Dual use of amphiphilic macromolecules as cholesterol efflux triggers and inhibitors of macrophage athero-inflammation

Nicole M. Iverson, Nicole M. Plourde, Sarah M. Sparks, Jinzhong Wang, Ekta N. Patel, Pratik S. Shah, Daniel R. Lewis, Kyle R. Zablocki, Gary B. Nackman, Kathryn E. Uhrich, Prabhas Moghe

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Activated vascular wall macrophages can rapidly internalize modified lipoproteins and escalate the growth of atherosclerotic plaques. This article proposes a biomaterials-based therapeutic intervention for depletion of non-regulated cholesterol accumulation and inhibition of inflammation of macrophages. Macromolecules with high scavenger receptor (SR)-binding activity were investigated for SR-mediated delivery of agonists to cholesterol-trafficking nuclear liver-X receptors. From a diverse feature space of a family of amphiphilic macromolecules of linear and aromatic mucic acid backbones modified with varied aliphatic chains and conjugated with differentially branched poly(ethylene glycol), a key molecule (carboxyl-terminated, C12-derivatized, linear mucic acid backbone) was selected for its ability to preferentially bind scavenger receptor A (SR-A) as the key target. At a basal level, this macromolecule suppressed the pro-inflammatory signaling of activated THP-1 macrophages while competitively lowering oxLDL uptake in vitro through scavenger receptor SRA-1 targeting. To further deplete intracellular cholesterol, the core macromolecule structure was exploited to solubilize a hydrophobic small molecule agonist for nuclear Liver-X Receptors, which regulate the efflux of intracellular cholesterol. The macromolecule-encapsulated agonist system was found to reduce oxLDL accumulation by 88% in vitro in comparison to controls. in vivo studies were designed to release the macromolecules (with or without encapsulated agonist) to injured carotid arteries within Sprague Dawley rats fed a high fat diet, conditions that yield enhanced cholesterol accumulation and macrophage recruitment. The macromolecules lowered intimal levels of accumulated cholesterol (50% for macromolecule alone; 70% for macromolecule-encapsulated agonist) and inhibited macrophage retention (92% for macromolecule; 96% for macromolecule-encapsulated agonist; 4 days) relative to non-treated controls. Thus, this study highlights the promise of designing bioactive macromolecule therapeutics based on scavenger receptor targeting, for potential management of vascular arterial disease.

Original languageEnglish (US)
Pages (from-to)8319-8327
Number of pages9
JournalBiomaterials
Volume32
Issue number32
DOIs
StatePublished - Nov 1 2011

Fingerprint

Macrophages
Cholesterol
Scavenger Receptors
Macromolecules
Inflammation
Tunica Intima
Ethylene Glycol
Biocompatible Materials
High Fat Diet
Atherosclerotic Plaques
Vascular Diseases
Carotid Arteries
Liver
Lipoproteins
Blood Vessels
Sprague Dawley Rats
Molecules
Therapeutics
Nutrition
Growth

All Science Journal Classification (ASJC) codes

  • Mechanics of Materials
  • Ceramics and Composites
  • Bioengineering
  • Biophysics
  • Biomaterials

Cite this

Iverson, Nicole M. ; Plourde, Nicole M. ; Sparks, Sarah M. ; Wang, Jinzhong ; Patel, Ekta N. ; Shah, Pratik S. ; Lewis, Daniel R. ; Zablocki, Kyle R. ; Nackman, Gary B. ; Uhrich, Kathryn E. ; Moghe, Prabhas. / Dual use of amphiphilic macromolecules as cholesterol efflux triggers and inhibitors of macrophage athero-inflammation. In: Biomaterials. 2011 ; Vol. 32, No. 32. pp. 8319-8327.
@article{33c32e74e4b0464695b1ac31b9e676a1,
title = "Dual use of amphiphilic macromolecules as cholesterol efflux triggers and inhibitors of macrophage athero-inflammation",
abstract = "Activated vascular wall macrophages can rapidly internalize modified lipoproteins and escalate the growth of atherosclerotic plaques. This article proposes a biomaterials-based therapeutic intervention for depletion of non-regulated cholesterol accumulation and inhibition of inflammation of macrophages. Macromolecules with high scavenger receptor (SR)-binding activity were investigated for SR-mediated delivery of agonists to cholesterol-trafficking nuclear liver-X receptors. From a diverse feature space of a family of amphiphilic macromolecules of linear and aromatic mucic acid backbones modified with varied aliphatic chains and conjugated with differentially branched poly(ethylene glycol), a key molecule (carboxyl-terminated, C12-derivatized, linear mucic acid backbone) was selected for its ability to preferentially bind scavenger receptor A (SR-A) as the key target. At a basal level, this macromolecule suppressed the pro-inflammatory signaling of activated THP-1 macrophages while competitively lowering oxLDL uptake in vitro through scavenger receptor SRA-1 targeting. To further deplete intracellular cholesterol, the core macromolecule structure was exploited to solubilize a hydrophobic small molecule agonist for nuclear Liver-X Receptors, which regulate the efflux of intracellular cholesterol. The macromolecule-encapsulated agonist system was found to reduce oxLDL accumulation by 88{\%} in vitro in comparison to controls. in vivo studies were designed to release the macromolecules (with or without encapsulated agonist) to injured carotid arteries within Sprague Dawley rats fed a high fat diet, conditions that yield enhanced cholesterol accumulation and macrophage recruitment. The macromolecules lowered intimal levels of accumulated cholesterol (50{\%} for macromolecule alone; 70{\%} for macromolecule-encapsulated agonist) and inhibited macrophage retention (92{\%} for macromolecule; 96{\%} for macromolecule-encapsulated agonist; 4 days) relative to non-treated controls. Thus, this study highlights the promise of designing bioactive macromolecule therapeutics based on scavenger receptor targeting, for potential management of vascular arterial disease.",
author = "Iverson, {Nicole M.} and Plourde, {Nicole M.} and Sparks, {Sarah M.} and Jinzhong Wang and Patel, {Ekta N.} and Shah, {Pratik S.} and Lewis, {Daniel R.} and Zablocki, {Kyle R.} and Nackman, {Gary B.} and Uhrich, {Kathryn E.} and Prabhas Moghe",
year = "2011",
month = "11",
day = "1",
doi = "https://doi.org/10.1016/j.biomaterials.2011.07.039",
language = "English (US)",
volume = "32",
pages = "8319--8327",
journal = "Biomaterials",
issn = "0142-9612",
publisher = "Elsevier BV",
number = "32",

}

Iverson, NM, Plourde, NM, Sparks, SM, Wang, J, Patel, EN, Shah, PS, Lewis, DR, Zablocki, KR, Nackman, GB, Uhrich, KE & Moghe, P 2011, 'Dual use of amphiphilic macromolecules as cholesterol efflux triggers and inhibitors of macrophage athero-inflammation', Biomaterials, vol. 32, no. 32, pp. 8319-8327. https://doi.org/10.1016/j.biomaterials.2011.07.039

Dual use of amphiphilic macromolecules as cholesterol efflux triggers and inhibitors of macrophage athero-inflammation. / Iverson, Nicole M.; Plourde, Nicole M.; Sparks, Sarah M.; Wang, Jinzhong; Patel, Ekta N.; Shah, Pratik S.; Lewis, Daniel R.; Zablocki, Kyle R.; Nackman, Gary B.; Uhrich, Kathryn E.; Moghe, Prabhas.

In: Biomaterials, Vol. 32, No. 32, 01.11.2011, p. 8319-8327.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dual use of amphiphilic macromolecules as cholesterol efflux triggers and inhibitors of macrophage athero-inflammation

AU - Iverson, Nicole M.

AU - Plourde, Nicole M.

AU - Sparks, Sarah M.

AU - Wang, Jinzhong

AU - Patel, Ekta N.

AU - Shah, Pratik S.

AU - Lewis, Daniel R.

AU - Zablocki, Kyle R.

AU - Nackman, Gary B.

AU - Uhrich, Kathryn E.

AU - Moghe, Prabhas

PY - 2011/11/1

Y1 - 2011/11/1

N2 - Activated vascular wall macrophages can rapidly internalize modified lipoproteins and escalate the growth of atherosclerotic plaques. This article proposes a biomaterials-based therapeutic intervention for depletion of non-regulated cholesterol accumulation and inhibition of inflammation of macrophages. Macromolecules with high scavenger receptor (SR)-binding activity were investigated for SR-mediated delivery of agonists to cholesterol-trafficking nuclear liver-X receptors. From a diverse feature space of a family of amphiphilic macromolecules of linear and aromatic mucic acid backbones modified with varied aliphatic chains and conjugated with differentially branched poly(ethylene glycol), a key molecule (carboxyl-terminated, C12-derivatized, linear mucic acid backbone) was selected for its ability to preferentially bind scavenger receptor A (SR-A) as the key target. At a basal level, this macromolecule suppressed the pro-inflammatory signaling of activated THP-1 macrophages while competitively lowering oxLDL uptake in vitro through scavenger receptor SRA-1 targeting. To further deplete intracellular cholesterol, the core macromolecule structure was exploited to solubilize a hydrophobic small molecule agonist for nuclear Liver-X Receptors, which regulate the efflux of intracellular cholesterol. The macromolecule-encapsulated agonist system was found to reduce oxLDL accumulation by 88% in vitro in comparison to controls. in vivo studies were designed to release the macromolecules (with or without encapsulated agonist) to injured carotid arteries within Sprague Dawley rats fed a high fat diet, conditions that yield enhanced cholesterol accumulation and macrophage recruitment. The macromolecules lowered intimal levels of accumulated cholesterol (50% for macromolecule alone; 70% for macromolecule-encapsulated agonist) and inhibited macrophage retention (92% for macromolecule; 96% for macromolecule-encapsulated agonist; 4 days) relative to non-treated controls. Thus, this study highlights the promise of designing bioactive macromolecule therapeutics based on scavenger receptor targeting, for potential management of vascular arterial disease.

AB - Activated vascular wall macrophages can rapidly internalize modified lipoproteins and escalate the growth of atherosclerotic plaques. This article proposes a biomaterials-based therapeutic intervention for depletion of non-regulated cholesterol accumulation and inhibition of inflammation of macrophages. Macromolecules with high scavenger receptor (SR)-binding activity were investigated for SR-mediated delivery of agonists to cholesterol-trafficking nuclear liver-X receptors. From a diverse feature space of a family of amphiphilic macromolecules of linear and aromatic mucic acid backbones modified with varied aliphatic chains and conjugated with differentially branched poly(ethylene glycol), a key molecule (carboxyl-terminated, C12-derivatized, linear mucic acid backbone) was selected for its ability to preferentially bind scavenger receptor A (SR-A) as the key target. At a basal level, this macromolecule suppressed the pro-inflammatory signaling of activated THP-1 macrophages while competitively lowering oxLDL uptake in vitro through scavenger receptor SRA-1 targeting. To further deplete intracellular cholesterol, the core macromolecule structure was exploited to solubilize a hydrophobic small molecule agonist for nuclear Liver-X Receptors, which regulate the efflux of intracellular cholesterol. The macromolecule-encapsulated agonist system was found to reduce oxLDL accumulation by 88% in vitro in comparison to controls. in vivo studies were designed to release the macromolecules (with or without encapsulated agonist) to injured carotid arteries within Sprague Dawley rats fed a high fat diet, conditions that yield enhanced cholesterol accumulation and macrophage recruitment. The macromolecules lowered intimal levels of accumulated cholesterol (50% for macromolecule alone; 70% for macromolecule-encapsulated agonist) and inhibited macrophage retention (92% for macromolecule; 96% for macromolecule-encapsulated agonist; 4 days) relative to non-treated controls. Thus, this study highlights the promise of designing bioactive macromolecule therapeutics based on scavenger receptor targeting, for potential management of vascular arterial disease.

UR - http://www.scopus.com/inward/record.url?scp=80052372756&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052372756&partnerID=8YFLogxK

U2 - https://doi.org/10.1016/j.biomaterials.2011.07.039

DO - https://doi.org/10.1016/j.biomaterials.2011.07.039

M3 - Article

VL - 32

SP - 8319

EP - 8327

JO - Biomaterials

JF - Biomaterials

SN - 0142-9612

IS - 32

ER -