Novel PEGylated cholephytosomes for targeting fisetin to breast cancer: in vitro appraisal and in vivo antitumoral studies

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-& beta;1and its non-canonical related signaling pathway; ERK1/2, NF-& kappa;B, and MMP-9 were involved in halting tumorigenesis. Thus, tailoring novel phytosomal nanosystems for FIS could open opportunity for its clinical utility against cancer.

Automated summary

In this study, a novel biocompatible phytosomal system, cholephytosomes, was formed by complexing fisetin with soy phosphatidylcholine in the presence of cholesterol. Modified vesicles, mPHY and HPHY, showed promising physicochemical properties and significantly improved the antitumor activity against breast cancer cells. These findings suggest that tailoring novel phytosomal nanosystems for fisetin could be a potential approach for its clinical utility against cancer.