Inhibition of IL-1 beta release from macrophages targeted with necrosulfonamide-loaded porous nanoparticles

Boersma, Bart; Moeller, Karin; Wehl, Lisa; Puddinu, Viola; Huard, Arnaud; Fauteux-Daniel, Sebastien; Bourquin, Carole; Palmer, Gaby und Bein, Thomas (2022): Inhibition of IL-1 beta release from macrophages targeted with necrosulfonamide-loaded porous nanoparticles. In: Journal of Controlled Release, Bd. 351: S. 989-1002

Abstract

Inflammation is required for protective responses against pathogens and is thus essential for survival, but sus-tained inflammation can lead to diseases, such as atherosclerosis and cancer. Two important mediators of inflammation are the cytokines IL-1 beta and IL-18, which are produced by myeloid cells of the immune system, including macrophages. These cytokines are released into the extracellular space through pores formed in the plasma membrane by the oligomerized protein gasdermin D (GSDMD). Necrosulfonamide (NSA) was recently identified as an effective GSDMD inhibitor and represents a promising therapeutic agent in GSDMD-dependent inflammatory diseases. Here, we targeted NSA to both mouse and human macrophages by using three different types of porous nanoparticles (NP), i.e. mesoporous silica (MSN), porous crosslinked cyclodextrin carriers (CD-NP), and a mesoporous magnesium-phosphate carrier (MPC-NP), all displaying high loading ca-pacities for this hydrophobic drug. Cellular uptake and intracellular NSA delivery were tracked in time-lapse experiments by live-cell, high-throughput fluorescence microscopy, demonstrating rapid nanoparticle uptake and effective targeted delivery of NSA to phagocytic cells. Notably, a strong cytostatic effect was observed when a macrophage cell line was exposed to free NSA. In contrast, cell growth was much less affected when NSA was delivered via the nanoparticle carriers. Utilizing NSA-loaded nanoparticles, a successful concentration-dependent suppression of IL-1 beta secretion from freshly differentiated primary murine and human macrophages was observed. Functional assays showed the strongest suppressive effect on human macrophages when using CD-NP for NSA delivery, followed by MSN-NP. In contrast, MPC-NP completely blocked the metabolic activity in macrophages when loaded with NSA. This study demonstrates the potential of porous nanoparticles for the effective delivery of hydrophobic drugs to macrophages in order to suppress inflammatory responses.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department Chemie
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 0168-3659
• Sprache: Englisch