Brush Conformation of Polyethylene Glycol Determines the Stealth Effect of Nanocarriers in the Low Protein Adsorption Regime

Abstract

For nanocarriers with low protein affinity, we show that the interaction of nanocarriers with cells is mainly affected by the density, the molecular weight, and the conformation of polyethylene glycol (PEG) chains bound to the nanocarrier surface. We achieve a reduction of nonspecific uptake of ovalbumin nanocarriers by dendritic cells using densely packed PEG chains with a “brush” conformation instead of the collapsed “mushroom” conformation. We also control to a minor extent the dysopsonin adsorption by tailoring the conformation of attached PEG on the nanocarriers. The brush conformation of PEG leads to a stealth behavior of the nanocarriers with inhibited uptake by phagocytic cells, which is a prerequisite for successful in vivo translation of nanomedicine to achieve long blood circulation and targeted delivery. We can clearly correlate the brush conformation of PEG with inhibited phagocytic uptake of the nanocarriers. This study shows that, in addition to the surface’s chemistry, the conformation of polymers controls cellular interactions of the nanocarriers.

Understanding the Adsorption of Peptides and Proteins onto PEGylated Gold Nanoparticles

“…We observe that both the adsorption rate and the number of biomolecules adsorbed onto PEGylated AuNPs increase as the size of PEG-SH increases, from 5K-, 10K-, to 30K-PEG-AuNPs. This validates previous observations that smaller PEGs have a better passivation effect on AuNPs due to their higher grafting density, making diffusion of biomolecules into the dense PEG polymer chains less efficient, and leaving less AuNP surface for biomolecule loading [16,34,[51][52][53]. On the contrary, larger PEG can stabilize AuNPs as well as allow biomolecules to diffuse efficiently and bind to the AuNPs.…”

“…In conclusion, our study indicates that larger PEG molecules are less effective in passivating biomolecules molecules with small sizes (GSH and H1.5) and macromolecules with thiol groups (H1.5-Cys, K19C GB3, and BSA). Larger PEG constructs adopt a “mushroom”-like structure, leaving voids in between the PEG chains [ 16 ]. Due to this mushroom-like structure, the surface density of larger PEG on AuNPs is lower than the short PEG chains.…”

“…A well-known method to avoid phagocytosis is to functionalize NP surfaces with polyethylene glycol (PEG), also called PEGylation [ 12 , 13 ]. There are numerous studies indicating that PEG-coated AuNPs reduce the protein corona formation and increase the retention time of the NPs in the circulatory system [ 14 , 15 , 16 ]. The passivating effect of PEG on AuNPs is thought to be conferred due to a reduced tendency for protein binding to a PEGylated surface [ 17 , 18 ].…”

“…The effect of the PEGylation depends on the PEG molecular weight, polymer chain architecture, and PEG surface density on the NP surface [ 29 , 30 ]. For example, a high density of PEG favors an extended “brush” conformation, which is more effective at passivation than the “mushroom” conformation adopted during less dense PEGylation [ 16 ]. This improved passivation likely results from a shift in PEG dynamics, with more constrained motions favoring improved passivation [ 31 ].…”

Differently PEGylated Polymer Nanoparticles for Pancreatic Cancer Delivery: Using a Novel Near-Infrared Emissive and Biodegradable Polymer as the Fluorescence Tracer

“…Poly(ethylene oxide)-block-poly(ε-caprolactone) and PEG-DSPE are among the common strategies to modify the hydrophobic substances with hydrophilic PEG on surface, to fabricate the stealth nanoparticles for enhanced blood circulation ( Jokerst et al, 2011 ; Suk et al, 2016 ). The density and the molecular weight of PEG chains bound to the nanoparticle surface could also contribute to the efficacy of this shielding effect ( Li et al, 2021 ). Here, both PEGylated on their surfaces, PEO-PCL-P and PEG-DSPE-P demonstrated a similar circulation in vivo but different profiles of tumor accumulation.…”