Modulation of the anti‐inflammatory effects of phosphatidylserine‐containing liposomes by PEGylation

Abstract

Inhibiting liposome uptake by macrophages using polyethylene glycol (PEG) surface modifications is a widely used approach for extending the half-life of liposomes circulating in the blood. However, the biological effects of PEGylated liposomes on macrophages have not yet been thoroughly investigated. The purpose of this study was to examine the effects of PEGylated phosphatidylserine-containing liposomes (PEG-PSLs) on the expression of two inflammation-associated cytokines, tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β), in the murine macrophage-like cell line RAW 264.7. Previous studies have demonstrated that PSLs inhibit TNF-α secretion and enhance TGF-β synthesis in macrophages by mimicking apoptotic cells. We found that PEGylation differentially affected the TNF-α and TGF-β levels. The PSL-mediated inhibitory effect on TNF-α secretion was enhanced by PEGylation, and PEG-PSLs decreased TGF-β levels compared with non-PEGylated PSLs. Fluorescence-activated cell sorting analysis demonstrated that 1% PEGylation disturbed the incorporation of PSLs into macrophages. The interference of uptake is thought to extend the binding interaction between PS to PS receptors for PSL-mediated inhibition of TNF-α expression. Together, these findings indicate that PEG-PSLs can prevent TNF-α secretion without increasing TGF-β levels in macrophages, and they support the potential clinical use of PEG-PSLs as anti-inflammatory agents with a relatively low potential to induce tissue fibrosis. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1479-1486, 2017.

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“…In accordance with previous literature, PEG concentration had a profound effect on liposome characteristics 34–37 . PEGylated liposomes with superior properties were achieved by through optimal PEG concentration.…”

Formulation and manufacturing of lymphatic targeting liposomes using microfluidics

“…production such as Interleukin 6 (IL6) and Prostaglandin E2 (PGE2), in Interleukin 1 beta (IL-1β) stimulated in vitro and in vivo animal models [29], through induction of active anti-inflammatory or suppressive properties in macrophages [30]. Indeed, a previous study has shown the effects of PEGylated PS-containing liposomes on the expression of two inflammation associated cytoki nes, tumour necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β), in the murine macrophage-like cell line RAW 264.7 [31]. These results demonstrated that the incorporation of PEGylated PS-containing liposomes into cells decreased compared with non-PEGylated PS liposomes, suggesting that the interactions between PS and the PS receptors that influence TNF-α and TGF-β levels were differentially affected by the PEGylation of PS liposomes [31,32].…”

“…Indeed, a previous study has shown the effects of PEGylated PS-containing liposomes on the expression of two inflammation associated cytoki nes, tumour necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β), in the murine macrophage-like cell line RAW 264.7 [31]. These results demonstrated that the incorporation of PEGylated PS-containing liposomes into cells decreased compared with non-PEGylated PS liposomes, suggesting that the interactions between PS and the PS receptors that influence TNF-α and TGF-β levels were differentially affected by the PEGylation of PS liposomes [31,32]. As PEGylated PS containing liposomes are capable of efficiently inhibiting the inflammatory cytokine TNF-α without upregulating TGF-β mRNA [33], they demonstrate promising anti-inflammatory effect.…”

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“…The activation and phenotype of macrophages is likely affected by implanted biomaterials, and the resulting state of macrophages may, in turn, determine the quality of tissue regeneration on the surface of the biomaterials. Since the beginning of biomaterial design, there have been many attempts to regulate the state of macrophages to improve their biocompatibility [5][6][7]. To enhance the biocompatibility of biomaterials, M2 polarization of macrophages is generally recommended, because anti-inflammatory M2 macrophages are supposed to end inflammation and promote tissue regeneration.…”