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PEGylation of ORMOSIL nanoparticles differently modulates the in vitro toxicity toward human lung cells

ABSTRACT: ORganically MOdified SILica (ORMOSIL) nanoparticles (NPs) appear promising carriers for the delivery of drugs to target tissues and cells but some concerns on possible cytotoxic effects still exist. We therefore studied the in vitro responses to ORMOSIL NPs in different types of human lung cells (i.e. CCD-34Lu normal fibroblasts, carcinoma alveolar type II A549 cells, NCI-H2347 adenocarcinoma cells) to determine the effects of polyethylene glycol (PEG) coating on NP cytotoxicity. Our results show that non-PEG NPs caused a concentration-dependent decrease of viability of all types of cells. On the contrary, PEG-coated NPs increased plasma membrane permeability and induced cell death only in carcinoma alveolar type II A549 cells, while did not produce deleterious effects on CCD-34Lu and NCI-H2347 cells. PEG-coated NPs promoted the formation of reactive oxygen species (ROS) in A549 and CCD-34Lu cells; nevertheless, the decrease of ROS levels in the presence of superoxide dismutase and catalase did not protect A549 cells from death, suggesting that the oxidative stress was not the main determinant of cytotoxicity. Analysis of gene expression in A549 cells exposed to PEG-coated NPs showed alterations in genes involved in inflammation, signal transduction and cell death, while the transcriptional response was not significantly affected in CCD-34Lu fibroblasts. Our transmission electron microscopy analysis evidenced a unique intracellular localization of PEG NPs in the lamellar bodies of A549 cells, which could be the most relevant factor leading to cytotoxicity by reducing the production of surfactant proteins and by interfering with the pulmonary surfactant system.

ORGANISM(S): Homo sapiens

PROVIDER: GSE25991 | GEO | 2014/07/15

SECONDARY ACCESSION(S): PRJNA135419

REPOSITORIES: GEO

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Project description:Poly-ethylene-glycol (PEG)-based nanoparticles (NPs) - including cylindrical micelles (CNPs), spherical micelles (SNPs), and PEGylated liposomes (PLs) - are hypothesized to be cleared in vivo by opsonization followed by liver macrophage phagocytosis. This hypothesis has been used to explain the rapid and significant localization of NPs to the liver after administration into the mammalian vasculature. Here, we show that the opsonization-phagocytosis nexus is not the major factor driving PEG-NP – macrophage interactions. First, mouse and human blood proteins had insignificant affinity for PEG-NPs. Second, PEG-NPs bound macrophages in the absence of serum proteins. Third, lipoproteins blocked PEG-NP binding to macrophages. Because of these findings, we tested the postulate that PEG-NPs bind (apo)lipoprotein receptors. Indeed, PEG-NPs triggered an in vitro macrophage transcription program that was similar to that triggered by lipoproteins and different from that triggered by lipopolysaccharide (LPS) and group A Streptococcus. Unlike LPS and pathogens, PLs did not increase transcripts involved in phagocytosis or inflammation. High-density lipoprotein (HDL) and SNPs triggered remarkably similar mouse bone-marrow-derived macrophage transcription programs. Unlike opsonized pathogens, CNPs, SNPs, and PLs lowered macrophage autophagosome levels and either reduced or did not increase the secretion of key macrophage pro-inflammatory cytokines and chemokines. Thus, the sequential opsonization and phagocytosis process is likely a minor aspect of PEG-NP – macrophage interactions. Instead, PEG-NP interactions with (apo)lipoprotein and scavenger receptors appear to be a strong driving force for PEG-NP – macrophage binding, entry, and downstream effects. We hypothesize that the high presence of these receptors on liver macrophages and on liver sinusoidal endothelial cells is the reason PEG-NPs localize rapidly and strongly to the liver. To investigate the response of macrophages to nanoparticles, we incubated PEGylated liposomes (PLs), spherical nanoparticles (SNPs), high-density lipoproteins (HDL), low-density lipoproteins (LDL), Group A Streptococcus pathogens (JRS4), and lipopolysaccharide (LPS) with RAW264.7 and primary bone-marrow derived mouse macrophages

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PEGylation of ORMOSIL nanoparticles differently modulates the in vitro toxicity toward human lung cells

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