

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.

Tissue Engineering and Targeted Drug Delivery in Cardiovascular Disease: The Role of Polymer Nanocarrier for Statin Therapy

“…Statin treatment represents a milestone, but the effects of systemic administration could be enhanced by targeted delivery of statins, through polymers and nanoparticles [ 76 ].…”

“…Preliminary studies showed encouraging results in inflammation reduction when using statins as targeted therapy. According to Leal et al [ 76 ], PLGA can be used as a carrier in delivering atorvastatin combined with miRNA-124a, drastically reducing the levels of proinflammatory cytokines such as TNF-α and IL-6, and of reactive oxygen species (ROS), in LPS-activated macrophages and vessel endothelial cells.…”

Emerging applications of single-cell profiling in precision medicine of atherosclerosis

“…Considering the growing interest in nanomedicine, numerous efficient nano-preparations have been utilized in the treatment of atherosclerosis. It is conceivable to combine genes that promote atherosclerosis plaque regression with nano-carriers through entrapment, encapsulation, adsorption, or covalent bonding to create a "nano-drug delivery system" for achieving effective early treatment of atherosclerosis [ 99 ].…”

Research Status and Prospect of Non-Viral Vectors Based on siRNA: A Review

“…They can be synthetically or chemically modified to improve gene transfection efficiency and reduce cytotoxicity [ 104 ]. Compared with neutral polymers, cationic polymers have better targeting capability [ 105 , 106 ]. Moreover, cationic polymers are positively charged, caused by the amine group in their structures.…”