Intranasal Delivery of Temozolomide-Conjugated Gold Nanoparticles Functionalized with Anti-EphA3 for Glioblastoma Targeting

Abstract

Glioblastoma multiforme (GBM) is a highly lethal and aggressive tumor of the brain that carries a poor prognosis. Temozolomide (TMZ) has been widely used as a first-line treatment for GBM. However, poor brain targeting, side effects, and drug resistance limit its application for the treatment of GBM. We designed a Temozolomide-conjugated gold nanoparticle functionalized with an antibody against the ephrin type-A receptor 3 (anti-EphA3-TMZ@GNPs) for targeted GBM therapy via intranasal administration. The system can bypass the blood− brain barrier and target active glioma cells to improve the glioma targeting of TMZ and enhance the treatment efficacy, while reducing the peripheral toxicity and drug resistance. The prepared anti-EphA3-TMZ@GNPs were 46.12 ± 2.0 nm and suitable for intranasal administration, which demonstrated high safety to the nasal mucosa in a toxicity assay. In vitro studies showed that anti-EphA3-TMZ@GNPs exhibited significantly enhanced cellular uptake and toxicity, and a higher cell apoptosis ratio has been seen compared with that of TMZ (54.9 and 14.1%, respectively) toward glioma cells (C6). The results from experiments on TMZresistant glioma cells (T98G) demonstrated that the IC 50 of anti-EphA3-TMZ@GNPs (64.06 ± 0.16 μM) was 18.5-fold lower than that of TMZ. In addition, Western blot analysis also revealed that anti-EphA3-TMZ@GNPs effectively down-modulated expression of O 6 -methylguanine-DNA methyltransferase and increased chemosensitivity of T98G to TMZ. The antiglioma efficacy in vivo was investigated in orthotopic glioma-bearing rats, and the results demonstrated that the anti-EphA3-TMZ@GNPs prolonged the median survival time to 42 days and increased tumor-cell apoptosis dramatically compared with TMZ. In conclusion, anti-EphA3-TMZ@GNPs could serve as an intranasal drug delivery system for efficacious treatment of GBM.

Intranasal Delivery of Functionalized Polymeric Nanomaterials to the Brain

“…These nanocomposites were able to promote higher accumulation rate, lower drug resistance, and greater specificity of the drug targeting the glioma site, providing practically a robust candidate for GBM treatment via IN route. [ 125 ]…”

“…delivery. Currently, there are few exciting translational application reports regarding PEG‐modified NPs in biomedical fields, namely, GBM treatment, [ 125 ] neuroprotection in PD, [ 140 ] and AD therapy. [ 141 ] Liu et al.…”

Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

“…Quite a few proven preclinical successes of Eph inhibition in GB are published [ 334 , 335 , 337 , 343 , 344 , 345 ]. Importantly, co-targeting multiple Eph receptors might be necessary to achieve a therapeutic response [ 62 , 330 , 346 , 347 ].…”

Green synthesis of gold nanoparticles for immune response regulation: Mechanisms, applications, and perspectives

“…They suggested that GNPs, with tunable size (1‐100 nm) and shapes (sphere, rod, star, and cube), can be synthesized in a more immunogenic form than large polymeric particles or liposomes (>100 nm) and synergically enhance antigen presentation. The intranasal route is also leveraged by Wang et al 92 to deliver temozolomide (TMZ) to the brain with improved brain targets, reduced haematologic toxicity, and less drug resistance (Figure 4d). GNPs are tropically co‐delivered with antibiotics to exhibit their intrinsic antimicrobial property.…”

“…(d) Temozolomide‐conjugated GNPs functionalized with anti‐EphA3 and their ability to induce tumour apoptosis. Reproduced with permission 92 . Copyright 2021, American Chemical Society.…”