Mechanism of hard-nanomaterial clearance by the liver

Tsoi, Kim; MacParland, Sonya A.; Zhong, Xue; Spetzler, Vinzent N.; Echeverri, Juan; Ouyang, Ben; Fadel, Saleh; Sykes, Edward A.; Goldaracena, Nicolás; Kaths, J. Moritz; Conneely, John B.; Alman, Benjamin A.; Selzner, Markus; Ostrowski, Mario; Adeyi, Oyedele; Zilman, Anton; McGilvray, Ian; Chan, Warren C. W.

doi:10.1038/nmat4718

Cited by 740 publications

(712 citation statements)

References 46 publications

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“…By contrast, nanoparticles can access tissues like the liver via porous ECs and discontinuous basement membranes in the hepatic sinusoids 11–15 . In addition to these barriers, blood flow rates affect nanoparticle targeting by affecting the likelihood a particle leaves the bloodstream 16 .…”

Section: Introductionmentioning

confidence: 99%

A Direct Comparison of in Vitro and in Vivo Nucleic Acid Delivery Mediated by Hundreds of Nanoparticles Reveals a Weak Correlation

et al. 2018

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Endothelial cells and macrophages play active roles in disease, and as a result, are important targets for nucleic acid therapies. While thousands of chemically distinct lipid nanoparticles (LNPs) can be synthesized to deliver nucleic acids, studying more than a few LNPs in vivo is challenging. As a result, it is difficult to understand how nanoparticles target these cells in vivo. Using high throughput LNP barcoding, we quantified how well LNPs delivered DNA barcodes to endothelial cells and macrophages in vitro, as well as endothelial cells and macrophages isolated from the lung, heart, and bone marrow in vivo. We focused on two fundamental questions in drug delivery. First, does in vitro LNP delivery predict in vivo LNP delivery? By comparing how 281 LNPs delivered barcodes to endothelial cells and macrophages in vitro and in vivo, we found in vitro delivery did not predict in vivo delivery. Second, does LNP delivery change within the microenvironment of a tissue? We quantified how 85 LNPs delivered barcodes to eight splenic cell populations, and found that cell types derived from myeloid progenitors tended to be targeted by similar LNPs, relative to cell types derived from lymphoid progenitors. These data demonstrate that barcoded LNPs can elucidate fundamental questions about in vivo nanoparticle delivery.

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Section: Introductionmentioning

confidence: 99%

A Direct Comparison of in Vitro and in Vivo Nucleic Acid Delivery Mediated by Hundreds of Nanoparticles Reveals a Weak Correlation

et al. 2018

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“…Despite the fact that the liver is a major barrier for drug delivery, mechanisms for nanoparticle accumulation in this organ are poorly understood. In particular, it is unclear to what extent each component of the liver contributes to nanoparticle deposition, and it is thought that both cells and physical features play a role [7]. Specifically, the physical organization of the vascular network in the liver is likely to be a major contributing factor [8, 9].…”

Section: Introductionmentioning

confidence: 99%

Contribution of Kupffer cells to liposome accumulation in the liver

Samuelsson

Shen

Blanco

et al. 2017

Colloids and Surfaces B: Biointerfaces

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The liver is a major barrier for site-specific delivery of systemically injected nanoparticles, as up to 90% of the dose is usually captured by this organ. Kupffer cells are thought to be the main cellular component responsible for nanoparticle accumulation in the liver. These resident macrophages form part of the mononuclear phagocyte system, which recognizes and engulfs foreign bodies in the circulatory system. In this study, we have compared two strategies for reducing nanoparticle accumulation in the liver, in order to investigate the specific contribution of Kupffer cells. Specifically, we have performed a comparison of the capability of pegylation and Kupffer cell depletion to reduce liposome accumulation in the liver. Pegylation reduces nanoparticle interactions with all types of cells and can serve as a control for elucidating the role of specific cell populations in liver accumulation. The results indicate that liposome pegylation is a more effective strategy for avoiding liver uptake compared to depletion of Kupffer cells, suggesting that nanoparticle interactions with other cells in the liver may also play a contributing role. This study highlights the need for a more complete understanding of factors that mediate nanoparticle accumulation in the liver and for the exploration of microenvironmental modulation strategies for reducing nanoparticle-cell interactions in this organ.

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“…5 While it is generally accepted that nanoparticles are taken up by liver-resident macrophages (Kupffer cells (KCs)), 6 the principal cell type of the MPS in the liver, significant nanoparticle interactions with other hepatic cells, including liver sinusoidal endothelial cells (LSECs), hepatocytes, and hepatic B-cells, have also been observed. 7−10 In these instances however, the cell-specific mechanisms underpinning these interactions have not been elucidated. A detailed understanding of exactly where and how nanoparticles are sequestered and cleared within the liver is crucial for the effective optimization of nanoparticle-mediated drug delivery.…”

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confidence: 99%

Directing Nanoparticle Biodistribution through Evasion and Exploitation of Stab2-Dependent Nanoparticle Uptake

et al. 2018

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Up to 99% of systemically administered nanoparticles are cleared through the liver. Within the liver, most nanoparticles are thought to be sequestered by macrophages (Kupffer cells), although significant nanoparticle interactions with other hepatic cells have also been observed. To achieve effective cell-specific targeting of drugs through nanoparticle encapsulation, improved mechanistic understanding of nanoparticle–liver interactions is required. Here, we show the caudal vein of the embryonic zebrafish (Danio rerio) can be used as a model for assessing nanoparticle interactions with mammalian liver sinusoidal (or scavenger) endothelial cells (SECs) and macrophages. We observe that anionic nanoparticles are primarily taken up by SECs and identify an essential requirement for the scavenger receptor, stabilin-2 (stab2) in this process. Importantly, nanoparticle–SEC interactions can be blocked by dextran sulfate, a competitive inhibitor of stab2 and other scavenger receptors. Finally, we exploit nanoparticle–SEC interactions to demonstrate targeted intracellular drug delivery resulting in the selective deletion of a single blood vessel in the zebrafish embryo. Together, we propose stab2 inhibition or targeting as a general approach for modifying nanoparticle–liver interactions of a wide range of nanomedicines.

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Mechanism of hard-nanomaterial clearance by the liver

Cited by 740 publications

References 46 publications

A Direct Comparison of in Vitro and in Vivo Nucleic Acid Delivery Mediated by Hundreds of Nanoparticles Reveals a Weak Correlation

A Direct Comparison of in Vitro and in Vivo Nucleic Acid Delivery Mediated by Hundreds of Nanoparticles Reveals a Weak Correlation

Contribution of Kupffer cells to liposome accumulation in the liver

Directing Nanoparticle Biodistribution through Evasion and Exploitation of Stab2-Dependent Nanoparticle Uptake

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