Selective Targeting of Liposomes to Macrophages Using a Ligand with High Affinity for the Macrophage Scavenger Receptor Class A

Rensen, Patrick C.N.; Gras, J; Lindfors, Eva K.; Dijk, Ko Willems van; Jukema, J Wouter; Berkel, Theo J.C. Van; Biessen, Erik A.L.

doi:10.2174/157016306778108893

Cited by 30 publications

(20 citation statements)

References 35 publications

(68 reference statements)

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“…Selective SR-AI mediated uptake of PP1 targeted streptavidin could be confirmed in vivo, as in vivo kinetics of this carrier was altered in SR-AI Ϫ/Ϫ / CD36 Ϫ/Ϫ mice. Poly-I was able to displace phage binding to SR-AI, 31 but it does not bind to CD36, indicating that immobilized PP1 uptake is mainly SR-AI dependent.…”

Section: Discussionmentioning

confidence: 94%

“…31 Differences in accumulation in heart, spleen and lung likely reflect intrinsic differences in M13 phage versus streptavidin clearance. It should be noted that the relative organ uptake of 125 I-streptavidin may in fact be considerably underestimated because of the very effective breakdown and excretion of iodinated substrates by SR-AI.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, targeted delivery with oligodeoxyguanosine lacked the desired specificity and elicited Toll-like receptor dependent immune response. 31 Synthetic PP1 may contrast favorably to these tools in this regard. It shows a similar to higher in vivo accumulation ratio compared with alternatives, such as macrophage-targeted immunomicelles, 17 MDA2, 18 oxidized low-density lipoprotein targeted 18 and tyrosine polyethylene glycol micelles 37 and high-density lipoprotein-based contrast agent 38 (Table II in the online-only Data Supplement).…”

mentioning

confidence: 99%

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Design and Validation of a Specific Scavenger Receptor Class AI Binding Peptide for Targeting the Inflammatory Atherosclerotic Plaque

Segers

Molenaar

et al. 2012

ATVB

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Objective-Scavenger receptor A (SR-A) is abundantly expressed by macrophage and plays a critical role in foam cell formation and atherogenesis. In search of selective SR-AI antagonists, we have used affinity selection of a phage displayed peptide library on the synthetic extracellular domain of SR-AI. Methods and Results-Phage selection led to an almost 1,000-fold enrichment of SR-AI binding phage, which bound avidly to human THP-1 cells. A 15-mer corresponding to the peptide insert of the major SR-AI binding phage (PP1) displaced phage binding to SR-AI. Peptides, docked to a streptavidin scaffold, were effectively internalized by macrophages in an SR-AI-dependent manner. The enriched phage pool and streptavidin bound PP1 exhibited marked uptake by hepatic macrophages in mice. Importantly, PP1 significantly increased streptavidin as well as particulate accumulation in advanced aortic plaques, and in particular intraplaque macrophage, of apolipoprotein E Ϫ/Ϫ mice. 2,6 and can exist in 1 of 3 isoforms (SR-AI, SR-AII, and SR-AIII). Conclusion7,8 As a pattern recognition receptor, it displays a very broad substrate profile, internalizing modified low-density lipoprotein, polynucleotides (eg, polyinosinic and polyguanylic acid), polysaccharides (eg, fucoidan), and lipopolysaccharides.9-11 SR-A was found to be abundantly expressed by macrophages, foam cells, and smooth muscle cells 12 in atherosclerotic lesions but not in the normal vessel wall.13,14 A causal role of SR-A in atherogenesis was first established by Suzuki et al, 4 showing reduced lesion formation in SR-A-deficient apolipoprotein E (ApoE) Ϫ/Ϫ , a notion confirmed in further studies. 15The marked expression of SR-AI by macrophages in plaques-especially vulnerable plaques-and the efficient endocytosis of its substrates by SR-AI render it not only an interesting candidate for therapeutic intervention in atherosclerosis but also for targeted drug delivery and imaging approaches. 16 Application of selective SR-AI ligands as homing device for contrast agents may therefore allow molecular imaging of atherosclerotic plaques in general but also give insight into their actual composition and stability. Illustrative, macrophagetargeted molecular magnetic resonance imaging of atherosclerotic plaques has already been shown for immunomicelles equipped with antibodies for macrophage scavenger receptor 17 or for oxidation specific epitopes. 18The bulky and chemically complex nature of its macromolecular substrates make ligand design for SR-AI rather unsuccessful, and only a single report was published on a synthetic, moderately selective SR-A antagonist. 19 In this study, we describe the unbiased design of SR-AI antagonists involving the use of phage display on a synthetic receptor comprising the actual ligand-binding pocket of SR-AI. A selective peptide antagonist for SR-AI was identified, which constitutes a promising lead to the development of SR-AI targeted therapy and imaging of atherosclerotic lesions.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Design and Validation of a Specific Scavenger Receptor Class AI Binding Peptide for Targeting the Inflammatory Atherosclerotic Plaque

Segers

Molenaar

et al. 2012

ATVB

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“…The results for the different LXR isoforms suggest that although a selective LXRβ agonist may avoid undesirable hypertriglyceridemia, it may not maximally promote plaque regression. With progress in tissue-specific drug targeting (69)(70)(71)(72), one potential alternative approach to halting the progression of atherosclerosis and promoting its regression would be to develop macrophagespecific LXR agonists.…”

Section: Discussionmentioning

confidence: 99%

LXR promotes the maximal egress of monocyte-derived cells from mouse aortic plaques during atherosclerosis regression

Feig¹,

Pineda-Torra²,

Sanson³

et al. 2010

J. Clin. Invest.

160

161

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We have previously shown that mouse atherosclerosis regression involves monocyte-derived (CD68 + ) cell emigration from plaques and is dependent on the chemokine receptor CCR7. Concurrent with regression, mRNA levels of the gene encoding LXRα are increased in plaque CD68 + cells, suggestive of a functional relationship between LXR and CCR7. To extend these results, atherosclerotic Apoe -/-mice sufficient or deficient in CCR7 were treated with an LXR agonist, resulting in a CCR7-dependent decrease in plaque CD68 + cells. To test the requirement for LXR for CCR7-dependent regression, we transplanted aortic arches from atherosclerotic Apoe -/-mice, or from Apoe -/-mice with BM deficiency of LXRα or LXRβ, into WT recipients. Plaques from both LXRα-and LXRβ-deficient Apoe -/-mice exhibited impaired regression. In addition, the CD68 + cells displayed reduced emigration and CCR7 expression. Using an immature DC line, we found that LXR agonist treatment increased Ccr7 mRNA levels. This increase was blunted when LXRα and LXRβ levels were reduced by siRNAs. Moreover, LXR agonist treatment of primary human immature DCs resulted in functionally significant upregulation of CCR7. We conclude that LXR is required for maximal effects on plaque CD68 + cell expression of CCR7 and monocyte-derived cell egress during atherosclerosis regression in mice.

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“…The challenge for the future in the stabilization of atherosclerotic plaques will be to turn on the protective prosurvival effects of autophagy in a selective manner, without activating unwanted death pathways or proinflammatory signaling cascades. With progress being made in tissue-specific drug targeting using nanoparticles, 48 one potential future approach to stabilize atherosclerotic plaques would be to develop macrophage-specific autophagy inducers combined with antiinflammatory drugs. However, stimulation of autophagy can only be beneficial if autophagic flux is not impaired, because this condition could lead to lysosomal leakage or ejection of autophagosomes, as well as the induction of cell death.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Autophagy in Atherosclerosis

Schrijvers

Meyer

Martinet

2011

ATVB

159

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Abstract-Evidence is accumulating that autophagy occurs in advanced atherosclerotic plaques. Although there is an almost relentless discovery of molecules that are involved in autophagy, studies of selective autophagy induction or inhibition using knockout mice are just now beginning to reveal its biological significance. Most likely, autophagy safeguards plaque cells against cellular distress, in particular oxidative injury, by degrading the damaged intracellular material. In this way, autophagy is protective and contributes to cellular recovery in an unfavorable environment. Pharmacological approaches have recently been developed to stabilize vulnerable, rupture-prone lesions through induction of autophagy. This approach has proven to be successful in short-term studies. However, how autophagy induction affects processes such as inflammation remains to be elucidated and is currently under investigation. This review highlights the possibilities for exploiting autophagy as a drug target for plaque stabilization. Key Words: atherosclerosis Ⅲ pharmacology Ⅲ autophagy Ⅲ cell death Ⅲ plaque stabilization A utophagy, or "self eating," refers to a conserved cellular process for the turnover of organelles and proteins that occurs in all eukaryotic cells. 1 It is activated as an adaptive response to environmental stress (eg, nutrient deprivation, hypoxia, oxidative stress, exposure to xenobiotics) to promote cell survival through the recycling of precursors (amino acids, free fatty acids, nucleotides) derived from the degradation of endogenous cellular components. Typical of autophagy is the formation of double-membrane structures, called phagophores, that engulf intracellular material such as protein aggregates, lipid droplets, and complete organelles for degradation (Figure 1). The phagophore expands and, on completion, forms an autophagosome, which then fuses with lysosomes, thereby generating an autophagolysosome. 2 Incorporation of the outer autophagosomal membrane in the lysosomal membrane allows the degradation of the remaining inner single membrane and the cytoplasmic content of the autophagosome by lysosomal hydrolases. The molecular machinery and the signaling cascades that regulate autophagy are very complex and beyond the scope of this review, but they are nicely reviewed elsewhere. 3,4 Autophagy generally acts as a housekeeping mechanism, and it is crucially involved in the maintenance of normal cellular homeostasis. When stimulated by cellular stress conditions, autophagy functions as a self-cannibalization pathway that promotes cell survival in an unfavorable environment. Preclinical studies have demonstrated that autophagy is associated with cancer, neurodegenerative disorders (eg, Alzheimer, Parkinson, and Huntington diseases), embryogenesis, aging, and immunity, and also with cardiovascular disease, including ischemia-reperfusion injury of the heart, cardiomyopathy, and atherosclerosis. 5-9 Despite tremendous recent advances in the field, the functional significance of autophagy in human disease remain...

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Selective Targeting of Liposomes to Macrophages Using a Ligand with High Affinity for the Macrophage Scavenger Receptor Class A

Cited by 30 publications

References 35 publications

Design and Validation of a Specific Scavenger Receptor Class AI Binding Peptide for Targeting the Inflammatory Atherosclerotic Plaque

Design and Validation of a Specific Scavenger Receptor Class AI Binding Peptide for Targeting the Inflammatory Atherosclerotic Plaque

LXR promotes the maximal egress of monocyte-derived cells from mouse aortic plaques during atherosclerosis regression

Autophagy in Atherosclerosis

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