Reducing Chemo-/Radioresistance to Boost the Therapeutic Efficacy against Temozolomide-Resistant Glioblastoma

Abstract

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.

Targeting the pathogenesis and boosting the therapeutic efficacy of Parkinson's disease by advanced nanoparticles

“…To date, focused ultrasound has been used to assist in the delivery of various compounds into the brain, such as nanoparticles, 74 antibodies (e.g., trastuzumab 75 ), chemotherapy drugs (e.g., temozolomide 76 ), nucleotide small interfering RNA (siRNAs), 77 neurotrophins, 78 viral and nonviral vectors 79 . Recent works have demonstrated that focused ultrasound can be used to efficiently deliver nanoprobes or nanomedicine into the brain for imaging of immunosuppressive M 2 − tumor‐associated macrophages in orthotopic glioma, 80 significantly reducing chemo‐/radio‐resistance of glioblastoma, 81 and improving the radiation therapy 82 and immunotherapy of orthotopic glioblastoma 83 . Moreover, the focused ultrasound has been used for the treatment of brain tumors in clinical practice with encouraging results 75 .…”

Boosting the therapy of glutamine-addiction glioblastoma by combining glutamine metabolism therapy with photo-enhanced chemodynamic therapy

“…3 Therefore, many strategies have been developed for precise diagnosis and treatment of GBM, including magnetic hyperthermia, 4,5 gene therapy, 6,7 high intensity focused ultrasound therapy, 8,9 immunotherapy 10,11 and gas therapy. 12,13 Recently, modulating the tumor metabolism has emerged as a promising therapeutic strategy. 14,15 In this aspect, the Warburg effect has always been considered as a hallmark of cancer cells, wherein glycolysis is preferred over oxidative phosphorylation even under aerobic conditions.…”

“…3 Therefore, many strategies have been developed for precise diagnosis and treatment of GBM, including magnetic hyperthermia, 4,5 gene therapy, 6,7 high intensity focused ultrasound therapy, 8,9 immunotherapy 10,11 and gas therapy. 12,13…”

Photocleavable Visible Light-Triggered Anthraquinone-Derived Water-Soluble Block Copolymer for Peroxynitrite Generation in Cancer Therapy

“…To date, a number of strategies have been reported to enhance drug penetration and improve the therapeutic outcome. 14−16 Thus, a vasodilating agent can help overcome this barrier, 17 and when the design incorporates spatiotemporal release of ROS and RNS, then it provides an added control. Nitric oxide (NO), a widely used gasotransmitter, also plays a regulatory role in various biological activities such as vasodilation, cardiac relaxation, inflammatory activities, angiogenesis, and so on.…”