Fisetin (FIS) is a multifunctional bioactive flavanol that has been recently exploited as anticancer
drug against various
cancers including
breast cancer. However, its poor aqueous solubility has constrained its clinical application. In the current work,
fisetin is complexed for the first time with soy
phosphatidylcholine in the presence of
cholesterol to form a novel biocompatible phytosomal system entitled "cholephytosomes." To improve
fisetin antitumor activity against
breast cancer,
stearylamine bearing cationic cholephytosomes (mPHY) were prepared and furtherly modified with
hyaluronic acid (HPHY) to allow their orientation to
cancer cells through their surface exposed
phosphatidylserine and CD-44 receptors, respectively. In vitro characterization studies revealed promising physicochemical properties of both modified vesicles (mPHY and HPHY) including excellent FIS complexation efficiency (˷100%), improved octanol/water solubility along with a sustained drug release over 24 h. In vitro cell line studies against MDA-MB-231 cell line showed about 10- and 3.5-fold inhibition in IC50 of modified vesicles compared with free
drug and conventional
drug-
phospholipid complex, respectively. Preclinical studies revealed that both modified cholephytosomes (mPHY and HPHY) had comparable cytotoxicity that is significantly surpassing free
drug cytotoxicity. TGF-β1and its non-canonical related signaling pathway; ERK1/2, NF-κB, and MMP-9 were involved in halting
tumorigenesis. Thus, tailoring novel phytosomal nanosystems for FIS could open opportunity for its clinical utility against
cancer.