CuS Nanoparticles as a Photodynamic Nanoswitch for Abrogating Bypass Signaling To Overcome Gefitinib Resistance.

Abstract

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 IGF1R and its downstream AKT/ERK/NF-κB 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.

• Authors: Xiajing Gu, Yuanyuan Qiu, Miao Lin, Kai Cui, Gaoxian Chen, Yingzhi Chen, Chenchen Fan, Yongming Zhang, Lu Xu, Hongzhuan Chen, Jian-Bo Wan, Wei Lu, Zeyu Xiao
• Journal: Nano letters (Nano Lett) Vol. 19 Issue 5 Pg. 3344-3352 (05 08 2019) ISSN: 1530-6992 [Electronic] United States
• PMID: 30974946 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Copper
• cupric sulfide

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Copper (chemistry, pharmacology)
• Drug Resistance, Neoplasm
• Humans
• Mice
• Mutation
• Nanoparticles (chemistry)
• Xenograft Model Antitumor Assays