Anionic and cationic vitamin E-TPGS mixed polymeric phospholipid micellar vehicles

Abstract

Berberine (Brb) is an active isoquinoline alkaloid occurring in various common plant species, with well-known potential for cancer therapy. Earlier reports has shown that Brb not only augments the efficacy of antineoplastic chemotherapy and radiotherapy, but it also exhibits direct anti-mitotic, and pro-apoptotic activities, plus significant anti-angiogenic and anti-metastatic activities in a variety of solid tumors. Notwithstanding its low systemic toxicity, a few pharmaceutical limitations severely hamper the application of Brb in cancer therapy (namely, very slight aqueous solubility and exceedingly low membrane permeability; combined with poor systemic pharmacokinetic, PK, profile). Lipid-based nanocarriers, amphiphilic mixed micelles (Mic) composed of polymeric phospholipid conjugates and PEG-succinate ester of tocopherol were investigated as promising strategy, to improve Brb delivery into tumors. Following physicochemical characterization of micellar Brb, in vitro release studies in simulated physiological media were performed, combined with PK-simulation and in vitro assays of cytotoxicity and direct apoptosis induction in different human prostate cancer cell lines (PC3 and LNPaC). Optimized stealth PEG-PE/TPGS-mixed micelles achieved efficient solubilization of Brb to potentially improve its systemic PK profiles (>30-fold). Our mixed micellar platform resulted in significant enhancement of the pro-apoptotic action and overall anticancer efficacy of Brb, against various in vitro (monolayer and spheroid) models of prostate cancers.