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- W2894888949 endingPage "10485" @default.
- W2894888949 startingPage "10473" @default.
- W2894888949 abstract "Multivalent presentation of ligands on nanoparticles (NPs) is considered a general strategy for enhancing receptor binding and activation through amplification of ligand–receptor interactions within the footprint of the individual NPs. The spatial clustering of ligand-functionalized NPs represents an additional, less well understood mechanism for increasing local ligand–receptor interactions, especially for receptors that form higher-order assemblies, such as the epidermal growth factor (EGF) receptor (EGFR). To shed light on the interplay between ligand density (i.e., multivalency) and NP clustering in signal amplification, we apply EGF-functionalized 72 ± 1 nm gold nanoparticles (NP-EGF) with known ligand loading (10–200 EGF/NP) as quantifiable and experimentally tractable units of EGFR activation and characterize the NP-mediated amplification of EGFR phosphorylation as a function of both EGF surface density and NP-EGF clustering for two cancer cell lines (HeLa and MDA-MB-468). The measurements confirm a strong multivalent amplification of EGFR phosphorylation through NP-EGF on the cellular level that results in EGF-loading-dependent maximum EGFR phosphorylation levels. A microscopic analysis of NP-EGF-induced EGFR phosphorylation reveals a heterogeneous spatial distribution of EGFR activation across the cell surface. Clustering of multivalent NP-EGF on sub-diffraction-limited length scales is found to result in a local enhancement of EGFR phosphorylation in signaling “hot spots” from where the signal can spread laterally in an EGF-independent fashion. Increasing EGF loadings of the NP enhances NP-EGF clustering and intensifies EGFR phosphorylation. These observations suggest that NP-EGF clustering and the associated local enhancement of ligand–receptor interactions are intrinsic components of the multivalent amplification of phosphorylation for the heterogeneously distributed EGFR through NP-EGF." @default.
- W2894888949 created "2018-10-12" @default.
- W2894888949 creator A5052563154 @default.
- W2894888949 creator A5067330655 @default.
- W2894888949 date "2018-10-05" @default.
- W2894888949 modified "2023-10-05" @default.
- W2894888949 title "Ligand Density and Nanoparticle Clustering Cooperate in the Multivalent Amplification of Epidermal Growth Factor Receptor Activation" @default.
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- W2894888949 doi "https://doi.org/10.1021/acsnano.8b06141" @default.