Ethoxy acetalated dextran-based nanocarriers accomplish efficient inhibition of leukotriene formation by a novel FLAP antagonist in human leukocytes and blood

• DOI: 10.1007/s00018-021-04039-7
• Publication Date: 2021-12-31T05:02:24Z
• Authors: Christian Kretzer; Blerina Shkodra; Paul Klemm; Paul M. Jordan; Daniel Schröder; Gizem Cinar; Antje Vollrath; Stephanie Schubert; Ivo Nischang; Stephanie Hoeppener; Steffi Stumpf; Erden Banoglu; Frederike Gladigau; Rossella Bilancia; Antonietta Rossi; Christian Eggeling; Ute Neugebauer; Ulrich S. Schubert; Oliver Werz
• Keywords: Nanocarriers; Leukotriene B4; PLGA

Abstract Leukotrienes are pro-inflammatory lipid mediators generated by 5-lipoxygenase aided the 5-lipoxygenase-activating protein (FLAP). BRP-201, a novel benzimidazole-based FLAP antagonist, inhibits leukotriene biosynthesis in isolated leukocytes. However, like other antagonists, BRP-201 fails to effectively suppress formation blood, which limits its therapeutic value. Here, we describe encapsulation of into poly(lactide- co -glycolide) (PLGA) and ethoxy acetalated dextran (Ace-DEX) nanoparticles (NPs), aiming overcome these detrimental pharmacokinetic limitations enhance bioactivity BRP-201. NPs loaded with were produced via nanoprecipitation physicochemical properties analyzed in-depth using dynamic light scattering (size, dispersity, degradation), electrophoretic (effective charge), NP tracking analysis dispersity), scanning electron microscopy (size morphology), UV–VIS spectroscopy (drug loading), an analytical ultracentrifuge release, degradation kinetics), Raman (chemical attributes). Biological assays performed study cytotoxicity, cellular uptake, efficiency BRP-201-loaded versus free primary human leukocytes whole blood. Both PLGA- Ace-DEX-based significantly more efficient inhibit neutrophils drug. Whole blood experiments revealed that Ace-DEX strongly increases potency, especially upon pro-longed (≥ 5 h) incubations lipopolysaccharide-challenge Finally, intravenous injection suppressed levels mice vivo. These results reveal feasibility our pharmacological approach antagonist encapsulated improved biosynthesis.