Journal
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
Volume 133, Issue -, Pages 240-249Publisher
ELSEVIER
DOI: 10.1016/j.ejpb.2018.10.018
Keywords
beta-casein micelles; Target-activated oral delivery; Gastric cancer; Multidrug resistance reversal; SN-38; Elacridar; Chemotherapeutic drug combinations; Chemosensitizer
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Gastric cancer is the third leading cause of cancer-related mortality worldwide. A dominant hindrance towards curative cancer therapy is multidrug resistance (MDR) mediated by ATP-dependent efflux pumps. We have previously demonstrated the ability of beta-casein (beta-CN) micelles and re-assembled casein micelles to serve as nanovehicles for oral delivery and target-activated release of hydrophobic chemotherapeutics in the stomach, and to overcome P-glycoprotein-dependent MDR in gastric cancer. Herein we investigated the modularity and versatility of this beta-CN-based delivery system using a different synergistic drug duo to treat MDR gastric cancer cells overexpressing the breast cancer resistance protein (BCRP). The chemotherapeutic drug SN-38, a BCRP transport substrate, and the BCRP efflux transport inhibitor, elacridar, exhibited high binding affinity to beta-CN, as demonstrated by spectrophotometry and spectrofluorometry. Furthermore, light microscopy and dynamic light scattering confirmed that beta-CN solubilized these drugs and suppressed drug crystal growth. In vitro cytotoxicity against MDR human gastric carcinoma cells overexpressing BCRP revealed a synergistic activity of this drug combination and a complete MDR reversal. Hence, our findings highlight the great promise of casein-based nanovehicles, harboring hydrophobic synergistic drug combinations, as a modular and versatile oral delivery system for local drug release in the stomach to overcome chemoresistance in gastric cancer.
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