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

Sokolova, Viktoriya; Mekky, Gehad; Meer, Selina Beatrice van der; Seeds, Michael C.; Atala, Anthony; Epple, Matthias

doi:10.1038/s41598-020-75125-2

Cited by 60 publications

(92 citation statements)

References 54 publications

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“…More complex in vivo systems can also be reproduced in a spheroid model, such as a blood-brain barrier made up multiple cell types in a multicellular spheroid. This was explored by Sokolova et al that showed that ultrasmall GNPs can cross this barrier, illustrating the useful nature of the 3D spheroid [ 46 ]. Ultrasmall GNPs have previously been explored in a 3D tumor spheroid model, demonstrating that smaller 2 nm and 6 nm GNPs can penetrate deeper into the tissue when compared to that of 15 nm GNPs [ 47 ].…”

Section: Introductionmentioning

confidence: 99%

Three-Dimensional Tumor Spheroids as a Tool for Reliable Investigation of Combined Gold Nanoparticle and Docetaxel Treatment

Bromma

Alhussan

Monica

et al. 2021

Cancers

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Radiotherapy and chemotherapy are the gold standard for treating patients with cancer in the clinic but, despite modern advances, are limited by normal tissue toxicity. The use of nanomaterials, such as gold nanoparticles (GNPs), to improve radiosensitivity and act as drug delivery systems can mitigate toxicity while increasing deposited tumor dose. To expedite a quicker clinical translation, three-dimensional (3D) tumor spheroid models that can better approximate the tumor environment compared to a two-dimensional (2D) monolayer model have been used. We tested the uptake of 15 nm GNPs and 50 nm GNPs on a monolayer and on spheroids of two cancer cell lines, CAL-27 and HeLa, to evaluate the differences between a 2D and 3D model in similar conditions. The anticancer drug docetaxel (DTX) which can act as a radiosensitizer, was also utilized, informing future potential of GNP-mediated combined therapeutics. In the 2D monolayer model, the addition of DTX induced a small, non-significant increase of uptake of GNPs of between 13% and 24%, while in the 3D spheroid model, DTX increased uptake by between 47% and 186%, with CAL-27 having a much larger increase relative to HeLa. Further, the depth of penetration of 15 nm GNPs over 50 nm GNPs increased by 33% for CAL-27 spheroids and 17% for HeLa spheroids. These results highlight the necessity to optimize GNP treatment conditions in a more realistic tumor-life environment. A 3D spheroid model can capture important details, such as different packing densities from different cancer cell lines, which are absent from a simple 2D monolayer model.

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Section: Introductionmentioning

confidence: 99%

Three-Dimensional Tumor Spheroids as a Tool for Reliable Investigation of Combined Gold Nanoparticle and Docetaxel Treatment

Bromma

Alhussan

Monica

et al. 2021

Cancers

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“…While the blood–brain barrier permeability of CB839 is challenging, as described in several in vitro studies [ 19 , 54 ], its specificity to inhibit GLS1 and the connection between response and IDH1 DNA mutation status of cancer patients [ 9 ] makes it a promising candidate for precision cancer therapy. Although an increased diffusion through the barrier is expected when attaching the small molecule to Au NPs [ 55 , 56 , 57 ], CB839 could also be part of an intraventrical, intrathecal, or localized intracranial chemotherapy. For intracranial chemotherapy, the BBB problematic could even be avoided because the drug is directly applied to the tumor cavity during tumor resection [ 58 , 59 ].…”

Section: Resultsmentioning

confidence: 99%

Augmented Therapeutic Potential of Glutaminase Inhibitor CB839 in Glioblastoma Stem Cells Using Gold Nanoparticle Delivery

et al. 2021

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Gold nanoparticles (Au NPs) are studied as delivery systems to enhance the effect of the glutaminase1 inhibitor CB839, a promising drug candidate already in clinical trials for tumor treatments. Au NPs were synthesized using a bottom-up approach and covered with polymers able to bind CB839 as a Au-polymer-CB839 conjugate. The drug loading efficiency (DLE) was determined using high-performance liquid chromatography and characterization of the CB839-loaded NPs was done with various microscopic and spectroscopic methods. Despite the chemical inertness of CB839, Au NPs were efficient carriers with a DLE of up to 12%, depending on the polymer used. The therapeutic effect of CB839 with and without Au was assessed in vitro in 2D and 3D glioblastoma (GBM) cell models using different assays based on the colony formation ability of GBM stem cells (GSCs). To avoid readout disturbances from the Au metal, viability methods which do not require optical detection were hereby optimized. These showed that Au NP delivery increased the efficacy of CB839 in GSCs, compared to CB839 alone. Fluorescent microscopy proved successful NP penetration into the GSCs. With this first attempt to combine CB839 with Au nanotechnology, we hope to overcome delivery hurdles of this pharmacotherapy and increase bioavailability in target sites.

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“…The blood–brain barrier (BBB) is impermeable to most of the conventional drugs whereas nano-drugs can penetrate through it, treating CNS and brain disorders ( Sokolova et al, 2020 ; Kumarasamy and Sosnik, 2021 ). However, NP-induced neurotoxicity needs to be evaluated properly using a suitable toxicity evaluation model.…”

Section: Nanotoxicity Assessment Using the Organoid Modelmentioning

confidence: 99%

Organoid Technology: A Reliable Developmental Biology Tool for Organ-Specific Nanotoxicity Evaluation

Prasad

Kumar

Buragohain

et al. 2021

Front. Cell Dev. Biol.

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Engineered nanomaterials are bestowed with certain inherent physicochemical properties unlike their parent materials, rendering them suitable for the multifaceted needs of state-of-the-art biomedical, and pharmaceutical applications. The log-phase development of nano-science along with improved “bench to beside” conversion carries an enhanced probability of human exposure with numerous nanoparticles. Thus, toxicity assessment of these novel nanoscale materials holds a key to ensuring the safety aspects or else the global biome will certainly face a debacle. The toxicity may span from health hazards due to direct exposure to indirect means through food chain contamination or environmental pollution, even causing genotoxicity. Multiple ways of nanotoxicity evaluation include several in vitro and in vivo methods, with in vitro methods occupying the bulk of the “experimental space.” The underlying reason may be multiple, but ethical constraints in in vivo animal experiments are a significant one. Two-dimensional (2D) monoculture is undoubtedly the most exploited in vitro method providing advantages in terms of cost-effectiveness, high throughput, and reproducibility. However, it often fails to mimic a tissue or organ which possesses a defined three-dimensional structure (3D) along with intercellular communication machinery. Instead, microtissues such as spheroids or organoids having a precise 3D architecture and proximate in vivo tissue-like behavior can provide a more realistic evaluation than 2D monocultures. Recent developments in microfluidics and bioreactor-based organoid synthesis have eased the difficulties to prosper nano-toxicological analysis in organoid models surpassing the obstacle of ethical issues. The present review will enlighten applications of organoids in nanotoxicological evaluation, their advantages, and prospects toward securing commonplace nano-interventions.

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

Cited by 60 publications

References 54 publications

Three-Dimensional Tumor Spheroids as a Tool for Reliable Investigation of Combined Gold Nanoparticle and Docetaxel Treatment

Three-Dimensional Tumor Spheroids as a Tool for Reliable Investigation of Combined Gold Nanoparticle and Docetaxel Treatment

Augmented Therapeutic Potential of Glutaminase Inhibitor CB839 in Glioblastoma Stem Cells Using Gold Nanoparticle Delivery

Organoid Technology: A Reliable Developmental Biology Tool for Organ-Specific Nanotoxicity Evaluation

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