Publications

Cells tightly regulate membrane composition to maintain homeostasis and adapt to perturbations. Disruptions in lipid metabolism, such as those occurring in Gaucher disease (GD), can disturb this balance. In GD, excess glucosylceramide (GlcCer) accumulates in lysosomes, altering overall lipid metabolism and potentially impacting membrane composition. This study investigates how GlcCer influences lipid distribution and the local mechanical properties of model lipid bilayers composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), egg sphingomyelin (SME), cholesterol (Chol) and GlcCer in varying ratios, using atomic force microscopy and force spectroscopy. In simple bilayers (DOPC and DOPC:Chol), GlcCer forms rigid, unstable domains with high lateral packing. In contrast, in complex DOPC:Chol:SME membranes, higher GlcCer concentrations are accommodated but significantly alter domain organization and nanomechanical properties. Excess GlcCer preferentially partitions into segregated domains, sequestering cholesterol and SME, thereby reshaping lipid distribution with potential implications for membrane curvature, protein diffusion and localization.

JTD Keywords: Afm, Atomic force microscopy, Atomic-force microscopy, Force spectroscopy, Functional roles, Gaucher disease, Glucosylceramide, Lipid membranes, Membrane structure, Models, Nanomechanical properties, Nanomechanics, Neutral glycosphingolipids, Phase-diagram, Spectroscopy, Sphingomyelin, Supported lipid-bilayers

Nanoparticles (NPs) are commonly functionalized using targeting ligands to drive their selective uptake in cells of interest. Typical target cell types are cancer cells, which often overexpress distinct surface receptors that can be exploited for NP therapeutics. However, these targeted receptors are also moderately expressed in healthy cells, leading to unwanted off-tumor toxicities. Multivalent interactions between NP ligands and cell receptors have been investigated to increase the targeting selectivity towards cancer cells due to their non-linear response to receptor density. However, to exploit the multivalent effect, multiple variables have to be considered such as NP valency, ligand affinity, and cell receptor density. Here, we synthesize a panel of aptamer-functionalized silica-supported lipid bilayers (SSLB) to study the effect of valency, aptamer affinity, and epidermal growth factor receptor (EGFR) density on targeting specificity and selectivity. We show that there is an evident interplay among those parameters that can be tuned to increase SSLB selectivity towards high-density EGFR cells and reduce accumulation at non-tumor tissues. Specifically, the combination of high-affinity aptamers and low valency SSLBs leads to increased high-EGFR cell selectivity. These insights provide a better understanding of the multivalent interactions of NPs with cells and bring the nanomedicine field a step closer to the rational design of cancer nanotherapeutics.Copyright © 2023. Published by Elsevier B.V.

JTD Keywords: aptamer avidity and affinity, delivery, microscopy, multivalency, multivalent, nanoparticle targeting, silica -supported lipid bilayers, Aptamer avidity and affinity, Multivalency, Nanoparticle targeting, Silica-supported lipid bilayers, Supported lipid-bilayers, Tumor targeting