Action of Nanoparticles on Platelet Activation and Plasmatic Coagulation

Frőhlich, Eleonore

doi:10.2174/0929867323666160106151428

Cited by 85 publications

(57 citation statements)

References 130 publications

(96 reference statements)

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“…The mechanisms underlying platelet activation/aggregation differ with the various types of NPs . Moreover, conflicting results were obtained testing NP with different sizes and surface charges . Our results demonstrated that the preincubation of whole blood with NC did not induce any detectable platelet aggregation both prior and after ADP addition, suggesting that physical properties of NC do not influence the platelet biology.…”

Section: Discussionmentioning

confidence: 70%

“…The platelets play an important role in the maintenance of hemostasis and in thrombus formation . NPs can lead to platelet activation directly or interfere with platelet agonist, causing blood‐clotting disorders . The mechanisms underlying platelet activation/aggregation differ with the various types of NPs .…”

Section: Discussionmentioning

confidence: 99%

“…42 NPs can lead to platelet activation directly or interfere with platelet agonist, causing blood-clotting disorders. 19,43 The mechanisms underlying platelet activation/aggregation differ with the various types of NPs. 44 Moreover, conflicting results were obtained testing NP with different sizes and surface charges.…”

Section: Discussionmentioning

confidence: 99%

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Effects of cerium oxide nanoparticles on hemostasis: Coagulation, platelets, and vascular endothelial cells

Turco

Ciofani

Cappello

et al. 2019

J Biomedical Materials Res

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Cerium oxide nanoparticles (nanoceria [NC]) have attracted much attention in biomedicine due to their surface composition that confers interesting redox activities and regenerative properties. Studies have demonstrated that the application of NPs in biomedicine can influence components of hemostatic system, inducing blood clotting, alterations of blood cells, and endothelial cell functions. NC were tested in vitro to assess their hemocompatibility and anticoagulant, anti‐inflammatory, and anti‐senescence activity in human endothelial cells. Hemocompatibility has been evaluated in vitro looking at the impact of NC on coagulation times, fibrinogen, and platelet aggregation. The effect of NC on vascular endothelial cells were assayed by testing cell viability, antioxidant activity, anticoagulant (tissue factor [TF]‐mRNA expression) and anti‐inflammatory properties (VCAM‐1 exposure, cytokine release), and senescence (telomere shortening). NC did not show significant effects on coagulation process, hemolysis, or platelet aggregation. In endothelial cells, NC did not affect cell viability, reduced oxidative stress, inhibited mRNA‐TF expression, VCAM‐1 expression, and cytokine release. Moreover, NC reduce telomere shortening, possibly counteracting premature senescence. The hemocompatibility combined with anticoagulant and anti‐inflammatory phenotype and the ability of counteract the premature senescence in vascular cells make NC a promising therapeutic tool in oxidative stress‐related conditions. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2019.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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Effects of cerium oxide nanoparticles on hemostasis: Coagulation, platelets, and vascular endothelial cells

Turco

Ciofani

Cappello

et al. 2019

J Biomedical Materials Res

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“…Examples include gold (AuNP) and silver (AgNP) nanoparticles, as well as CdTe and CdSe quantum dots [39][40][41]. As far as coating is concerned, carboxyl, amino, phosphate, or hydroxyls are all known to lead to platelet activation [42]. On the other hand, negatively charged surfaces can more easily initiate thrombotic events because, in physiological coagulation, platelet contact with anionic surface starts the coagulation cascade [43].…”

Section: Interaction Of Nanomaterials With Plateletsmentioning

confidence: 99%

Interaction of Nanoparticles with Blood Components and Associated Pathophysiological Effects

Cruz¹,

Rodríguez-Fragoso²,

JorgeReyes-Esparza³

et al. 2018

Unraveling the Safety Profile of Nanoscale Particles and Materials - From Biomedical to Environmental Applications

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Nanotechnology currently plays a pivotal role in several fields and has enabled substantial advances in a relatively short time. In biomedicine, nanomaterials can be potentially employed as a tool for early diagnosis and an innovative mode of drug delivery. Novel nanomaterials are currently widely manipulated without a full assessment of their potential health risks. It is commonly thought that nanomaterials' first contact with the organism is through the different components of the immune system. However, if the entry route is intravenous, the first contact will be with the blood's components (erythrocytes, platelets, white cells, plasma and complement proteins). The presence of nanomaterials within a dynamic environment such as the bloodstream can produce potential harmful effects following interaction with several blood components. The design of innovative strategies leading to the development of more hemocompatible nanomaterials is also necessary.

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“…Schematic of proposed mechanism for PAF-mediated effects upon intravenous administration of nucleic acid nanocarriers.Our findings suggest important implications particularly for the use of nucleic acid delivery vehicles in cancer treatment. The increased sensitivity of tumor-bearing to PAFmediated toxicity may carry over to human cancer patients, who often exhibit myeloid dysfunction, elevated platelet counts, and an increased risk of clotting due to the secretion of proclotting factors by tumor macrophages (44,45,54). While PAFR is present on all of the same cell types in humans as in rodents, humans additionally possess PAFR on platelets.…”

mentioning

confidence: 99%

Kupffer Cell Release of Platelet Activating Factor Drives Dose Limiting Toxicities of Nucleic Acid Nanocarriers

Jackson

Patel

et al. 2020

Preprint

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In vivo nanocarrier-associated toxicity is a significant and poorly understood hurdle to clinical translation of siRNA nanomedicines. In this work, we demonstrate that platelet activating factor (PAF), an inflammatory lipid mediator, plays a key role in nanocarrierassociated toxicities, and that prophylactic inhibition of the PAF receptor (PAFR) completely prevents these toxicities. High-dose intravenous injection of siRNA-polymer nano-complexes (si-NPs) elicited acute, shock-like symptoms (vasodilation and vascular leak) in mice and caused a three-fold increase in blood PAF levels. PAFR inhibition completely prevented these toxicities, indicating PAF activity is a primary driver of systemic si-NP toxicity. Pre-treatment with clodronate liposomes fully abrogated si-NP-associated increases in blood PAF and consequent toxicities, suggesting that nanoparticle uptake by Kupffer macrophages is the source of PAF.Assessment of varied si-NP chemistries further confirmed that toxicity level correlated to relative uptake of the carrier by liver Kupffer cells and that this toxicity mechanism is dependent on the endosome disruptive function of the carrier. Finally, the PAF toxicity mechanism was shown to be generalizable to commercial delivery reagent in vivo-jetPEI ® and an MC3 lipid nanoparticle formulated to match an FDA-approved siRNA nanomedicine. Greater sensitivity to the PAF mechanism occurs in 4T1 tumor-bearing mice, a mammary tumor model known to exhibit increased circulating leukocytes and potential to respond to inflammatory insult. These results establish Kupffer cell release of PAF as a key mediator of in vivo nucleic acid nanocarrier toxicity and identify PAFR inhibition as an effective prophylactic strategy to increase maximum tolerated dose and reduce nanocarrier-associated adverse events. SignificanceNon-viral nucleic acid nanocarriers can enable in vivo gene therapy, but their potential interaction with innate immune cells can cause dose-limiting toxicities. Nanoparticle toxicities are currently poorly understood, making it difficult to identify relevant design criteria for maximizing nanoparticle safety. This work connects nanoparticle-associated toxicities to the release of platelet activating factor (PAF) by liver Kupffer cells. Small molecule inhibition of the PAF receptor (PAFR) completely prevents severe adverse events associated with high doses of multiple polymer-based formulations and a lipid nanoparticle matching the composition of the first clinically-approved siRNA nanomedicine. This study identifies PAF as a toxicity biomarker for future nanomedicine discovery programs. Further, PAFR inhibition should be explored as a strategy to expand the therapeutic index of nanomedicines.

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Action of Nanoparticles on Platelet Activation and Plasmatic Coagulation

Cited by 85 publications

References 130 publications

Effects of cerium oxide nanoparticles on hemostasis: Coagulation, platelets, and vascular endothelial cells

Effects of cerium oxide nanoparticles on hemostasis: Coagulation, platelets, and vascular endothelial cells

Interaction of Nanoparticles with Blood Components and Associated Pathophysiological Effects

Kupffer Cell Release of Platelet Activating Factor Drives Dose Limiting Toxicities of Nucleic Acid Nanocarriers

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