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

Mar 9, 2022Molecular pharmaceutics

Temozolomide-linked gold nanoparticle heat therapy for drug-resistant brain tumors and how it works

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Abstract

The survival time of subcutaneous glioblastoma model mice treated with anti-EphA3-TMZ-loaded gold nanoparticles was prolonged to 46 days, 1.64-fold longer compared to standard TMZ treatment.

Anti-EphA3-TMZ-loaded gold nanoparticles (TMZ@GNPs) were synthesized with a particle size of 45.88 ± 1.9 nm and a drug loading of 7.31 ± 0.38%.
In vitro experiments showed that anti-EphA3 enhanced the cellular uptake of gold nanoparticles in T98G glioma cells.
Laser irradiation of the anti-EphA3-TMZ@GNPs-treated group resulted in significantly higher cytotoxicity and apoptosis rates compared to control groups (< 0.001).
GNPs-PPTT treatment increased the expression of apoptotic signaling molecules and decreased MGMT expression, which may help reverse drug resistance.
In vivo thermal imaging indicated that gold nanoparticles could safely enter the brain through intranasal administration and were eliminated within 2 days.

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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 (< 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. p

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

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