Lipophilicity of Cationic Ligands Promotes Irreversible Adsorption of Nanoparticles to Lipid Bilayers

Abstract

A mechanistic understanding of the influence of the surface properties of engineered nanomaterials on their interactions with cells is essential for designing materials for applications such as bioimaging and drug delivery as well as for assessing nanomaterial safety. Ligand-coated gold nanoparticles have been widely investigated because their highly tunable surface properties enable investigations into the effect of ligand functionalization on interactions with biological systems. Lipophilic ligands have been linked to adverse biological outcomes through membrane disruption, but the relationship between ligand lipophilicity and membrane interactions is not well understood. Here, we use a library of cationic ligands coated on 2 nm gold nanoparticles to probe the impact of ligand end group lipophilicity on interactions with supported phosphatidylcholine lipid bilayers as a model for cytoplasmic membranes. Nanoparticle adsorption to and desorption from the model membranes were investigated by quartz crystal microbalance with dissipation monitoring. We find that nanoparticle adsorption to model membranes increases with ligand lipophilicity. The effects of ligand structure on gold nanoparticle attachment were further analyzed using atomistic molecular dynamics simulations, which showed that the increase in ligand lipophilicity promotes ligand intercalation into the lipid bilayer. Together, the experimental and simulation results could be described by a two-state model that accounts for the initial attachment and subsequent conversion to a quasi-irreversibly bound state. We find that only nanoparticles coated with the most lipophilic ligands in our nanoparticle library undergo conversion to the quasi-irreversible state. We propose that the initial attachment is governed by interaction between the ligands and phospholipid tail groups, whereas conversion into the quasi-irreversibly bound state reflects ligand intercalation between phospholipid tail groups and eventual lipid extraction from the bilayer. The systematic variation of ligand lipophilicity enabled us to demonstrate that the lipophilicity of cationic ligands correlates with nanoparticle-bilayer adsorption and suggested that changing the nonpolar ligand R group promotes a mechanism of ligand intercalation into the bilayer associated with irreversible adsorption.

Determination of Nanosized Adsorbate Mass in Solution Using Mechanical Resonators: Elimination of the So Far Inseparable Liquid Contribution

“…21,22 Additionally, QCM has been extensively employed to study discrete adsorbates such as abiotic and biological macromolecules and nanoparticles (NPs). These studies included investigations of biomolecular interactions of proteins 23,24 and viruses; 25,26 structure, 27,28 confirmation 29,30 and orientation changes 31 of biomacromolecules; spatial distribution, 32 size, 33−35 deformation 36,37 and dissolution 38 of NPs; protein corona formation on amyloids; 39 interactions between NPs and biomimetic membranes; 40,41 as well as bioanalytical sensor development. 42−46 Yet, the inseparable nature of the adsorbate and liquid contributions to the measured response puts a significant limitation on quantitative interpretation of adsorption measurements in a liquid environment.…”

“…Still, the rich information contained in combined Δ f n and Δ D n measurements, especially when complemented with theoretical models representing the response for viscoelastic films, − has turned out to be very valuable in multiple research areas, including hydration analysis of organic polymers, , proteins, and biological membranes. , QCM has also been widely applied to monitor and characterize thin films, including porosity determination, , monitoring the growth of mesoporous materials, probing responsiveness of polymeric coatings, and characterization of biomimetic membranes. , Additionally, QCM has been extensively employed to study discrete adsorbates such as abiotic and biological macromolecules and nanoparticles (NPs). These studies included investigations of biomolecular interactions of proteins , and viruses; , structure, , confirmation , and orientation changes of biomacromolecules; spatial distribution, size, − deformation , and dissolution of NPs; protein corona formation on amyloids; interactions between NPs and biomimetic membranes; , as well as bioanalytical sensor development. − …”

Surface Properties of Nanoparticles Dictate Their Toxicity by Regulating Adsorption of Humic Acid Molecules

“…15 The cascading effect of engineered NP properties on membrane attachment through dictating protein assemblage was elucidated by Melby et al 16 Recently, Lochbaum et al tuned the lipophilicity of cationic ligands on NPs and demonstrated its promotion to irreversible NP binding to supported lipid bilayers. 17 Using a complementary experimental and computational method, Tollefson et al determined the relative orientation of peripheral membrane proteins on functionalized NPs, 18 and proved its facilitating role in nanoparticle binding to model cell membranes. 19 Other properties, such as surface charge and chirality, were also found to modulate protein adsorption and conformation.…”

“…Due to the large surface-to-volume ratio, nanoparticles (NPs) acquire coatings of biomolecules, such as proteins and natural organic matter (NOM), upon entering an aquatic environment. − Often referred to as the ecocorona, such molecular coating endows NPs with a new surface identity influencing NP behaviors at environmental and biological interfaces. − Continuous efforts have been made to understand biomolecular adsorption on various NPs and its downstream impacts on NP attachment to cell membranes, often using solid-supported lipid bilayers as model systems. − One previous study showed a lower amount of fullerene accumulated in supported lipid bilayers when adsorbed with humic acid (HA) due to surface modification of fullerene and the steric repulsion with the membrane . Mensch et al found effective binding of functionalized diamond NPs to the supported lipid bilayer only at lower NOM-to-NP ratios, as ascribed to changes in the hydrodynamic and electrokinetic properties by forming coronas .…”

CD44/Folate Dual Targeting Receptor Reductive Response PLGA-Based Micelles for Cancer Therapy

“…Therefore, it is proposed that a drug delivery system that can transport DOX to the tumor site should be developed to achieve better antitumor effect and reduce adverse reactions. Due to the advantages that traditional delivery systems do not have, nano-drug delivery systems have been widely studied as drug carriers, and many nano-drug delivery systems have been developed, such as magnetic nanoparticles ( Hosseinpour Moghadam et al, 2019 ), microemulsion ( Lv et al, 2018 ; Wang et al, 2019 ), liposomes ( Antimisiaris et al, 2021 ), gold nanoparticles ( Lochbaum et al, 2021 ), platinum nanoparticles ( Kawawaki et al, 2021 ), polymer micelles ( Yang et al, 2021 ), etc. In these drug delivery systems, polymeric micelles are considered to be effective nanocarriers because they can encapsulate hydrophobic agents into their “core-shell” structures and deliver them to tumor regions through enhanced permeability and retention (EPR) effect.…”