PEGylation of Metal Oxide Nanoparticles Modulates Neutrophil Extracellular Trap Formation

Abstract

Novel metal oxide nanoparticle (NP) contrast agents may offer safety and functionality advantages over conventional gadolinium-based contrast agents (GBCAs) for cancer diagnosis by magnetic resonance imaging. However, little is known about the behavior of metal oxide NPs, or of their effect, upon coming into contact with the innate immune system. As neutrophils are the body’s first line of defense, we sought to understand how manganese oxide and iron oxide NPs impact leukocyte functionality. Specifically, we evaluated whether contrast agents caused neutrophils to release web-like fibers of DNA known as neutrophil extracellular traps (NETs), which are known to enhance metastasis and thrombosis in cancer patients. Murine neutrophils were treated with GBCA, bare manganese oxide or iron oxide NPs, or poly(lactic-co-glycolic acid) (PLGA)-coated metal oxide NPs with different incorporated levels of poly(ethylene glycol) (PEG). Manganese oxide NPs elicited the highest NETosis rates and had enhanced neutrophil uptake properties compared to iron oxide NPs. Interestingly, NPs with low levels of PEGylation produced more NETs than those with higher PEGylation. Despite generating a low rate of NETosis, GBCA altered neutrophil cytokine expression more than NP treatments. This study is the first to investigate whether manganese oxide NPs and GBCAs modulate NETosis and reveals that contrast agents may have unintended off-target effects which warrant further investigation.

Caveat Emptor: Commercialized Manganese Oxide Nanoparticles Exhibit Unintended Properties

“…In-house formulations of MnO and Mn 3 O 4 nanocrystals were systematically compared to commercially available MnO, Mn 2 O 3 , and Mn 3 O 4 nanocrystals purchased from two different companies (US Nano and Nanoshel) to evaluate their effectiveness as MRI contrast agents. As previously described, our In-house MnO and Mn 3 O 4 formulations were synthesized via thermal decomposition of Mn­(II)­AcAc with oleylamine as the capping agent. ,, Bare nanocrystals were characterized for crystal structure, chemical composition, impurities, size, morphology, and coating. Hydrophobic bare nanocrystals were encapsulated within PLGA and characterized for surface chemistry, size, morphology, encapsulation efficiency, pH-sensitive release of manganese ions, and resulting MRI signal.…”

“…In-house and commercialized MnO, Mn 2 O 3 , and Mn 3 O 4 nanocrystals were encapsulated in PLGA using an oil-in-water emulsion solvent evaporation method as previously described. , Each nanocrystal typeIn-house MnO and Mn 3 O 4 ; US Nano’s Mn 2 O 3 and Mn 3 O 4 ; and Nanoshel’s MnO, Mn 2 O 3 -30 nm, Mn 2 O 3 -80 nm, and Mn 3 O 4 was encapsulated within PLGA in triplicate. For each replicate, approximately 100 mg of PLGA was dissolved in 2 mL of dichloromethane (DCM).…”

The potential impact of nanomedicine on COVID-19-induced thrombosis

“…Several papers have reported nanoparticle-induced NETosis, which may aggravate the thrombogenic nature of the SARS-CoV-2 infection. Thus far, nanoparticle-induced NETosis has been reported for nanoparticles based on silver 38 , gold 39,40 , iron oxide 41,42 , manganese oxide 41 , graphene oxide 43 , cationic lipids 44 , polystyrene 45 and nanodiamonds 45 , although further research may reveal other materials exhibiting similar behaviour. There is as-of-yet contention over whether this is caused by the nanoparticles themselves or their dissolution products 46 .…”

“…Surface functionalization with biocompatible layers of human serum albumin or dextran has also been shown to reduce the NET-generating properties of iron oxide nanoparticles 42 , providing another strategy for minimizing NETosis. Interestingly, several papers have indicated that the addition of polyethylene glycol-which is normally seen as highly biocompatible-does not reduce NETosis 40 , and may even aggravate it 41 . Due to these variabilities, it is suggested that nanomedicines designed to treat COVID-19-induced thrombosis are optimized and tested pre-clinically for their ability to generate NETosis, to avoid potential pro-thrombotic effects.…”

Nylon-6-Coated Doxorubicin-Loaded Magnetic Nanoparticles and Nanocapsules for Cancer Treatment

“…However, in most cases, the magnetic core should be completely protected by various organic and inorganic materials. One of the popular approaches to achieve this is polymer coating [13,[49][50][51][52][53][54]. A wide range of polymers and their functional groups provide excellent diversification of colloidal stability, charge, solubility in water, salt and temperature stability, viscosity, and further modification by address or reporter groups [13,[49][50][51][52][53][54][55][56][57][58][59][60].…”