Polymerized Luteolin Nanoparticles: Synthesis, Structure Elucidation, and Anti-Inflammatory Activity

Luteolin is an anti-inflammatory flavonoid commonly found in many edible plants. The compound is popularly consumed as a supplement regardless of its poor water solubility (27.8 mu g/mL at 25 degrees C) and low bioavailability. Here, mild one-pot polymerization of luteolin into water-dispersible nanospheres, with an average dry size of 234.8 +/- 101.6 nm, an aqueous size distribution of 379.1 +/- 220.5 nm (PDI = 0.338), an average zeta-potential of -36.2 +/- 0.2 mV, and an 89.3 +/- 4.8% yield, is described. The nanospheres consist of polymerized luteolin (polyluteolin) with a weight-average molecular mass of around 410000 Da. The chemical structure of polyluteolin is identified through H-1-H-1 correlated spectroscopy (COSY), H-1-C-13 heteronuclear single-quantum coherence (HSQC), and H-1-C-13 heteronuclear multiple-bond correlation (HMBC) NMR spectroscopic analyses of the oligomers, and a polymerization mechanism is proposed. Unlike luteolin that showed both dose-dependent anti-inflammatory activity and cytotoxicity when tested in lipopolysaccharide-stimulated macrophages, the polyluteolin nanoparticles possess dose-dependent anti-inflammatory activity without causing cell death even at high concentrations.