Mitochondrial Artificial K+ Channel Construction Using MPTPP@5F8 Nanoparticles for Overcoming Cancer Drug Resistance via Disrupting Cellular Ion Homeostasis
Mitochondrial Artificial K+ Channel Construction Using MPTPP@5F8 Nanoparticles for Overcoming Cancer Drug Resistance via Disrupting Cellular Ion Homeostasis
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DOI：
10.1002/adhm.202302012
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发表时间：
2023
影响因子：
10
通讯作者：
Yun-Long Wu
中科院分区：
文献类型：
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作者：
Panqin Ma;Zheng Luo;Zhiguo Li;Yuchao Lin;Zibiao L;Zhen Wu;Changliang Ren;Yun-Long Wu
Mitochondrial potassium ion channels have become a promising target for cancer therapy. However, in malignant tumors, their low expression or inhibitory regulation typically leads to undesired cancer therapy, or even induces drug resistance. Herein, this work develops an in situ mitochondria-targeted artificial K+ channel construction strategy, with the purpose to trigger cancer cell apoptosis by impairing mitochondrial ion homeostasis. Considering the fact that cancer cells have a lower membrane potential than that of normal cells, this strategy can selectively deliver artificial K+ channel molecule 5F8 to the mitochondria of cancer cells, by using a mitochondria-targeting triphenylphosphine (TPP) modified block polymer (MPTPP) as a carrier. More importantly, 5F8 can further specifically form a K+-selective ion channel through the directional assembly of crown ethers on the mitochondrial membrane, thereby inducing mitochondrial K+ influx and disrupting ions homeostasis. Thanks to this design, mitochondrial dysfunction, including decreased mitochondrial membrane potential, reduced adenosine triphosphate (ATP) synthesis, downregulated antiapoptotic BCL-2 and MCL-1 protein levels, and increased reactive oxygen species (ROS) levels, can further effectively induce the programmed apoptosis of multidrug-resistant cancer cells, no matter in case of pump or nonpump dependent drug resistance. In short, this mitochondria-targeted artificial K+-selective ion channel construction strategy may be beneficial for potential drug resistance cancer therapy.
