Targeted Delivery of Anti‐miR‐712 by VCAM1‐Binding Au Nanospheres for Atherosclerosis Therapy

Abstract

Atherosclerosis is ac hronic, inflammatory disease of the vascular wall, which preferentially develops in regions under disturbed flow (d-flow). Once inflamed, the endothelial cellsi nitiate as ignaling cascadet hat culminates in the expression of pro-atherogenic genes such as mRNAs and miRNAs. Here we demonstrate that vascular cell adhesionm olecule 1( VCAM1), which is highly expressed on the surface of endothelial cellsu nder d-flow, can serve as am arker for the targeted delivery of drug to the inflamed endothelium.W ec ould selectively deliver anti-miR-712, an inhibitor of ak ey pro-atherogenic miRNA, to VCAM1-expressing immortalized mouse aortic endothelial cells (iMAECs) by hybridizing the inhibitor with acarrier DNA that has ac omplementary sequence and is conjugated to the surface of Au nanospheres. Our results suggest that the combination of VCAM1-binding peptidea nd Au nanosphere could providea ne ffective strategy for the selective deliveryo fa nti-athero-miRNAs or other drugs into inflamed endothelium for the purpose of inhibiting the formation of atherosclerotic plaques.Atherosclerosis is an inflammatorydisease that can lead to avariety of cardiovascular pathologies.[1] Atherosclerotic plaques preferentially develop in the curved or branched arterial regions exposed to disturbed flow (d-flow), which is characterized by ah igh-magnitude, unidirectionals hear stress arising from laminar flow in the straight sections of av asculature. Vascular endothelial cells respond to blood flow through mechanosensors, whicht ransducet he mechanical force associated with flow (i.e.,t he shear stress) into cell signaling events, causing changes to gene expression.[2] One such mechanism of regulation is based upon microRNAs (miRNAs), small non-coding

Bolstering cholesteryl ester hydrolysis in liver: A hepatocyte-targeting gene delivery strategy for potential alleviation of atherosclerosis

“…Inhibition of pathological processes central to the development of disease, by pharmacologically active small molecules [62] or genetic manipulation by siRNA/miRNA/ASOs [63–65], is the most widely accepted/used strategy to reduce the progression of diseases. However, enhancing an endogenous biological process that is necessary for the prevention of disease progression, and more importantly the reversal of established disease, has proven to be challenging mainly because of the lack of suitable platforms for the introduction of the critical gene required to increase the affected pathway.…”

Nanoparticle-Based Approaches towards the Treatment of Atherosclerosis

“…A typical growth process involves two steps: the synthesis of seed nanoparticles and their subsequent growth in solutions containing metal precursors, reducing reagents, and shape-directing reagents [78]. Following these techniques, Sun et al [79] synthesized-via seed-mediated method-Au nanoparticles for further VCAM1 and anti-miR-712 immobilization and delivery to target endothelial cells.…”

Nanoparticles for diagnosis and therapy of atherosclerosis and myocardial infarction: evolution toward prospective theranostic approaches

“…Furthermore, an 80% lower dose of VHPK-CCL-anti-miR-712 as compared with naked anti-miR-712 prevented atheroma formation in a mouse model of atherosclerosis 52 . Recently, gold nanospheres (GNS) with VCAM-1-binding peptide (VHSPNKKGGSKGC) targeted to inflamed endothelium were also used as a vehicle for anti-miR-712 to inhibit the formation of atherosclerotic plaques 53 .…”