Nanoenabled Intracellular Calcium Bursting for Safe and Efficient Reversal of Drug Resistance in Tumor Cells

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Abstract
Multidrug resistance (MDR) of a tumor is the main cause of failure of clinical chemotherapy. Herein, we report a simple, yet versatile, tumor-targeting “calcium ion nanogenerator” (TCaNG) to reverse drug resistance by inducing intracellular Ca2+ bursting. Consequently, the TCaNG could induce Ca2+ bursting in acidic lysosomes of tumor cells and then reverse drug resistance according to the following mechanisms: (i) Ca2+ specifically accumulates in mitochondria, suppressing cellular respiration and relieving tumor hypoxia, thus inhibiting P-glycoprotein biosynthesis by downregulating HIF-1α expression. (ii) Ca2+-bursting-induced respiratory depression blocks intracellular ATP production, which further leads to the P-gp incompetence. As a result, the TCaNG could decrease the IC50 of DOX to MCF-7/ADR cells by approximately 30 times and reduce the proliferation of drug-resistant tumors by approximately 13 times without obvious side effects. This simple, safe, and effective “Ca2+ bursting” strategy holds the potential for clinical application in tumor treatment.
Funding Information
  • Education Department of Henan Province (20A350009)
  • China Postdoctoral Science Foundation (2017M622380, 2018T110745)
  • Science and Technology Department of Henan Province (192102310147)
  • National Natural Science Foundation of China (21904119, 319009919, U1704178)
  • Henan Province (19HASTIT006)

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