Reducing Chemo-/Radioresistance to Boost the Therapeutic Efficacy against Temozolomide-Resistant Glioblastoma
2022
Yun, Baofeng | Gu, Zhengpeng | Liu, Zheng | Han, Yaobao | Sun, Qiao | Li, Zhen
Chemo-/radioresistance is the most important reason for the failure of glioblastoma (GBM) treatment. Reversing the chemo-/radioresistance of GBM for boosting therapeutic efficacy is very challenging. Herein, we report a significant decrease in the chemo-/radioresistance of GBM by the in situ generation of SO₂ within a tumor, which was released on demand from the prodrug 5-amino-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (ATD) loaded on rare-earth-based scintillator nanoparticles (i.e., NaYF₄:Ce@NaLuF₄:Nd@ATD@DSPE-PEG₅₀₀₀, ScNPs) under X-ray irradiation. Our novel X-ray-responsive ScNPs efficiently converted highly penetrating X-rays into ultraviolet rays for controlling the decomposition of ATD to generate SO₂, which effectively damaged the mitochondria of temozolomide-resistant U87 cells to lower the production of ATP and inhibit P-glycoprotein (P-gp) expression to reduce drug efflux. Meanwhile, the O⁶-methylguanine–DNA methyltransferase (MGMT) of drug-resistant tumor cells was also reduced to prevent the repair of damaged DNA and enhance cell apoptosis and the efficacy of chemo-/radiotherapy. The tumor growth was obviously suppressed, and the mice survived significantly longer than untreated temozolomide-resistant GBM-bearing mice. Our work demonstrates the potential of SO₂ in reducing chemo-/radioresistance to improve the therapeutic effect against resistant tumors if it can be well controlled and in situ generated in tumor cells. It also provides insights into the rational design of stimuli-responsive drug delivery systems for the controlled release of drugs.
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