Development of functionalized phytosome containing resveratrol and reserpine for targeting liver cancer

Abstract

Hepatocellular carcinoma (HCC) remains a significant challenge due to multidrug resistance (MDR) mechanisms, primarily involving alpha-fetoprotein (AFP) and glycoprotein (P-gp) overexpression, which reduces chemotherapeutic efficacy. Traditional treatments like chemotherapy, liver transplantation, and radiotherapy have limitations due to side effects, antimicrobial resistance, and sub-therapeutic drug concentrations at the tumor site. As a potential solution, flavonoids have emerged as promising anticancer agents due to their ability to induce apoptosis and inhibit cell proliferation. However, their clinical application is limited by low bioavailability, poor aqueous solubility, low permeability, and rapid metabolism. newlineTo enhance flavonoid efficacy, we propose developing lactobionic acid (LA)- functionalized self-assembled phytosomal nanoparticles (NPs). Phospholipids, as key components of these NPs, offer biocompatibility, amphiphilicity, and improved drug delivery across biological membranes. The LA-functionalized phospholipids, synthesized using phospholipase D coupling, will target liver cancer cells by binding to overexpressed LA receptors. The flavonoid-phospholipid complex, transformed into phytosomal NPs using thin-film hydration, will co-deliver flavonoids and a P-gp inhibitor, effectively bypassing MDR mechanisms and increasing therapeutic efficacy. The prepared nanoparticles was evaluated for physicochemical properties, controlled drug release, and anticancer potential through in vitro and in vivo studies using liver cancer cell lines. This novel dual-formulation approach integrates the advantages of phospholipid complexes and targeted delivery, paving the way for a new generation of nanotherapeutics for HCC. newline