RESUMEN
The oral delivery of insoluble and enterotoxic drugs has been largely plagued by gastrointestinal irritation, side effects, and limited bioavailability. Tripterine (Tri) ranks as the hotspot of anti-inflammatory research other than inferior water-solubility and biocompatibility. This study was intended to develop selenized polymer-lipid hybrid nanoparticles loading Tri (Se@Tri-PLNs) for enteritis intervention by improving its cellular uptake and bioavailability. Se@Tri-PLNs were fabricated by a solvent diffusion-in situ reduction technique and characterized by particle size, ζ potential, morphology, and entrapment efficiency (EE). The cytotoxicity, cellular uptake, oral pharmacokinetics, and in vivo anti-inflammatory effect were evaluated. The resultant Se@Tri-PLNs were 123 nm around in particle size, with a PDI of 0.183, ζ potential of -29.70 mV, and EE of 98.95%. Se@Tri-PLNs exhibited retardant drug release and better stability in the digestive fluids compared with the unmodified counterpart (Tri-PLNs). Moreover, Se@Tri-PLNs manifested higher cellular uptake in Caco-2 cells as evidenced by flow cytometry and confocal microscopy. The oral bioavailability of Tri-PLNs and Se@Tri-PLNs was up to 280% and 397% relative to Tri suspensions, respectively. Furthermore, Se@Tri-PLNs demonstrated more potent in vivo anti-enteritis activity, which resulted in a marked resolution of ulcerative colitis. Polymer-lipid hybrid nanoparticles (PLNs) enabled drug supersaturation in the gut and the sustained release of Tri to facilitate absorption, while selenium surface engineering reinforced the formulation performance and in vivo anti-inflammatory efficacy. The present work provides a proof-of-concept for the combined therapy of inflammatory bowel disease (IBD) using phytomedicine and Se in an integrated nanosystem. Selenized PLNs loading anti-inflammatory phytomedicine may be valuable for the treatment of intractable inflammatory diseases.
RESUMEN
Inflammation mediates a variety of physiological and pathological events, prompting an importance of inflammation management for prevention and treatment of inflammatory diseases. This study formulated tripterine (Tri) into selenized phytosomes in an attempt to attenuate its cytotoxicity and potentiate its inflammation-regulating effect with selenium. Tri-loaded phytosomes (Tri-PTs) with selenium modification were prepared by a melting-hydration followed by in situ reduction technique. Then, selenized Tri-PTs (Se@Tri-PTs) were characterized by particle size, entrapment efficiency, and transmission electron microscope. The in vitro drug release and cellular uptake were performed to examine the formulation performance of Se@Tri-PTs. The cytotoxicity and anti-inflammatory efficacy through inhibiting NLRP3 inflammasome activation and pyroptosis were appreciated in murine J774A.1 macrophage cell line, respectively. The resultant Se@Tri-PTs presented a particle size of 125 nm around. Se@Tri-PTs exhibited attenuated cytotoxicity and improved cellular uptake in macrophages compared with free Tri or Tri-PTs. Also, Se@Tri-PTs inhibited the releases of caspase-1p20 and mature IL-1ß, resulting in restriction of NLRP3 inflammasome activation that inhibits the formation of GSDMD-NT whereby to initiate pyroptosis. Altogether, our findings suggest that Se@Tri-PTs can inhibit inflammatory response by regulating the NLRP3/caspase-1 pathway, which in turn reduces pyroptosis via suppressing the cleavage of GSDMD.