Engineered Polymeric Nanoparticles for Receptor-Targeted Blockage of Oxidized Low Density Lipoprotein Uptake and Atherogenesis in Macrophages

Chnari, Evangelia; Nikitczuk, Jessica S.; Wang, Jinzhong; Uhrich, Kathryn E.; Moghe, Prabhas V.

doi:10.1021/bm0600872

Cited by 54 publications

(73 citation statements)

References 51 publications

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“…2C). Many of these same stereochemistries also demonstrated significant binding and cellular uptake via SR MSR1; notably, within this group only M 12 PEG and aM 12 PEG revealed binding to CD36 ( Fig. 2D and SI Appendix, Fig.…”

Section: Am Nps With Comprehensive Atheroprotective Profiles Can Bementioning

confidence: 90%

“…Interestingly, the NPs with shell AMs composed of specific stereochemistry with chiral symmetry, M 12 PEG, bM 12 PEG, cM 12 PEG, aM 12 PEG, and T Meso 12 PEG, prevented the uptake of oxLDL in cultured hMDMs to a greater extent than AMs with alternate stereochemistries (Fig. 2C).…”

Section: Am Nps With Comprehensive Atheroprotective Profiles Can Bementioning

confidence: 96%

“…Finally, to evaluate the atheroprotective effects of NPs, we screened the ability of NP formulations to down-regulate scavenger receptor surface expression. Several of the most potent oxLDL-inhibiting and MSR1-binding NP formulations also revealed the ability to down-regulate MSR1 and CD36 surface expression, specifically the NPs with M 12 PEG, bM 12 PEG, cM 12 . These results suggests that, in addition to receptor binding, the NPs are able to disrupt the cycle of SR replenishment induced by oxLDL that leads to uncontrolled oxLDL uptake and foam cell formation.…”

Section: Am Nps With Comprehensive Atheroprotective Profiles Can Bementioning

confidence: 99%

“…Sugar-based amphiphilic macromolecules (AM) have been conceptualized as fully synthetic constructs that exhibit binding to SRs by mimicking the charge and hydrophobicity of oxidized lipoproteins (12). Using both in vitro and in silico models, AMs were found to competitively bind macrophage SRs, thus inhibiting modified lipid internalization and foam cell formation (13)(14)(15).…”

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confidence: 99%

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Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo

Lewis¹,

Petersen²,

York³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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104

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Atherosclerosis, the build-up of occlusive, lipid-rich plaques in arterial walls, is a focal trigger of chronic coronary, intracranial, and peripheral arterial diseases, which together account for the leading causes of death worldwide. Although the directed treatment of atherosclerotic plaques remains elusive, macrophages are a natural target for new interventions because they are recruited to lipid-rich lesions, actively internalize modified lipids, and convert to foam cells with diseased phenotypes. In this work, we present a nanomedicine platform to counteract plaque development based on two building blocks: first, at the single macrophage level, sugarbased amphiphilic macromolecules (AMs) were designed to competitively block oxidized lipid uptake via scavenger receptors on macrophages; second, for sustained lesion-level intervention, AMs were fabricated into serum-stable core/shell nanoparticles (NPs) to rapidly associate with plaques and inhibit disease progression in vivo. An AM library was designed and fabricated into NP compositions that showed high binding and down-regulation of both MSR1 and CD36 scavenger receptors, yielding minimal accumulation of oxidized lipids. When intravenously administered to a mouse model of cardiovascular disease, these AM NPs showed a pronounced increase in lesion association compared with the control nanoparticles, causing a significant reduction in neointimal hyperplasia, lipid burden, cholesterol clefts, and overall plaque occlusion. Thus, synthetic macromolecules configured as NPs are not only effectively mobilized to lipid-rich lesions but can also be deployed to counteract atheroinflammatory vascular diseases, highlighting the promise of nanomedicines for hyperlipidemic and metabolic syndromes.atherosclerosis | nanomedicine | biomaterials | macrophages C ardiovascular disease is responsible for one in every three deaths in the United States (1). Chronically high circulating levels of low-density lipoprotein (LDL) deposit and undergo oxidation (oxLDL) within arterial walls, which consequently stimulates endothelial inflammation and recruitment of circulating monocytes (2). These recruited cells differentiate into macrophages that overexpress scavenger receptors (SR), which internalize oxLDL in an unregulated fashion, propagating the inflammatory cascade and leading to multifocal sites of neo-intimal plaques (3, 4). The prevalent cardiovascular therapeutics, which are focused on lowering circulating levels of LDL, are unable to directly target these developing atherosclerotic lesions (5).To address this unmet need, nanoassemblies have been designed to reach narrow vessels and abrogate the lipid deposition and atheroinflammatory phenomena that catalyze plaque establishment, growth, and ensuing acute or chronic cardiovascular events (6). Reports on recent advances in amphiphilic micelles require release of pharmacologic factors to counteract plaque aggravation and local delivery or the conjugation of targeting ligands to reach areas of atherosclerotic lesions (7-9). The ma...

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Section: Am Nps With Comprehensive Atheroprotective Profiles Can Bementioning

confidence: 90%

Section: Am Nps With Comprehensive Atheroprotective Profiles Can Bementioning

confidence: 96%

Section: Am Nps With Comprehensive Atheroprotective Profiles Can Bementioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo

Lewis¹,

Petersen²,

York³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

104

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“…Cellular specificity combined with endocytosis ensures that once the nanoparticle reaches its target, it is readily internalized. For this reason, very often the receptor of choice is associated with endocytosis, such as transferrin receptors (Tanaka et al 2001;Iinuma et al 2002), EGF receptors (Kirpotin et al 2006;Zeng et al 2006;Lee et al 2007;Mi et al 2013), albumin receptors (Schmid et al 2007;Kratz 2008), folate receptors (Lee and Low 1994;Pan et al 2002;Zhang et al 2007;Han et al 2009), and LDL receptors (Chnari et al 2006), to name a few.…”

Section: Surface Chemistrymentioning

confidence: 99%

Exploiting Endocytosis for Nanomedicines

Akinc

Battaglia

2013

Cold Spring Harbor Perspectives in Biology

189

169

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In this article, we briefly review the endocytic pathways used by cells, pointing out their defining characteristics and highlighting physical limitations that may direct the internalization of nanoparticles to a subset of these pathways. A more detailed description of these pathways is presented in the literature. We then focus on the endocytosis of nanomedicines and present how various nanomaterial parameters impact these endocytic processes. This topic is an area of active research, motivated by the recognition that an improved understanding of how nanomaterials interact at the molecular, cellular, and whole-organism level will lead to the design of better nanomedicines in the future. Next, we briefly review some of the important nanomedicines already on the market or in clinical development that serve to exemplify how endocytosis can be exploited for medical benefit. Finally, we present some key unanswered questions and remaining challenges to be addressed by the field.

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ox‐LDL increases microRNA‐29a transcription through upregulating YY1 and STAT1 in macrophages

Jian

Dai

Yao

et al. 2017

Cell Biology International

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Macrophages and oxidized low-density lipoprotein (ox-LDL) have been verified playing vital roles in the pathogenesis of atherosclerosis (AS). Previous studies demonstrated that microRNA-29a (miR-29a) was upregulated in many atherogenic process and cells, thus acting as an important participant in AS. But the detailed regulation mechanism of miR-29a in AS has not been fully understood. In our study, we demonstrated a positive feedback loop of ox-LDL-SRA-miR-29a. Furthermore, we found that YY1 and STAT1 were upregulated in ox-LDL-stimulating macrophages followed by translocation in the nucleus and binding to the transcriptional promoter region of miR-29a, thus leading to the increase of miR-29a expression. In addition, we demonstrated that JAK1/2 signaling was involved in miR-29a upregulation. Finally, we found that miR-29a played important roles in the secretion of proinflammation factors and lipid uptake in macrophages. We uncovered the molecular mechanism and provide novel insights into the function and regulatory network of miR-29a expression regulated by ox-LDL in macrophages.

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Engineered Polymeric Nanoparticles for Receptor-Targeted Blockage of Oxidized Low Density Lipoprotein Uptake and Atherogenesis in Macrophages

Cited by 54 publications

References 51 publications

Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo

Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo

Exploiting Endocytosis for Nanomedicines

ox‐LDL increases microRNA‐29a transcription through upregulating YY1 and STAT1 in macrophages

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