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Πέμπτη 14 Ιανουαρίου 2021

Delivery of Anti‐microRNA‐712 to Inflamed Endothelial Cells Using Poly(β‐amino ester) Nanoparticles Conjugated with VCAM‐1 Targeting Peptide

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Delivery of Anti‐microRNA‐712 to Inflamed Endothelial Cells Using Poly(β‐amino ester) Nanoparticles Conjugated with VCAM‐1 Targeting Peptide

In this study, novel poly(β‐amino ester) (pBAE) nanoparticles (NPs) conjugated with VHPK peptides that target vascular cell adhesion molecule 1 are developed and used to deliver RNA interference drugs to inflamed endothelial cells (ECs). Specifically, these VHPK‐conjugated pBAE NPs successfully deliver anti‐microRNA‐712 to inflamed ECs both in vitro and in vivo and reduce expression of the pro‐atherogenic microRNA‐712.


Abstract

Endothelial cells (ECs) are an important target for therapy in a wide range of diseases, most notably atherosclerosis. Developing efficient nanoparticle (NP) systems that deliver RNA interference (RNAi) drugs specifically to dysfunctional ECs in vivo to modulate their gene expression remains a challenge. To date, several lipid‐based NPs are developed and shown to deliver RNAi to ECs, but few of them are optimized to specifically target dysfunctional endothelium. Here, a novel, targeted poly(β‐amino ester) (pBAE) NP is demonstrated. This pBAE NP is conjugated with VHPK peptides that target vascular cell adhesion molecule 1 protein, overexpressed on inflamed EC membranes. To test this approach, the novel NPs are used to deliver anti‐microRNA‐712 (anti‐miR‐712) specifically to inflamed ECs both in vitro and in vivo, reducing the high expression of pro‐atherogenic miR‐712. A single administration of anti‐miR‐712 using the VHPK‐conjugated‐pBAE NPs in mic e significantly reduce miR‐712 expression, while preventing the loss of its target gene, tissue inhibitor of metalloproteinase 3 (TIMP3) in inflamed endothelium. miR‐712 and TIMP3 expression are unchanged in non‐inflamed endothelium. This novel, targeted‐delivery platform may be used to deliver RNA therapeutics specifically to dysfunctional endothelium for the treatment of vascular disease.

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