Liposomal encapsulation of the natural flavonoid fisetin improves bioavailability and antitumor efficacy

The natural flavonoid fisetin (3,3′,4′,7-tetrahydroxyflavone) has shown antiangiogenic and anticancer properties. Because of fisetin limited water solubility, we designed a liposomal formulation and evaluated its biological properties in vitro and in Lewis lung carcinoma (LLC) bearing mice.A liposomal formulation was developed with DOPC and DODA-PEG2000, possessing a diameter in the nanometer range (173.5 ± 2.4 nm), a high homogeneity (polydispersity index 0.181 ± 0.016) and high fisetin encapsulation (58%). Liposomal fisetin incubated with LLC cells were internalized, induced a typical fisetin morphological effect and increased the sub-G1 cell distribution.In vivo, liposomal fisetin allowed a 47-fold increase in relative bioavailability compared to free fisetin. The effect of liposomal fisetin on LLC tumor growth in mice at low dose (21 mg/kg) allowed a higher tumor growth delay (3.3 days) compared to free fisetin at the same dose (1.6 day). Optimization of liposomal fisetin therapy was attempted by co-treatment with cyclophosphamide which led to a significant improvement in tumor growth delay (7.2 days) compared to cyclophosphamide with control liposomes (4.2 days).In conclusion, fisetin liposomes markedly improved fisetin bioavailability and anticancer efficacy in mice and this formulation could facilitate the administration of this flavonoid in the clinical setting.

Graphical abstractLiposomal formulation of fisetin improves its bioavailability (A) and antitumor efficacy in mice (B). Lewis lung carcinoma bearing mice treated with empty liposomes (solid squares), empty liposomes and cyclophosphamide at 30 mg/kg (solid triangles), and liposomal fisetin at 35 mg/kg in combination with cyclophosphamide at 30 mg/kg (empty triangles).Figure optionsDownload full-size imageDownload high-quality image (166 K)Download as PowerPoint slide