BETA-CASEIN BASED NANOVEHICLES FOR ORAL DELIVERY OF CHEMOTHERAPEUTIC COMBINATIONS OVERCOMING P-GLYCOPROTEIN-MEDIATED MULTIDRUG RESISTANCE IN GASTRIC CANCER CELLS

Cancer multidrug resistance (MDR) remains a primary hindrance toward curative therapy. Furthermore, most chemotherapeutic agents are lipid-soluble, hence administered intravenously using harmful solvents and surfactants. The availability of an effective and selective oral delivery system would significantly contribute to patients’ quality of life and save hospitalization costs. Bovine β-casein (β-CN) is an abundant milk protein that has a pronounced amphiphilic structure, promoting it`s self-assembly to stable micelles in aqueous solutions. β-CN has an open tertiary structure which is easily accessible to gastric proteases. We have previously demonstrated that β-CN micelles can serve as nanovehicles for oral delivery and target-activated release of hydrophobic bio-actives cargo, including nutraceuticals and chemotherapeutic agents in the stomach. Herein we developed a novel oral delivery platform comprising an individually encapsulated chemotherapeutic drug (Paclitaxel) and a P-glycoprotein-specific chemosensitizer (Tariquidar), which counteract MDR mechanisms, that expel a spectrum of anticancer drugs from cancer cells, based on ATP-driven MDR efflux pumps (e.g. P-glycoprotein). Hence, the rationally designed encapsulated pair is expected to display enhanced efficacy and synergy in the overcoming of MDR phenomena in gastric cancer. Discontinuous mucosal lining at the gastric tumor should facilitate better specificity of the local treatment. Light microscopy, dynamic light scattering and zeta potential analyses revealed solubilization of these drugs by β-CN, suppressing drug crystals growth. Spectrophotometry demonstrated high loading capacity and good encapsulation efficiency, whereas spectrofluorometry revealed high affinity of these drugs to β-CN. In vitro cytotoxicity assays exhibited remarkable synergistic efficacy against human MDR gastric carcinoma cells with P-glycoprotein overexpression. These findings indicate that oral delivery of β-CN-based nanovehicles carrying synergistic drug combinations to the stomach constitutes a novel therapeutic system that may overcome MDR gastric cancer.