Shuttle/sink model composed of β-cyclodextrin and simvastatin-loaded discoidal reconstituted high-density lipoprotein for enhanced cholesterol efflux and drug uptake in macrophage/foam cells

He, Jianhua; Yang, Yu-Chu; Zhou, Xingyao; Zhang, Wenli; Liu, Jianping

doi:10.1039/c9tb02101a

Cited by 26 publications

(20 citation statements)

References 42 publications

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“…In this delivery system, simvastatin (ST) was selected as a model statin drug to suppress plaque inflammation and promote cholesterol efflux [ [31] , [32] , [33] ]. β-CD-anchored discoidal recombinant high-density lipoprotein (rHDL), termed as NP 3 ST , was utilized as a core as it was shown to possess not only deep plaque penetration property by virtue of its small size but also plaque targeting and cholesterol removal ability [ 34 , 35 ]. Fc was grafted onto hyaluronic acid (HA), and the resulting HA-Fc conjugates were utilized to crosslink NP 3 ST through multivalent host-guest interactions between β-CD/Fc to form ROS-responsive nanoassemblies (HA-Fc/NP 3 ST ) [ 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Reactive oxygen species (ROS)-responsive size-reducible nanoassemblies for deeper atherosclerotic plaque penetration and enhanced macrophage-targeted drug delivery

Zhang

Zhou

et al. 2023

Bioactive Materials

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Section: Introductionmentioning

confidence: 99%

Reactive oxygen species (ROS)-responsive size-reducible nanoassemblies for deeper atherosclerotic plaque penetration and enhanced macrophage-targeted drug delivery

Zhang

Zhou

et al. 2023

Bioactive Materials

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“…The increased penetration of miNano due to the impaired endothelial barrier in atherosclerotic arteries may be another mechanism. We also observed that miNano co-localized well with macrophages within plaques, implying that phagocytosis by monocyte in the circulation followed by accumulation in the plaque may be another way for miNano to enter into plaques, though the latter is less likely since the relatively small diameter of miNano prevents it from phagocytosis [ 58 ]. Like most rHDLs [ 59 ], miNano is eliminated by the liver with limited elimination by the kidney, as shown by fluorescence signal accumulation.…”

Section: Discussionmentioning

confidence: 99%

Phospholipid nanoparticles: Therapeutic potentials against atherosclerosis via reducing cholesterol crystals and inhibiting inflammation

et al. 2021

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Background: Atherosclerosis-related cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Cholesterol crystals (CCs) induce inflammation in atherosclerosis and are associated with unstable plaques and poor prognosis, but no drug can remove CCs in the clinic currently. Methods: We generated a phospholipid-based and high-density lipoprotein (HDL)-like nanoparticle, miNano, and determined CC-dissolving capacity, cholesterol efflux property, and anti-inflammation effects of miNano in vitro. Both normal C57BL/6J and Apoe-deficient mice were used to explore the accumulation of miNano in atherosclerotic plaques. The efficacy and safety of miNano administration to treat atherosclerosis were evaluated in the Ldlr-deficient atherosclerosis model. The CC-dissolving capacity of miNano was also detected using human atherosclerotic plaques ex vivo. Findings: We found that miNano bound to and dissolved CCs efficiently in vitro, and miNano accumulated in atherosclerotic plaques, co-localized with CCs and macrophages in vivo. Administration of miNano inhibited atherosclerosis and improved plaque stability by reducing CCs and macrophages in Ldlr-deficient mice with favorable safety profiles. In macrophages, miNano prevented foam cell formation by enhancing cholesterol efflux and suppressed inflammatory responses via inhibiting TLR4-NF-kB pathway. Finally, in an ex vivo experiment, miNano effectively dissolved CCs in human aortic atherosclerotic plaques. Interpretation: Together, our work finds that phospholipid-based and HDL-like nanoparticle, miNano, has the potential to treat atherosclerosis by targeting CCs and stabilizing plaques.

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“…Low concentrations of HP-β-CD can extract cholesterol from the cell membrane, especially from lipid rafts. At the same time, it can slightly decrease the levels of intracellular cholesterol; however, a high concentration of β-CD causes cholesterol accumulation in the ER [ 37 ]. Lipid rafts are mainly composed of sphingolipids and cholesterol.…”

Section: Discussionmentioning

confidence: 99%

2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress

Zhao

Zhu

et al. 2021

Metabolites

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Cholesterol metabolism affects endoplasmic reticulum (ER) stress and modulates epithelial-mesenchymal transition (EMT). Our previous study demonstrated that 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) attenuated EMT by blocking the transforming growth factor (TGF)-β/Smad signaling pathway and activating ER stress in MDA-MB-231 cells. To further assess the detailed mechanisms between cholesterol metabolism, ER stress, and EMT, LXR-623 (an agonist of LXRα) and simvastatin were used to increase and decrease cholesterol efflux and synthesis, respectively. Here, we found that high HP-β-CD concentrations could locally increase cholesterol levels in the ER by decreasing LXRα expression and increasing Hydroxymethylglutaryl-Coenzyme A reductase (HMGCR) expression in MDA-MB-231 and BT-549 cells, which triggered ER stress and inhibited EMT. Meanwhile, tunicamycin-induced ER stress blocked the TGF-β/Smad signaling pathway. However, low HP-β-CD concentrations can decrease the level of membrane cholesterol, enhance the TGF-β receptor I levels in lipid rafts, which helped to activate TGF-β/Smad signaling pathway, inhibit ER stress and elevate EMT. Based on our findings, the use of high HP-β-CD concentration can lead to cholesterol accumulation in the ER, thereby inducing ER stress, which directly suppresses TGF-β pathway-induced EMT. However, HP-β-CD is proposed to deplete membrane cholesterol at low concentrations and concurrently inhibit ER stress and induce EMT by promoting the TGF-β signaling pathways.

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Shuttle/sink model composed of β-cyclodextrin and simvastatin-loaded discoidal reconstituted high-density lipoprotein for enhanced cholesterol efflux and drug uptake in macrophage/foam cells

Abstract: The combination of β-CD and ST-d-rHDL could serve as a shuttle/sink model to enhance cholesterol efflux and drug uptake in macrophage/foam cells.

Cited by 26 publications

References 42 publications

Reactive oxygen species (ROS)-responsive size-reducible nanoassemblies for deeper atherosclerotic plaque penetration and enhanced macrophage-targeted drug delivery

Reactive oxygen species (ROS)-responsive size-reducible nanoassemblies for deeper atherosclerotic plaque penetration and enhanced macrophage-targeted drug delivery

Phospholipid nanoparticles: Therapeutic potentials against atherosclerosis via reducing cholesterol crystals and inhibiting inflammation

2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress

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