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Synergic modulation of the inflammatory state of macrophages utilizing anti-oxidant and phosphatidylserine-containing polymer-lipid hybrid nanoparticles.

ABSTRACT: Inflammatory activation of macrophages is a key factor in chronic inflammatory diseases such as ulcerative colitis. The excessive production of reactive oxygen species (ROS)/reactive nitrogen species (RNS) by macrophages causes oxidative stress during the inflammatory response and exaggerates inflammatory lesions in ulcerative colitis. Inhibition of the inflammatory activation of macrophages is a promising treatment for chronic inflammatory diseases. Here, we prepared self-filling polymer-lipid hybrid nanoparticles (PST-PLNPs) consisting of poly dl-lactic acid as a hydrophobic biodegradable polymer core encapsulating α-tocopherol (T) and phosphatidylserine (PS) both on the surface and interior of the particle. We confirmed the anti-inflammatory response of these hybrid nanoparticles in activated murine macrophages. PS has anti-inflammatory effects on macrophages by modulating the macrophage phenotype, while α-tocopherol is an antioxidant that neutralizes ROS. We found that PS-containing (PS-PLNPs) and PS plus α-tocopherol-containing (PST-PLNPs) polymer-lipid hybrid nanoparticles significantly increased the viability of lipopolysaccharide (LPS)-treated macrophages compared with phosphatidylcholine-containing PLNPs. PST-PLNPs had a better effect than PS-PLNPs, which was attributed to the synergy between PS and α-tocopherol. This synergic action of PST-PLNPs reduced NO and pro-inflammatory cytokine (IL-6) production and increased anti-inflammatory cytokine (TGF-β1) production when incubated with activated macrophages. Thus, these self-filling biodegradable polymer-lipid hybrid nanoparticles (PST-PLNPs) containing anti-oxidant and anti-inflammatory molecules might be potential alternative drug carriers to liposomes and polymeric nanoparticles for the treatment of chronic inflammatory diseases such as ulcerative colitis.

SUBMITTER: Hosain MZ

PROVIDER: S-EPMC6071953 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Macrophages are innate immune cells with great phenotypic plasticity, which allows them to regulate an array of physiological processes such as host defense, tissue repair, and lipid/lipoprotein metabolism. In this proof-of-principle study, we report that macrophages of the M1 inflammatory phenotype can be selectively targeted by model hybrid lipid-latex (LiLa) nanoparticles bearing phagocytic signals. We demonstrate a simple and robust route to fabricate nanoparticles and then show their efficacy through imaging and drug delivery in inflammatory disease models of atherosclerosis and obesity. Self-assembled LiLa nanoparticles can be modified with a variety of hydrophobic entities such as drug cargos, signaling lipids, and imaging reporters resulting in sub-100nm nanoparticles with low polydispersities. The optimized theranostic LiLa formulation with gadolinium, fluorescein and "eat-me" phagocytic signals (Gd-FITC-LiLa) a) demonstrates high relaxivity that improves magnetic resonance imaging (MRI) sensitivity, b) encapsulates hydrophobic drugs at up to 60% by weight, and c) selectively targets inflammatory M1 macrophages concomitant with controlled release of the payload of anti-inflammatory drug. The mechanism and kinetics of the payload discharge appeared to be phospholipase A2 activity-dependent, as determined by means of intracellular Förster resonance energy transfer (FRET). In vivo, LiLa targets M1 macrophages in a mouse model of atherosclerosis, allowing noninvasive imaging of atherosclerotic plaque by MRI. In the context of obesity, LiLa particles were selectively deposited to M1 macrophages within inflamed adipose tissue, as demonstrated by single-photon intravital imaging in mice. Collectively, our results suggest that phagocytic signals can preferentially target inflammatory macrophages in experimental models of atherosclerosis and obesity, thus opening the possibility of future clinical applications that diagnose/treat these conditions. Tunable LiLa nanoparticles reported here can serve as a model theranostic platform with application in various types of imaging of the diseases such as cardiovascular disorders, obesity, and cancer where macrophages play a pathogenic role.

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Synergic modulation of the inflammatory state of macrophages utilizing anti-oxidant and phosphatidylserine-containing polymer-lipid hybrid nanoparticles.

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