Developing a stable and safe oral delivery system for luteolin with a dual cyclodextrin-liposome encapsulation strategyOA

Background: Luteolin, a multifunctional natural flavonoid, suffers from poor aqueoussolubility and low oral bioavailability, which severely limit its clinical potential. Methods:To address these challenges, the study developed a novel dual-encapsulation system byembedding luteolin-hydroxypropyl-β-cyclodextrin inclusion complex (Lut-HP-β-CD) intoliposomes (Lut-HP-β-CD-Lip). The system was comprehensively characterized, and itsperformance was evaluated in vitro. Results: Phase solubility and dissolution studiesconfirmed that the Lut-HP-β-CD complex significantly enhanced the aqueous solubility ofluteolin, with the dissolution rate increasing from 40.95% (physical mixture) to 90.97%.The resulting Lut-HP-β-CD-Lip exhibited favourable colloidal properties (particle size 290.6± 3.76 nm, polydispersity index (PDI) 0.211 ± 0.022, zeta potential –48.69 ± 2.52 mV)and markedly improved physical stability during storage and under simulatedgastrointestinal conditions compared to conventional luteolin liposomes (Lut-Lip). In vitrorelease profiles demonstrated a pH-responsive pattern, with more complete release at pH 6.8than at pH 7.4. Critically, while Lut-HP-β-CD-Lip maintained the anti-inflammatory,anti-lung cancer, lipid-lowering, and anti-senescence activities of free luteolin, itsignificantly reduced its cytotoxicity toward normal cells. For example, the CC50 value inhepatocytes (L02) increased from 22.57 μM (free luteolin) to 42.66 μM (Lut-HP-β-CD-Lip).Conclusion: These findings collectively demonstrate that the dual-encapsulation strategybased on cyclodextrin and liposomes not only improves the solubility and stability ofluteolin but also substantially enhances its safety profile, offering a promising and robustoral delivery platform for further development.