Uptake of Functional Ultrasmall Gold Nanoparticles in 3D Gut Cell Models

Sokolova, Viktoriya; Ebel, Jana-Fabienne; Kollenda, Sebastian; Klein, Kai; Kruse, Benedikt; Veltkamp, Claudia; Lange, Christian; Westendorf, Astrid M.; Epple, Matthias

doi:10.1002/smll.202201167

Cited by 14 publications

(20 citation statements)

References 82 publications

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“…In order to further increase the valency and at the same time facilitate cell uptake, we chose us-AuNPs as scaffolds for the multivalent presentation of TW and TMs. With their size of ∼2 nm, they are in the range of other small biomolecules and readily pass the cell membrane and even the brain–blood barrier . Functionalization of the gold surface with thiol-containing molecules is straightforward and leads to a very stable Au–S bond, enabling the loading and transport of drug-like molecules. , …”

Section: Results and Discussionmentioning

confidence: 99%

Potentiating Tweezer Affinity to a Protein Interface with Sequence-Defined Macromolecules on Nanoparticles

Seiler,

Lennartz,

Klein

et al. 2023

Biomacromolecules

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Survivin, a well-known member of the inhibitor of apoptosis protein family, is upregulated in many cancer cells, which is associated with resistance to chemotherapy. To circumvent this, inhibitors are currently being developed to interfere with the nuclear export of survivin by targeting its protein–protein interaction (PPI) with the export receptor CRM1. Here, we combine for the first time a supramolecular tweezer motif, sequence-defined macromolecular scaffolds, and ultrasmall Au nanoparticles (us-AuNPs) to tailor a high avidity inhibitor targeting the survivin-CRM1 interaction. A series of biophysical and biochemical experiments, including surface plasmon resonance measurements and their multivalent evaluation by EVILFIT, reveal that for divalent macromolecular constructs with increasing linker distance, the longest linkers show superior affinity, slower dissociation, as well as more efficient PPI inhibition. As a drawback, these macromolecular tweezer conjugates do not enter cells, a critical feature for potential applications. The problem is solved by immobilizing the tweezer conjugates onto us-AuNPs, which enables efficient transport into HeLa cells. On the nanoparticles, the tweezer valency rises from 2 to 16 and produces a 100-fold avidity increase. The hierarchical combination of different scaffolds and controlled multivalent presentation of supramolecular binders was the key to the development of highly efficient survivin-CRM1 competitors. This concept may also be useful for other PPIs.

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Section: Results and Discussionmentioning

confidence: 99%

Potentiating Tweezer Affinity to a Protein Interface with Sequence-Defined Macromolecules on Nanoparticles

Seiler,

Lennartz,

Klein

et al. 2023

Biomacromolecules

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“…Consequently, the nanoparticles appear considerably smaller in DCS than they actually are. [ 11,20,22,44 ] Previous studies utilizing high resolution transmission electron microscopy (HRTEM) already revealed that the gold core is present as uniform particles with an average diameter of ≈ 2.0–2.2 nm. [ 23,44c ] The concentration of conjugated biomolecules was determined by UV–vis spectroscopy (Figure 3D).…”

Section: Resultsmentioning

confidence: 99%

“…[ 51a,52 ] The underlying mechanisms have not been fully elucidated for ultrasmall nanoparticles, but it appears to be an active endocytic uptake rather than a passive membrane penetration. [ 22 ]…”

Section: Discussionmentioning

confidence: 99%

“…Although previous studies already demonstrated negligible cytotoxicity of usAuNPs, [20,22] we first performed a cell viability assay to control for possible toxic effects of our nanoparticle conjugates. As expected, neither the peptide-labeled (P-N) nor the SuN-conjugated (SuN-N) nanoparticles revealed any signs of acute toxicity after 24 h, even in high concentrations (see, Figure S9, Supporting Information).…”

Section: Live Intracellular Tracking Of Survivin By Sun-nmentioning

confidence: 99%

“…[21] Besides size, the shape, charge, and surface functionalization emerged as critical parameters affecting cellular uptake efficiency of nanoparticles in vitro and in vivo. [22] In particular, ultrasmall gold nanoparticles (AuNPs) of sub-plasmonic size (1-2 nm), facilitate efficient transfer across biological barriers, including the cell membrane. Moreover, the use of AuNPs as carriers for siRNA led to a remarkable increase in RNA stability.…”

Section: Introductionmentioning

confidence: 99%

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Tuning Nanobodies’ Bioactivity: Coupling to Ultrasmall Gold Nanoparticles Allows the Intracellular Interference with Survivin

Stahl

Kollenda

Sager

et al. 2023

Small

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Nanobodies are highly affine binders, often used to track disease‐relevant proteins inside cells. However, they often fail to interfere with pathobiological functions, required for their clinical exploitation. Here, a nanobody targeting the disease‐relevant apoptosis inhibitor and mitosis regulator Survivin (SuN) is utilized. Survivin's multifaceted functions are regulated by an interplay of dynamic cellular localization, dimerization, and protein–protein interactions. However, as Survivin harbors no classical “druggable” binding pocket, one must aim at blocking extended protein surface areas. Comprehensive experimental evidence demonstrates that intracellular expression of SuN allows to track Survivin at low nanomolar concentrations but failed to inhibit its biological functions. Small angle X‐ray scattering of the Survivin‐SuN complex locates the proposed interaction interface between the C‐terminus and the globular domain, as such not blocking any pivotal interaction. By clicking multiple SuN to ultrasmall (2 nm) gold nanoparticles (SuN‐N), not only intracellular uptake is enabled, but additionally, Survivin crosslinking and interference with mitotic progression in living cells are also enabled. In sum, it is demonstrated that coupling of nanobodies to nanosized scaffolds can be universally applicable to improve their function and therapeutic applicability.

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Ultrasmall Nanoparticles Bind to Fibrinogen and Impair Normal Clot Formation

Mina,

Guido,

Lima

et al. 2023

Part & Part Syst Charact

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The formation of a proper fibrin clot is essential during blood coagulation, as abnormal clots can predispose individuals to bleeding or thrombosis. Despite these concerns, there is currently limited understanding of the potential adverse effects of engineered nanomaterials on fibrin clot formation. This is surprising, given that fibrinogen is highly concentrated in plasma and has a large surface area, making it prone to unintended interactions with nanomaterials. In this study, the impact of ultrasmall gold nanoparticles (usGNPs) on fibrin clot formation is investigated. UsGNPs have gained significant interest in biomedical applications due to their unique physicochemical properties and favorable behavior in complex biofluids. It is found that the usGNPs interacted with fibrinogen, delayed the onset of clot formation, and became physically trapped within the forming fibrin matrix. Confocal microscopy showed that the usGNPs disrupted the normal architecture of the fibrin clot, resulting in a less dense network structure. This disruption led to larger clot pore sizes and increased clot permeability to liquid. Considering the potential health risks associated with abnormal clot formation, a detailed examination of the clot formation process should be included in the standard safety assessment of usGNPs and other nanomedicines.

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Uptake of Functional Ultrasmall Gold Nanoparticles in 3D Gut Cell Models

Cited by 14 publications

References 82 publications

Potentiating Tweezer Affinity to a Protein Interface with Sequence-Defined Macromolecules on Nanoparticles

Potentiating Tweezer Affinity to a Protein Interface with Sequence-Defined Macromolecules on Nanoparticles

Tuning Nanobodies’ Bioactivity: Coupling to Ultrasmall Gold Nanoparticles Allows the Intracellular Interference with Survivin

Ultrasmall Nanoparticles Bind to Fibrinogen and Impair Normal Clot Formation

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