The Laboratory of Biopolymers for Food and Health, Department of Biotechnology and Food Engineering, Technion - Israel Institute of Technology, Haifa 3200000, Israel; Russell Berrie Nanotechnology Institute, Technion - Israel Institute of Technology, Haifa 3200000, Israel; The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion - Israel Institute of Technology, Haifa 3200000, Israel.
The Laboratory of Biopolymers for Food and Health, Department of Biotechnology and Food Engineering, Technion - Israel Institute of Technology, Haifa 3200000, Israel.
Eur J Pharm Biopharm. 2018 Dec;133:240-249. doi: 10.1016/j.ejpb.2018.10.018. Epub 2018 Oct 24.
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 β-casein (β-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 β-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 β-CN, as demonstrated by spectrophotometry and spectrofluorometry. Furthermore, light microscopy and dynamic light scattering confirmed that β-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.
胃癌是全球癌症相关死亡的第三大主要原因。多药耐药（MDR）是癌症治疗的主要障碍，其由 ATP 依赖性外排泵介导。我们之前已经证明了β-酪蛋白（β-CN）胶束和重新组装的酪蛋白胶束作为纳米载体的能力，用于在胃部口服递送和靶向激活释放疏水性化疗药物，并克服胃癌中的 P 糖蛋白依赖性 MDR。在此，我们使用不同的协同药物对来研究基于β-CN 的这种递药系统的多功能性，以治疗过表达乳腺癌耐药蛋白（BCRP）的多药耐药胃癌细胞。化疗药物 SN-38 是 BCRP 的转运底物，BCRP 外排转运抑制剂 elacridar 与β-CN 具有高结合亲和力，这一点通过分光光度法和荧光分光光度法得到证实。此外，光学显微镜和动态光散射证实β-CN 溶解了这些药物并抑制了药物晶体生长。体外对过表达 BCRP 的人胃腺癌多药耐药细胞的细胞毒性研究揭示了这种药物组合的协同作用和完全逆转多药耐药性。因此，我们的研究结果强调了基于酪蛋白的纳米载体作为一种模块化和多功能的口服递药系统的巨大潜力，该系统可用于在胃部局部释放疏水性协同药物组合以克服胃癌的化疗耐药性。
