Ultrasmall gold nanoparticles (2 nm) can penetrate and enter cell nuclei in an in vitro 3D brain spheroid model

Sokolova, Viktoriya; Nzou, Goodwell; Meer, Selina Beatrice van der; Ruks, Tatjana; Heggen, Marc; Loza, Kateryna; Hagemann, Nina; Murke, Florian; Giebel, Bernd; Hermann, Dirk M.; Atala, Anthony; Epple, Matthias

doi:10.1016/j.actbio.2020.04.023

Cited by 59 publications

(66 citation statements)

References 53 publications

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“…for future therapies to deliver functional drugs into the brain. Together with our earlier observation that such nanoparticles can enter cells and also the cell nucleus (in contrast to the dissolved dye) 28,30 , this opens a potential pathway for targeted therapies inside the brain which are not possible with water-dissolved drugs. However, while the toxicity was very low in this model, a study of cumulative injury in animal models will be required to better predict applications in humans, since the clearance kinetics of the particles are still unknown.…”

Section: Discussionsupporting

confidence: 64%

“…iron oxide, cerium oxide, molybdenum, silica or gold nanoparticles [40][41][42][43][44] . Compared to other types of nanoparticles, gold nanoparticles have received considerable www.nature.com/scientificreports/ interest because of their relative low cytotoxicity, predominant optical properties for imaging, well-established syntheses, and their potential to cross the BBB 14,28,45,46 . The penetration mechanism across the BBB depends on the nanoparticle size and composition.…”

Section: Discussionmentioning

confidence: 99%

“…; Panreac Synthesis of clicked nanoparticles. The synthesis and click reaction of the ultra-small gold nanoparticles were performed as reported earlier 28,30 . Briefly, the ultrasmall gold nanoparticles were produced by a modified one-phase Brust synthesis, and subsequently a copper-catalyzed azide-alkyne cycloaddition (CuAAC) was www.nature.com/scientificreports/ performed 52,53 .…”

Section: Methodsmentioning

confidence: 99%

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Transport of ultrasmall gold nanoparticles (2 nm) across the blood–brain barrier in a six-cell brain spheroid model

Sokolova

Mekky

Meer

et al. 2020

Sci Rep

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The blood–brain barrier (BBB) is an efficient barrier for molecules and drugs. Multicellular 3D spheroids display reproducible BBB features and functions. The spheroids used here were composed of six brain cell types: Astrocytes, pericytes, endothelial cells, microglia cells, oligodendrocytes, and neurons. They form an in vitro BBB that regulates the transport of compounds into the spheroid. The penetration of fluorescent ultrasmall gold nanoparticles (core diameter 2 nm; hydrodynamic diameter 3–4 nm) across the BBB was studied as a function of time by confocal laser scanning microscopy, with the dissolved fluorescent dye (FAM-alkyne) as a control. The nanoparticles readily entered the interior of the spheroid, whereas the dissolved dye alone did not penetrate the BBB. We present a model that is based on a time-dependent opening of the BBB for nanoparticles, followed by a rapid diffusion into the center of the spheroid. After the spheroids underwent hypoxia (0.1% O2; 24 h), the BBB was more permeable, permitting the uptake of more nanoparticles and also of dissolved dye molecules. Together with our previous observations that such nanoparticles can easily enter cells and even the cell nucleus, these data provide evidence that ultrasmall nanoparticle can cross the blood brain barrier.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Transport of ultrasmall gold nanoparticles (2 nm) across the blood–brain barrier in a six-cell brain spheroid model

Sokolova

Mekky

Meer

et al. 2020

Sci Rep

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“…The ultrasmall gold nanoparticles were conjugated with OAAs during the nanoparticle synthesis as described previously for peptide‐coated ultrasmall gold nanoparticles, [5d] in contrast to ligand exchange as reported previously for larger gold nanoparticles [4] . The nature of the ligand‐particle binding was probed by solution 1 H NMR spectroscopy.…”

Section: Resultsmentioning

confidence: 99%

“…The ultrasmall gold nanoparticles were prepared by a modified one‐phase Brust synthesis, [11] following the synthetic protocols reported earlier [5a–d] . The cysteine‐terminated OAAs (short‐/long‐2, 3.75 μmol, or short‐/long‐6, 1.25 μmol) were dissolved in 10 mL ultrapure water, respectively.…”

Section: Methodsmentioning

confidence: 99%

Controlling the Surface Functionalization of Ultrasmall Gold Nanoparticles by Sequence‐Defined Macromolecules

Meer

Seiler

Buchmann

et al. 2020

Chemistry A European J

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Ultrasmall gold nanoparticles (diameter about 2nm) were surface-functionalizedw ith cysteine-carrying precision macromolecules. These consistedo fs equence-defined oligo(amidoamine)s (OAAs)w ith either two or six cysteine molecules for binding to the gold surface and either with or withoutaPEG chain (3400 Da). They were characterized by 1 HNMR spectroscopy, 1 HNMR diffusion-ordered spectroscopy (DOSY), small-angle X-ray scattering(SAXS), and high-resolution transmission electron microscopy.T he number of precision macromolecules per nanoparticle was determined after fluorescent labeling by UV spectroscopya nd also by quantitative 1 HNMR spectroscopy.E ach nanoparticle carried between4 0a nd 100 OAA ligands, depending on the number of cysteine units per OAA.T he footprint of each ligandw as about 0.074 nm 2 per cysteinem olecule. OAAs are well suited to stabilize ultrasmall gold nanoparticlesb ys electives urface conjugation and can be used to selectively cover their surface. The presence of the PEG chain considerably increasedt he hydrodynamicd iametero fb oth dissolved macromolecules and macromolecule-conjugated gold nanoparticles.

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Engineering Neurovascular Unit and Blood–Brain Barrier for Ischemic Stroke Modeling

Liu

Tang

Zhang

et al. 2023

Adv Healthcare Materials

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Ischemic stroke is a primary vascular disease of the central nervous system characterized by high morbidity, mortality, and healthcare costs. As conventional ischemic stroke models fail to predict therapeutic efficacy, in vitro neurovascular unit (NVU)/blood–brain barrier (BBB) models are utilized to model ischemic stroke through replicating the cell–cell interactions and mimicking the blood flow and anatomical features of the brain. Here, an overview of transwell, microfluidic, and hydrogel‐based NVU/BBB models is provided, including cell types, engineering approaches, and the simulation of physiological and pathological features of NVU/BBB after ischemic stroke. Collectively, recent advances in 3D‐printed NVU models are emphasized, which are anticipated to be a promising system for more reliable mechanistic studies and preclinical drug screenings that can eventually accelerate the drug development process for the ischemic stroke therapy.

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Ultrasmall gold nanoparticles (2 nm) can penetrate and enter cell nuclei in an in vitro 3D brain spheroid model

Cited by 59 publications

References 53 publications

Transport of ultrasmall gold nanoparticles (2 nm) across the blood–brain barrier in a six-cell brain spheroid model

Transport of ultrasmall gold nanoparticles (2 nm) across the blood–brain barrier in a six-cell brain spheroid model

Controlling the Surface Functionalization of Ultrasmall Gold Nanoparticles by Sequence‐Defined Macromolecules

Engineering Neurovascular Unit and Blood–Brain Barrier for Ischemic Stroke Modeling

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