期刊
ACS BIOMATERIALS SCIENCE & ENGINEERING
卷 3, 期 10, 页码 2431-2442出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsbiomaterials.7b00569
关键词
multidrug resistance; copper; doxorubicin; synergism; liposome; mesoporous silica nanoparticles
资金
- National Natural Science Foundation of China [U1605225, 31570974, 31470927]
- Public Science and Technology Research Funds Projects of Ocean [201505029]
- Promotion Program for Young and Middle-aged Teacher in Science and Technology Research of Huaqiao University [ZQN-PY107]
- Huaqiao University [16BS803]
- Ministry of Science and Technology, Taiwan [MOST 105-2113-M-259-004, MOST 105-2627-M-259-003]
Recently, multidrug resistance (MDR) has become a major clinical chemotherapeutic burden that robustly diminishes the intracellular drug levels through various mechanisms. To overcome the doxorubicin (Dox) resistance in tumor cells, we designed a hierarchical nanohybrid system possessing copper-substituted mesoporous silica nanoparticles (Cu-SNs). Further, Dox was conjugated to copper metal in the Cu-MSNs framework through a pH-sensitive coordination link, which is acutely sensitive to the tumor acidic environment (pH 5.0-6.0). In the end, the nanocarrier was coated with D-alpha-Tocopherol polyethylene glycol 1000 succinate (TPGS), a P-gp inhibitor-entrenched compact liposome net for obstructing the drug efflux pump. Copper ions in the framework synergize the antitumor activity of Dox by enhancing the intracellular reactive oxygen species (ROS) levels through a Fenton-like reaction-mediated conversion of hydrogen peroxide. Furthermore, intracellularly generated ROS triggered the apoptosis by reducing the cellular as well as mitochondrial membrane integrity in MDR cells, which was confirmed by the mitochondrial membrane potential (MMP) measurement. The advancement of the design and critical improvement of cytotoxic properties through free radical attack demonstrate that the proposed hierarchical design can devastate the MDR for efficient cancer treatment.
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