Multifunctional Nanoparticles Facilitate Molecular Targeting and miRNA Delivery to Inhibit Atherosclerosis in ApoE-/- Mice

Azadeh Kheirolomoom, Chan Woo Kim, Jai Seo, Sandeep Kumar, Dong Ju Son, M. Karen J Gagnon, Elizabeth S. Ingham, Katherine W. Ferrara, Hanjoong Jo

Research output: Contribution to journalArticle

58 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)8885-8897
Number of pages13
JournalACS Nano
Volume9
Issue number9
DOIs
StatePublished - Sep 22 2015

Fingerprint

arteriosclerosis
Apolipoproteins E
MicroRNAs
Gene expression
mice
delivery
Tissue Inhibitor of Metalloproteinase-3
Nanoparticles
nanoparticles
Molecules
Vascular Cell Adhesion Molecule-1
gene expression
Cell adhesion
Endothelial cells
Metalloproteases
organs
Peptides
Cysteine
Toxicity
Genes

Keywords

  • anti-miRNA
  • atherosclerosis
  • endothelial inflammation
  • microRNA
  • multifunctional particles
  • targeted delivery

ASJC Scopus subject areas

  • Engineering(all)
  • Materials Science(all)
  • Physics and Astronomy(all)

Cite this

Multifunctional Nanoparticles Facilitate Molecular Targeting and miRNA Delivery to Inhibit Atherosclerosis in ApoE-/- Mice. / Kheirolomoom, Azadeh; Kim, Chan Woo; Seo, Jai; Kumar, Sandeep; Son, Dong Ju; Gagnon, M. Karen J; Ingham, Elizabeth S.; Ferrara, Katherine W.; Jo, Hanjoong.

In: ACS Nano, Vol. 9, No. 9, 22.09.2015, p. 8885-8897.

Research output: Contribution to journalArticle

Kheirolomoom, A, Kim, CW, Seo, J, Kumar, S, Son, DJ, Gagnon, MKJ, Ingham, ES, Ferrara, KW & Jo, H 2015, 'Multifunctional Nanoparticles Facilitate Molecular Targeting and miRNA Delivery to Inhibit Atherosclerosis in ApoE-/- Mice', ACS Nano, vol. 9, no. 9, pp. 8885-8897. https://doi.org/10.1021/acsnano.5b02611
Kheirolomoom, Azadeh ; Kim, Chan Woo ; Seo, Jai ; Kumar, Sandeep ; Son, Dong Ju ; Gagnon, M. Karen J ; Ingham, Elizabeth S. ; Ferrara, Katherine W. ; Jo, Hanjoong. / Multifunctional Nanoparticles Facilitate Molecular Targeting and miRNA Delivery to Inhibit Atherosclerosis in ApoE-/- Mice. In: ACS Nano. 2015 ; Vol. 9, No. 9. pp. 8885-8897.
@article{3ebdcba32960465f80a23160e5fd6902,
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.",
keywords = "anti-miRNA, atherosclerosis, endothelial inflammation, microRNA, multifunctional particles, targeted delivery",
author = "Azadeh Kheirolomoom and Kim, {Chan Woo} and Jai Seo and Sandeep Kumar and Son, {Dong Ju} and Gagnon, {M. Karen J} and Ingham, {Elizabeth S.} and Ferrara, {Katherine W.} and Hanjoong Jo",
year = "2015",
month = "9",
day = "22",
doi = "10.1021/acsnano.5b02611",
language = "English (US)",
volume = "9",
pages = "8885--8897",
journal = "ACS Nano",
issn = "1936-0851",
publisher = "American Chemical Society",
number = "9",

}

TY - JOUR

T1 - Multifunctional Nanoparticles Facilitate Molecular Targeting and miRNA Delivery to Inhibit Atherosclerosis in ApoE-/- Mice

AU - Kheirolomoom, Azadeh

AU - Kim, Chan Woo

AU - Seo, Jai

AU - Kumar, Sandeep

AU - Son, Dong Ju

AU - Gagnon, M. Karen J

AU - Ingham, Elizabeth S.

AU - Ferrara, Katherine W.

AU - Jo, Hanjoong

PY - 2015/9/22

Y1 - 2015/9/22

N2 - 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.

AB - 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.

KW - anti-miRNA

KW - atherosclerosis

KW - endothelial inflammation

KW - microRNA

KW - multifunctional particles

KW - targeted delivery

UR - http://www.scopus.com/inward/record.url?scp=84942357979&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84942357979&partnerID=8YFLogxK

U2 - 10.1021/acsnano.5b02611

DO - 10.1021/acsnano.5b02611

M3 - Article

C2 - 26308181

AN - SCOPUS:84942357979

VL - 9

SP - 8885

EP - 8897

JO - ACS Nano

JF - ACS Nano

SN - 1936-0851

IS - 9

ER -