title: Multifunctional Nanoparticles Facilitate Molecular Targeting and miRNA Delivery to Inhibit Atherosclerosis in ApoE(-/-) Mice.
abstract: The current study presents an effective and selective multifunctional nanoparticle used to deliver antiatherogenic therapeutics to inflamed pro-atherogenic regions without off-target changes in gene expression or particle-induced toxicities. MicroRNAs (miRNAs) regulate gene expression, playing a critical role in biology and disease including atherosclerosis. While anti-miRNA are emerging as therapeutics, numerous challenges remain due to their potential off-target effects, and therefore the development of carriers for selective delivery to diseased sites is important. Yet, co-optimization of multifunctional nanoparticles with high loading efficiency, a hidden cationic domain to facilitate lysosomal escape and a dense, stable incorporation of targeting moieties is challenging. Here, we create coated, cationic lipoparticles (CCLs), containing anti-miR-712 (∼1400 molecules, >95% loading efficiency) within the core and with a neutral coating, decorated with 5 mol % of peptide (VHPK) to target vascular cell adhesion molecule 1 (VCAM1). Optical imaging validated disease-specific accumulation as anti-miR-712 was efficiently delivered to inflamed mouse aortic endothelial cells in vitro and in vivo. As with the naked anti-miR-712, the delivery of VHPK-CCL-anti-miR-712 effectively downregulated the d-flow induced expression of miR-712 and also rescued the expression of its target genes tissue inhibitor of metalloproteinase 3 (TIMP3) and reversion-inducing-cysteine-rich protein with kazal motifs (RECK) in the endothelium, resulting in inhibition of metalloproteinase activity. Moreover, an 80% lower dose of VHPK-CCL-anti-miR-712 (1 mg/kg dose given twice a week), as compared with naked anti-miR-712, prevented atheroma formation in a mouse model of atherosclerosis. While delivery of naked anti-miR-712 alters expression in multiple organs, miR-712 expression in nontargeted organs was unchanged following VHPK-CCL-anti-miR-712 delivery.
authors: Department of Biomedical Engineering, University of California , Davis, California 95616, United States.
authors: Azadeh
authors: A
authors: Kheirolomoom
authors: Chan Woo
authors: CW
authors: Kim
authors: Department of Biomedical Engineering, University of California , Davis, California 95616, United States.
authors: Jai Woong
authors: JW
authors: Seo
authors: Sandeep
authors: S
authors: Kumar
authors: Dong Ju
authors: DJ
authors: Son
authors: Department of Biomedical Engineering, University of California , Davis, California 95616, United States.
authors: M Karen J
authors: MK
authors: Gagnon
authors: Department of Biomedical Engineering, University of California , Davis, California 95616, United States.
authors: Elizabeth S
authors: ES
authors: Ingham
authors: Department of Biomedical Engineering, University of California , Davis, California 95616, United States.
authors: Katherine W
authors: KW
authors: Ferrara
authors: Hanjoong
authors: H
authors: Jo
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D018014:Gene Transfer Techniques; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D001057:Apolipoproteins E; D035683:MicroRNAs
keywords: anti-miRNA; atherosclerosis; endothelial inflammation; microRNA; multifunctional particles; targeted delivery