β-casein nanovehicles for oral delivery of chemotherapeutic drug combinations overcoming P-glycoprotein-mediated multidrug resistance in human gastric cancer cells

// Maya Bar-Zeev 1, 2, 3 , Yehuda G. Assaraf 3 , Yoav D. Livney 1, 2 1 Russell Berrie Nanotechnology Institute, Technion - Israel Institute of Technology, Haifa 3200000, Israel 2 The Laboratory of Food Physical Chemistry and Biopolymeric Delivery Systems for Health, Department of Biotechnology and Food Engineering, Technion - Israel Institute of Technology, Haifa 3200000, Israel 3 The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion - Israel Institute of Technology, Haifa 3200000, Israel Correspondence to: Yoav D. Livney, e-mail: livney@technion.ac.il Yehuda G. Assaraf, e-mail: assaraf@technion.ac.il Keywords: β-casein micelles, target-activated oral delivery, gastric cancer, multidrug resistance reversal, paclitaxel-tariquidar combination Received: November 18, 2015      Accepted: February 21, 2016      Published: March 10, 2016 ABSTRACT Multidrug resistance (MDR) is a primary obstacle to curative cancer therapy. We have previously demonstrated that β-casein (β-CN) micelles (β-CM) can serve as nanovehicles for oral delivery and target-activated release of hydrophobic drugs in the stomach. Herein we introduce a novel nanosystem based on β-CM, to orally deliver a synergistic combination of a chemotherapeutic drug (Paclitaxel) and a P-glycoprotein-specific transport inhibitor (Tariquidar) individually encapsulated within β-CM, for overcoming MDR in gastric cancer. Light microscopy, dynamic light scattering and zeta potential analyses revealed solubilization of these drugs by β-CN, suppressing drug crystallization. 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. Oral delivery of β-CN - based nanovehicles carrying synergistic drug combinations to the stomach constitutes a novel efficacious therapeutic system that may overcome MDR in gastric cancer.