Journal
NANO LETTERS
Volume 20, Issue 11, Pages 8102-8111Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.nanolett.0c03042
Keywords
calcium ion nanogenerator; intracellular Ca2+ bursting; reversal of drug resistance; calcium interference
Categories
Funding
- National Natural Science Foundation of China [21904119, 319009919, U1704178]
- Innovation Talent Support Program of Henan Province [19HASTIT006]
- Key Scientific Research Projects (Education Department of Henan Province) [20A350009]
- Key Scientific Research Projects (Science and Technology Department of Henan Province) [192102310147]
- Postdoctoral Science Foundation of China [2018T110745, 2017M622380]
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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 Ca' 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-la 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.
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