Evaluation of endocytosis of silica particles used in biodegradable implants in the brain

Zielinski, Jana; Möller, Anja-Maria; Frenz, Martin; Mevissen, Meike

doi:10.1016/j.nano.2016.02.009

Cited by 15 publications

(19 citation statements)

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“…However, smaller silica NPs of 20–100 nm were also shown to be internalized mainly by the macropinocytosis [45–47]. However, their size and state of agglomeration in complete medium was unfortunately not studied and it cannot be excluded that, similarly to Rubipy-SiO 2 NPs, the initial small monodispersed NPs became large agglomerates in the presence of serum proteins.…”

Section: Discussionmentioning

confidence: 99%

The agglomeration state of nanoparticles can influence the mechanism of their cellular internalisation

et al. 2017

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BackgroundSignificant progress of nanotechnology, including in particular biomedical and pharmaceutical applications, has resulted in a high number of studies describing the biological effects of nanomaterials. Moreover, a determination of so-called “critical quality attributes”, that is specific physicochemical properties of nanomaterials triggering the observed biological response, has been recognised as crucial for the evaluation and design of novel safe and efficacious therapeutics. In the context of in vitro studies, a thorough physicochemical characterisation of nanoparticles (NPs), also in the biological medium, is necessary to allow a correlation with a cellular response. Following this concept, we examined whether the main and frequently reported characteristics of NPs such as size and the agglomeration state can influence the level and the mechanism of NP cellular internalization.ResultsWe employed fluorescently-labelled 30 and 80 nm silicon dioxide NPs, both in agglomerated and non-agglomerated form. Using flow cytometry, transmission electron microscopy, the inhibitors of endocytosis and gene silencing we determined the most probable routes of cellular uptake for each form of tested silica NPs. We observed differences in cellular uptake depending on the size and the agglomeration state of NPs. Caveolae-mediated endocytosis was implicated particularly in the internalisation of well dispersed silica NPs but with an increase of the agglomeration state of NPs a combination of endocytic pathways with a predominant role of macropinocytosis was noted.ConclusionsWe demonstrated that the agglomeration state of NPs is an important factor influencing the level of cell uptake and the mechanism of endocytosis of silica NPs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-017-0281-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The agglomeration state of nanoparticles can influence the mechanism of their cellular internalisation

et al. 2017

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“…Nanoparticle synthesis and characterization as well as the chemical and physical properties of the PCL-NPs have been described previously [3, 4, 24]. Briefly, a core shell nanoparticle system was developed consisting of a defined silica-core of 80 nm with a hydrophobic PCL coating acting as carrier system for ICG.…”

Section: Methodsmentioning

confidence: 99%

“…The stock solution was sonicated three times for 5 min with cooling steps in between to enable homogeneous nanoparticle suspension just before treatment of the cells. The final concentration of PCL-NPs [2.6 × 10 10 PCL-NPs/ml] used for all experiments was obtained by dilution of the stock with culture medium containing 1% FBS as previously reported [4, 5]. …”

Section: Methodsmentioning

confidence: 99%

“…Nanoparticle exposure did not result in increased cytotoxicity and apoptosis in microglial and neuron-like cell lines even though a transient depletion of glutathione was found indicating reactive oxygen species (ROS) formation [3]. Moreover, nanoparticles were demonstrated to be taken up by microglial cells in a time- and particle-dependent manner [4]; the uptake in primary hippocampal cultures was time- and concentration-dependent [5]. For all brain cells analyzed, no modulation of inflammatory cytokine secretion and autophagy was observed [4, 5], but neuronal differentiation markers including mitogen-activated protein kinase/extracellular signal-related kinase (MAP-K/ERK) 1/2 and phosphatidyl-inositol 3-kinase/serine/threonine specific protein kinase (PI3-K/Akt) kinases were shown to be downregulated after nanoparticle exposure [5].…”

Section: Introductionmentioning

confidence: 99%

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Effects of silica nanoparticle exposure on mitochondrial function during neuronal differentiation

et al. 2017

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BackgroundNanomedicine offers a promising tool for therapies of brain diseases, but potential effects on neuronal health and neuronal differentiation need to be investigated to assess potential risks. The aim of this study was to investigate effects of silica-indocyanine green/poly (ε-caprolactone) nanoparticles (PCL-NPs) engineered for laser tissue soldering in the brain before and during differentiation of SH-SY5Y cells. Considering adaptations in mitochondrial homeostasis during neuronal differentiation, metabolic effects of PCL-NP exposure before and during neuronal differentiation were studied. In addition, kinases of the PI3 kinase (PI3-K/Akt) and the MAP kinase (MAP-K/ERK) pathways related to neuronal differentiation and mitochondrial function were investigated.ResultsDifferentiation resulted in a decrease in the cellular respiration rate and the extracellular acidification rate (ECAR). PCL-NP exposure impaired mitochondrial function depending on the time of exposure. The cellular respiration rate was significantly reduced compared to differentiated controls when PCL-NPs were given before differentiation. The shift in ECAR was less pronounced in PCL-NP exposure during differentiation. Differentiation and PCL-NP exposure had no effect on expression levels and the enzymatic activity of respiratory chain complexes. The activity of the glycolytic enzyme phosphofructokinase was significantly reduced after differentiation with the effect being more pronounced after PCL-NP exposure before differentiation. The increase in mitochondrial membrane potential observed after differentiation was not found in SH-SY5Y cells exposed to PCL-NPs before differentiation. The cellular adenosine triphosphate (ATP) production significantly dropped during differentiation, and this effect was independent of the PCL-NP exposure. Differentiation and nanoparticle exposure had no effect on superoxide levels at the endpoint of the experiments. A slight decrease in the expression of the neuronal differentiation markers was found after PCL-NP exposure, but no morphological variation was observed.ConclusionsPCL-NP exposure affects mitochondrial function depending on the time of exposure before and during neuronal differentiation. PCL-NP exposure during differentiation was associated with impaired mitochondrial function, which may affect differentiation. Considering the importance of adaptations in cellular respiration for neuronal differentiation and function, further studies are needed to unravel the underlying mechanisms and consequences to assess the possible risks including neurodegeneration.

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“…Indeed, it was shown that phagocytosis and macropinocytosis are involved in silica nanoparticle uptake in murine microglial cells and were subsequently found in the endoplasmatic reticulum and lysosomes. 21 Moreover, the phagocytosis of nanoparticles by macrophages has driven the development of carriers to target drugs toward immune phagocytic cells. 22 The results obtained in this study clearly indicated different mechanisms of MTX-LNC uptake by cancer and immune cells in the brain.…”

Section: Mtx-lnc Uptake By Glioma and Microglial Cells Is Mediated Bymentioning

confidence: 99%

Mechanisms of the effectiveness of poly(ε-caprolactone) lipid-core nanocapsules loaded with methotrexate on glioblastoma multiforme treatment

Pereira¹,

Loiola²,

Rodrigues³

et al. 2018

IJN

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PurposeThe low penetration of drugs across the blood–brain barrier (BBB) compromises the delivery of chemotherapeutic agents to the brain parenchyma and contributes to the poor prognosis of glioblastoma multiforme (GBM). We investigated the efficacy of methotrexate-loaded lipid-core nanocapsules (MTX-LNC) administered by the oral route to treat murine GBM, its ability to cross the BBB, and the mechanisms of MTX-LNC uptake by cultured GL261 glioma and BV2 microglia cells.Materials and methodsFemale C57B/6 mice were used in intravital microscopy assays to investigate the penetrance of rhodamine B-label MTX-LNC (RhoB/MTX-LNC) in the brain after oral or IV administration, and to evaluate the BBB integrity. Intracranial implantation of GL261 cells was undertaken to induce a murine GBM model, and the effectiveness of oral MTX or MTX-LNC treatments (started on Day 10 of GBM, every 2 days for 12 days) was quantified by tumor size, body weight, and leukogram. Pharmacological blockade of endocytic pathways was done to investigate the mechanisms of MTX-LNC uptake by cultured GL261 and microglia BV2 cells by using fluorescence microscopy. The effect of MTX-LNC or MTX on GL261 and BV2 proliferation was evaluated to compare the cytotoxicity of such compounds.ResultsRhoB/MTX-LNC was detected in brain parenchyma of mice after IV or oral administration, without any damage on BBB. Oral treatment with MTX-LNC reduced tumor volume and prevented weight loss and leukopenia in comparison to MTX-treated mice. MTX-LNC uptake by GL261 is caveolae-dependent, whereas endocytosis of MTX-LNC by BV2 occurs via phagocytosis and macropinocytosis. Both MTX-LNC and MTX reduced GL261 and BV2 proliferation; however, MTX-LNC showed higher efficacy in the inhibition of glioma proliferation.ConclusionTogether, we infer that the higher ability of MTX-LNC to cross the BBB and be captured by cancer and immune brain cells by different mechanisms is responsible for the higher efficacy of oral MTX-LNC treatment in GBM.

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Evaluation of endocytosis of silica particles used in biodegradable implants in the brain

Cited by 15 publications

References 54 publications

The agglomeration state of nanoparticles can influence the mechanism of their cellular internalisation

The agglomeration state of nanoparticles can influence the mechanism of their cellular internalisation

Effects of silica nanoparticle exposure on mitochondrial function during neuronal differentiation

Mechanisms of the effectiveness of poly(ε-caprolactone) lipid-core nanocapsules loaded with methotrexate on glioblastoma multiforme treatment

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Evaluation of endocytosis of silica particles used in biodegradable implants in the brain

Cited by 15 publications

References 54 publications

The agglomeration state of nanoparticles can influence the mechanism of their cellular internalisation

The agglomeration state of nanoparticles can influence the mechanism of their cellular internalisation

Effects of silica nanoparticle exposure on mitochondrial function during neuronal differentiation

Mechanisms of the effectiveness of poly(&epsilon;-caprolactone) lipid-core nanocapsules loaded with methotrexate on glioblastoma multiforme treatment

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Mechanisms of the effectiveness of poly(ε-caprolactone) lipid-core nanocapsules loaded with methotrexate on glioblastoma multiforme treatment