Fisetin-loaded nanocochleates: formulation, characterisation, in vitro anticancer testing, bioavailability and biodistribution study

Background: The natural flavonoid fisetin has shown anticancer properties but its in vivo administration remains challenging due its poor aqueous solubility and extensive in vivo metabolism. This juncture demands an effective, controlled release and safe formulation of fisetin would be a significant advance for the treatment of cancer. Objectives: Nanocochleates are unique lipid-based supramolecular assemblies composed of a negatively charged phospholipid and a divalent cation. The aim was to develop and evaluate fisetin-loaded nanocochleates to improve its therapeutic efficacy. Using the trapping method, fisetin-loaded dimyristoylphosphatidylcholine liposomal vesicles were converted into nanocochleates by the action of Ca2+ ions. These nanocochleates were further evaluated for physicochemical, in vitro anticancer and haemolysis, pharmacokinetics and tissue distribution study in mice. Results: Stable rolled-up layers as well as elongated structure of nanocochleates possessing particle size and encapsulation efficiency (EE) of 275 + 4 nm and 84.31 +/- 2.52%, respectively were obtained. Nanocochleates demonstrated safety and a sustained release of fisetin at physiological pH. A 1.3-fold improvement in vitro anticancer towards human breast cancer MCF-7 cells was observed. Pharmacokinetics studies in mice revealed that nanocochleates injected intraperitonially showed a 141-fold higher relative bioavailability. Moreover, a low tissue distribution was observed. Conclusion: Developed nanocochleates markedly improved anticancer efficacy, bioavailability and safety of fisetin. The nanocochleates technology would facilitate the administration of this flavonoid in the clinical setting. Areas covered: In this research article, we focused on lipid-based supramolecular assembly 'nanocochleates' composed of negatively charged phospholipids and divalent cation as drug carrier for systemic delivery system and discussed their formulations, optimisation, characterization, in vitro and in vivo performance.