Development of a liposomal formulation of the natural flavonoid fisetin

• Published in: International journal of pharmaceutics 2012-02, Vol.423 (1), p.69-76
• Main Authors: Mignet, Nathalie, Seguin, Johanne, Ramos Romano, Miriam, Brullé, Laura, Touil, Yasmine S., Scherman, Daniel, Bessodes, Michel, Chabot, Guy G.
• Format: Article
• Language: English
• Subjects: Animals; anticarcinogenic activity; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line; Cell Line, Tumor; Cell Shape - drug effects; Cell Survival - drug effects; Chemistry, Pharmaceutical - methods; Cholesterol - chemistry; Cryoelectron Microscopy; Cytotoxicity; Drug Carriers - chemical synthesis; Drug Carriers - chemistry; Drug Stability; encapsulation; endothelial cells; Endothelial Cells - cytology; Endothelial Cells - drug effects; Fisetin; Flavonoid; flavonoids; Flavonoids - administration & dosage; Flavonoids - chemistry; Flavonoids - pharmacology; Humans; Life Sciences; Lipid Bilayers - chemistry; Lipids - chemical synthesis; Lipids - chemistry; Liposome optimization; Liposomes; Mice; Microscopy, Electron, Transmission; neoplasms; Particle Size; Phosphatidylcholines - chemistry; Phosphatidylethanolamines - chemistry; Polyethylene Glycols - chemistry; Unilamellar Liposomes - chemical synthesis; Unilamellar Liposomes - chemistry; water solubility
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2011.04.066

Development and optimization of a fisetin liposomal formulation that retains cytotoxic and morphological effects of free fisetin on endothelial cells. The natural flavonoid fisetin (3,3′,4′,7-tetrahydroxyflavone) has been shown to possess antiangiogenic and anticancer properties. Because of the limited water solubility of fisetin, our aim was to design and optimize a liposomal formulation that could facilitate its in vivo administration, taking into account the availability and cost of the various components. Several methods were evaluated such as probe sonication, homogeneization, film hydration and lipid cake formation. A selection of lipid and lipid-PEG was also performed via their incorporation in different formulations based on the size of the liposomes, their polydispersity index (PDI) and the fisetin encapsulation yield. An optimal liposomal formulation was developed with P90G and DODA-GLY-PEG2000, possessing a diameter in the nanometer scale (175 nm), a high homogeneity (PDI 0.12) and a high fisetin encapsulation (73%). Fisetin liposomes were stable over 59 days for their particle diameter and still retained 80% of their original fisetin content on day 32. Moreover, liposomal fisetin retained the cytotoxicity and typical morphological effect of free fisetin in different tumour and endothelial cell lines. In conclusion, based on its physico-chemical properties and retention of fisetin biological effects, the developed liposomal fisetin preparation is therefore suitable for in vivo administration.