Efficacy of Temozolomide-Conjugated Gold Nanoparticle Photothermal Therapy of Drug-Resistant Glioblastoma and Its Mechanism Study

Abstract

Temozolomide (TMZ) is a standard-of-care chemotherapeutic drug for the treatment of glioblastoma (GBM), but TMZ-acquired resistance limits its therapeutic effect. In this study, TMZ-loaded gold nanoparticles (TMZ@GNPs) with anti-EphA3 modification on the surface (anti-EphA3-TMZ@GNPs) were synthesized for chemical and auxiliary plasma photothermal treatment (GNPs-PPTT), aiming to overcome the problem of glioma resistance to TMZ and improve the therapeutic effects of GBM. The prepared anti-EphA3-TMZ@GNPs were spherical with a particle size of 45.88 ± 1.9 nm, and the drug loading was 7.31 ± 0.38%. In vitro, cell-culture-based experiments showed that anti-EphA3 increased the cellular uptake of GNPs in T98G cells. Upon laser irradiation, the cytotoxicity and apoptosis rate in the anti-EphA3-TMZ@GNPs-treated group were significantly higher than those in the GNPs and nonphotothermal groups (p < 0.001). The Western blot analysis showed that the GNPs-PPTT-mediated killing of tumor cells induced apoptosis by regulating the apoptotic signaling molecules and cell cycle inhibitors; the expression of MGMT significantly decreased upon p53 induction, thereby reversing drug resistance. After photothermal treatment, the survival time of the subcutaneous GBM model of nude mice in the anti-EphA3-TMZ@GNPs group was prolonged to 46 days, 1.64-fold longer as compared to that in the TMZ group. Based on H&E and TUNEL staining, GNPs-PPTT could elevate apoptosis in T98G cells. In vivo thermal imaging results showed that GNPs could enter the brain via intranasal administration and be eliminated in 2 days, indicating that GNPs are safe for brain. In conclusion, GNPs-PPTT could effectively induce apoptosis in glioma cells and reverse TMZ resistance, thereby, indicative of a promising treatment strategy for GBM.

Advanced biomaterials for human glioblastoma multiforme (GBM) drug delivery

“…This photothermal treatment prolonged the survival time of the GBM xenograft model by 1.64-fold compared to free TMZ. 192 In another study on the intranasal administration of TMZ, Au NPs were coated with methoxy polyethylene glycol (mPEG)-detachable (d)-polyethyleneimine (PEI) (Au@PP), and then electrostatic interactions with polyinosinicpolycytidylic acid ( poly(I:C)) were induced. The in vivo study on C57BL/6 mice bearing an intracranial GBM tumor demonstrated that Au@PP/poly(I:C) induced type I interferon (IFN-I) expression after endocytosis into GBM cells, and significantly accumulated in the glioma tissue after intranasal administration, and AuNPs@PP/poly(I:C) plus TMZ remarkably enhanced the overall survival of the mice in comparison with the free TMZ group.…”

cRGD-targeted gold-based nanoparticles overcome EGFR-TKI resistance of NSCLC via low-temperature photothermal therapy combined with sonodynamic therapy

“…Moreover, PTT as well as SDT have been used in the treatment of various cancers and bacterial drug resistance, and all of them have obtained better treatment results. [13][14][15][16] Some researchers have prepared temozolomidecoupled gold nanoparticles with photothermal therapeutic effects to overcome temozolomide resistance in glioma and improve the therapeutic effect of glioma. 13 Similarly, multidrug resistance in gastric cancer can be reversed by using DOX-loaded nanoparticles with sonodynamic therapeutic effects.…”

“…[13][14][15][16] Some researchers have prepared temozolomidecoupled gold nanoparticles with photothermal therapeutic effects to overcome temozolomide resistance in glioma and improve the therapeutic effect of glioma. 13 Similarly, multidrug resistance in gastric cancer can be reversed by using DOX-loaded nanoparticles with sonodynamic therapeutic effects. 17 There are currently very few studies utilizing physical approaches to cure drug resistance in lung cancer, despite PTT using multifunctional CuO/Cu 2 O nanocubes having been reported to treat multidrug-resistant lung cancer.…”

Polydopamine-based loaded temozolomide nanoparticles conjugated by peptide-1 for glioblastoma chemotherapy and photothermal therapy

“…TMZ also has some deficiencies, including inferior tumor targeting, considerable toxicities or adverse effects, drug resistance via DNA repair, and the regulation of several signaling pathways. The therapeutic effect of GBM remains unsatisfactory, even though timely operation and postoperative CT ( Yu et al, 2022 ). GBM remains a challenging and valuable research topic.…”