期刊
NANO LETTERS
卷 19, 期 5, 页码 3344-3352出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.nanolett.9b01065
关键词
Gefitinib; CuS nanoparticles; non-small cell lung cancer; drug resistance; reactive oxygen species
类别
资金
- National Natural Science Foundation of China [21874092, 31671003, 81673018]
- Thousand Young Talents Program
- Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning [TP2014028]
- Shanghai Jiao Tong University School of Medicine [BXJ201704]
Bypass signaling activation plays a crucial role in the acquired resistance of gefitinib, the first targeted drug in the clinic to treat advanced non-small cell lung cancer. Although the inactivation of bypass signaling by small-molecule inhibitors or monoclonal antibodies may overcome gefitinib resistance, their clinical use has been limited by the complex production process and off-target toxicity. Here we show CuS nanoparticles (NPs) behaved as a photodynamic nanoswitch to specifically abrogate overactive bypass signaling in resistant tumor cells without interfering with the same signal pathways in normal cells. In representative insulin growth factor-1 receptor (IGF1R) bypass activation-induced gefitinib resistant tumors, CuS NPs upon near-infrared laser irradiation locally elevated reactive oxygen species (ROS) level in tumor cells, leading to the blockage of bypass IGFIR and its downstream AKT/ERK/NF-kappa B signaling cascades. Consequently, laser-irradiated CuS NPs sensitized tumors to gefitinib treatment and prolonged the survival of mice with no obvious toxicity. Laser-irradiated CuS NPs may serve as a simple and safe nanomedicine strategy to overcome bypass activation-induced gefitinib resistance in a specific and controllable manner and provide insights into the treatment of a myriad of other resistant tumors in the field of cancer therapy.
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