Procoagulant Properties of Bare and Highly PEGylated Vinyl-Modified Silica Nanoparticles

Tavano, Regina; Segat, Daniela; Reddi, Elena; Kos, Janko; Rojnik, Matija; Kocbek, Petra; Iratni, Selma; Scheglmann, Dietrich; Colucci, Mario; Echevarria, I.M. Rio; Secci, Francesco; Mancin, Fabrizio; Papini, Emanuele

doi:10.2217/nnm.10.65

Cited by 49 publications

(40 citation statements)

References 42 publications

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“…57 Our experiments with coagulated plasma, in which not only fibrinogen but also the contact system (Kin-1, Kallikrein and F-XII) is depleted, confirm that these other minor corona components are not involved in inhibiting SiO 2 -NPs' macrophage capture. In fact, at high NP doses, in addition to Kin-1, partially processed as testified by its anomalous electrophoretic migration, Kallikrein and coagulation factor XII (F-XII or Hageman factor) are also present among other minor corona components.…”

Section: Discussionsupporting

confidence: 54%

The functional dissection of the plasma corona of SiO₂-NPs spots histidine rich glycoprotein as a major player able to hamper nanoparticle capture by macrophages

et al. 2015

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A coat of strongly-bound host proteins, or hard corona, may influence the biological and pharmacological features of nanotheranostics by altering their cell-interaction selectivity and macrophage clearance. With the goal of identifying specific corona-effectors, we investigated how the capture of amorphous silica nanoparticles (SiO2-NPs; Ø = 26 nm; zeta potential = -18.3 mV) by human lymphocytes, monocytes and macrophages is modulated by the prominent proteins of their plasma corona. LC MS/MS analysis, western blotting and quantitative SDS-PAGE densitometry show that Histidine Rich Glycoprotein (HRG) is the most abundant component of the SiO2-NP hard corona in excess plasma from humans (HP) and mice (MP), together with minor amounts of the homologous Kininogen-1 (Kin-1), while it is remarkably absent in their Foetal Calf Serum (FCS)-derived corona. HRG binds with high affinity to SiO2-NPs (HRG Kd ∼2 nM) and competes with other plasma proteins for the NP surface, so forming a stable and quite homogeneous corona inhibiting nanoparticles binding to the macrophage membrane and their subsequent uptake. Conversely, in the case of lymphocytes and monocytes not only HRG but also several common plasma proteins can interchange in this inhibitory activity. The depletion of HRG and Kin-1 from HP or their plasma exhaustion by increasing NP concentration (>40 μg ml(-1) in 10% HP) lead to a heterogeneous hard corona, mostly formed by fibrinogen (Fibr), HDLs, LDLs, IgGs, Kallikrein and several minor components, allowing nanoparticle binding to macrophages. Consistently, the FCS-derived SiO2-NP hard corona, mainly formed by hemoglobin, α2 macroglobulin and HDLs but lacking HRG, permits nanoparticle uptake by macrophages. Moreover, purified HRG competes with FCS proteins for the NP surface, inhibiting their recruitment in the corona and blocking NP macrophage capture. HRG, the main component of the plasma-derived SiO2-NPs' hard corona, has antiopsonin characteristics and uniquely confers to these particles the ability to evade macrophage capture.

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Section: Discussionsupporting

confidence: 54%

The functional dissection of the plasma corona of SiO₂-NPs spots histidine rich glycoprotein as a major player able to hamper nanoparticle capture by macrophages

et al. 2015

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“…Figure 7 shows that THP-1 cells alone did not exhibit any increase in the expression of TF after exposure to SiO 2 or Fe 3 O 4 particles. Another group has also reported that synthetic amorphous SiO 2 particles had virtually no effect on TF gene transcription in monocytes [39]. However, in the present study, THP-1 cells cocultured with HUVECs exhibited a significant increase in TF expression in response to SiO 2 particles, while Fe 3 O 4 particles did not induce TF expression in THP-1 cells in cocultures.…”

Section: Resultscontrasting

confidence: 77%

Enhancement of proinflammatory and procoagulant responses to silica particles by monocyte-endothelial cell interactions

et al. 2012

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BackgroundInorganic particles, such as drug carriers or contrast agents, are often introduced into the vascular system. Many key components of the in vivo vascular environment include monocyte-endothelial cell interactions, which are important in the initiation of cardiovascular disease. To better understand the effect of particles on vascular function, the present study explored the direct biological effects of particles on human umbilical vein endothelial cells (HUVECs) and monocytes (THP-1 cells). In addition, the integrated effects and possible mechanism of particle-mediated monocyte-endothelial cell interactions were investigated using a coculture model of HUVECs and THP-1 cells. Fe3O4 and SiO2 particles were chosen as the test materials in the present study.ResultsThe cell viability data from an MTS assay showed that exposure to Fe3O4 or SiO2 particles at concentrations of 200 μg/mL and above significantly decreased the cell viability of HUVECs, but no significant loss in viability was observed in the THP-1 cells. TEM images indicated that with the accumulation of SiO2 particles in the cells, the size, structure and morphology of the lysosomes significantly changed in HUVECs, whereas the lysosomes of THP-1 cells were not altered. Our results showed that reactive oxygen species (ROS) generation; the production of interleukin (IL)-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor (TNF)-α and IL-1β; and the expression of CD106, CD62E and tissue factor in HUVECs and monocytes were significantly enhanced to a greater degree in the SiO2-particle-activated cocultures compared with the individual cell types alone. In contrast, exposure to Fe3O4 particles had no impact on the activation of monocytes or endothelial cells in monoculture or coculture. Moreover, using treatment with the supernatants of SiO2-particle-stimulated monocytes or HUVECs, we found that the enhancement of proinflammatory response by SiO2 particles was not mediated by soluble factors but was dependent on the direct contact between monocytes and HUVECs. Furthermore, flow cytometry analysis showed that SiO2 particles could markedly increase CD40L expression in HUVECs. Our data also demonstrated that the stimulation of cocultures with SiO2 particles strongly enhanced c-Jun NH2-terminal kinase (JNK) phosphorylation and NF-κB activation in both HUVECs and THP-1 cells, whereas the phosphorylation of p38 was not affected.ConclusionsOur data demonstrate that SiO2 particles can significantly augment proinflammatory and procoagulant responses through CD40–CD40L-mediated monocyte-endothelial cell interactions via the JNK/NF-κB pathway, which suggests that cooperative interactions between particles, endothelial cells, and monocytes may trigger or exacerbate cardiovascular dysfunction and disease, such as atherosclerosis and thrombosis. These findings also indicate that the monocyte-endothelial cocultures represent a sensitive in vitro model system to assess the potential toxicity of particles and provide useful information that may h...

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“…Although we need to evaluate in greater detail the effects of nanosilica particles on activation or aggregation of platelets, our results and these previous reports suggest that nanosilica particles would induce platelet activation, resulting in activation of an intrinsic cascade pathway. Tavano et al suggested that synthetic amorphous silica (SAS), which is similar to our silica nanoparticles, and organically modified silica (ORMOSIL) nanoparticles induce significant abnormal activation of the coagulation system via a different mechanism in in vitro studies [41]. More specifically, SAS nanoparticles activate contact coagulation (factor XII dependent) but not TF transcription in monocytes.…”

Section: Discussionmentioning

confidence: 99%

Intranasal exposure to amorphous nanosilica particles could activate intrinsic coagulation cascade and platelets in mice

et al. 2013

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BackgroundNanomaterials with particle sizes <100 nm have been already applied in various applications such as cosmetics, medicines, and foods. Therefore, ensuring the safety of nanomaterials is becoming increasingly important. Here we examined the localization and biological responses of intranasally administered amorphous nanosilica particles in mice, focusing on the coagulation system.MethodsWe used nanosilica particles with diameters of 30, 70, or 100 nm (nSP30, nSP70, or nSP100 respectively), and conventional microscale silica particles with diameters of 300 or 1000 nm (mSP300 or mSP1000, respectively). BALB/c mice were intranasally exposed to nSP30, nSP70, nSP100, mSP300, or mSP1000 at concentrations of 500 μg/mouse for 7 days. After 24 hours of last administration, we performed the in vivo transmission electron microscopy analysis, hematological examination and coagulation tests.ResultsIn vivo transmission electron microscopy analysis showed that nanosilica particles with a diameter <100 nm were absorbed through the nasal cavity and were distributed into liver and brain. Hematological examination and coagulation tests showed that platelet counts decreased and that the activated partial thromboplastin time was prolonged in nSP30 or nSP70-treated groups of mice, indicating that nanosilica particles might have activated a coagulation cascade. In addition, in in vitro activation tests of human plasma, nanosilica particles had greater potential than did conventional microscale silica particles to activate coagulation factor XII. In nanosilica-particle-treated groups, the levels of soluble CD40 ligand, and von Willebrand factor which are involved in stimulating platelets tended to slightly increase with decreasing particle size.ConclusionsThese results suggest that intranasally administered nanosilica particles with diameters of 30 and 70 nm could induce abnormal activation of the coagulation system through the activation of an intrinsic coagulation cascade. This study provides information to advance the development of safe and effective nanosilica particles.

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Procoagulant Properties of Bare and Highly PEGylated Vinyl-Modified Silica Nanoparticles

Abstract: Stealth, highly PEGylated ORMOSIL-NPs with a poor procoagulant activity can be used as starting blocks to design hemocompatible nanomedical-devices.

Cited by 49 publications

References 42 publications

The functional dissection of the plasma corona of SiO₂-NPs spots histidine rich glycoprotein as a major player able to hamper nanoparticle capture by macrophages

The functional dissection of the plasma corona of SiO₂-NPs spots histidine rich glycoprotein as a major player able to hamper nanoparticle capture by macrophages

Enhancement of proinflammatory and procoagulant responses to silica particles by monocyte-endothelial cell interactions

Intranasal exposure to amorphous nanosilica particles could activate intrinsic coagulation cascade and platelets in mice

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Procoagulant Properties of Bare and Highly PEGylated Vinyl-Modified Silica Nanoparticles

Abstract: Stealth, highly PEGylated ORMOSIL-NPs with a poor procoagulant activity can be used as starting blocks to design hemocompatible nanomedical-devices.

Cited by 49 publications

References 42 publications

The functional dissection of the plasma corona of SiO2-NPs spots histidine rich glycoprotein as a major player able to hamper nanoparticle capture by macrophages

The functional dissection of the plasma corona of SiO2-NPs spots histidine rich glycoprotein as a major player able to hamper nanoparticle capture by macrophages

Enhancement of proinflammatory and procoagulant responses to silica particles by monocyte-endothelial cell interactions

Intranasal exposure to amorphous nanosilica particles could activate intrinsic coagulation cascade and platelets in mice

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The functional dissection of the plasma corona of SiO₂-NPs spots histidine rich glycoprotein as a major player able to hamper nanoparticle capture by macrophages

The functional dissection of the plasma corona of SiO₂-NPs spots histidine rich glycoprotein as a major player able to hamper nanoparticle capture by macrophages