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.

• Authors: Yawen Yu, Aiping Wang, Siqi Wang, Yuchen Sun, Liuxiang Chu, Lin Zhou, Xiaoyue Yang, Xincui Liu, Chunjie Sha, Kaoxiang Sun, Lixiao Xu
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 19 Issue 4 Pg. 1219-1229 (04 04 2022) ISSN: 1543-8392 [Electronic] United States
• PMID: 35262365 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Alkylating
• Pharmaceutical Preparations
• Gold
• Temozolomide

Topics

• Animals
• Antineoplastic Agents, Alkylating (pharmacology, therapeutic use)
• Apoptosis
• Brain Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Glioblastoma (drug therapy, metabolism)
• Gold (chemistry)
• Metal Nanoparticles (chemistry)
• Mice
• Mice, Nude
• Pharmaceutical Preparations
• Photothermal Therapy
• Temozolomide (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays