Intranasal Delivery of Temozolomide-Conjugated Gold Nanoparticles Functionalized with Anti-EphA3 for Glioblastoma Targeting
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-TMZGNPs) 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 TMZ-resistant glioma cells (T98G) demonstrated that the IC50 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 O6-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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:18 |
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| Enthalten in: |
Molecular pharmaceutics - 18(2021), 3 vom: 01. März, Seite 915-927 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Liangxiao [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.11.2021 Date Revised 02.11.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.molpharmaceut.0c00911 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM319810682 |
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| 100 | 1 | |a Wang, Liangxiao |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Intranasal Delivery of Temozolomide-Conjugated Gold Nanoparticles Functionalized with Anti-EphA3 for Glioblastoma Targeting |
| 264 | 1 | |c 2021 | |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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-TMZGNPs) 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 TMZ-resistant glioma cells (T98G) demonstrated that the IC50 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 O6-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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Temozolomide | |
| 650 | 4 | |a anti-EphA3 | |
| 650 | 4 | |a glioblastoma | |
| 650 | 4 | |a gold nanoparticles | |
| 650 | 4 | |a intranasal administration | |
| 650 | 7 | |a Gold |2 NLM | |
| 650 | 7 | |a 7440-57-5 |2 NLM | |
| 650 | 7 | |a EPHA3 protein, human |2 NLM | |
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| 650 | 7 | |a Receptor, EphA3 |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
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| 650 | 7 | |a YF1K15M17Y |2 NLM | |
| 700 | 1 | |a Tang, Shengnan |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Yawen |e verfasserin |4 aut | |
| 700 | 1 | |a Lv, Yanan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Aiping |e verfasserin |4 aut | |
| 700 | 1 | |a Yan, Xiuju |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Nuannuan |e verfasserin |4 aut | |
| 700 | 1 | |a Sha, Chunjie |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Kaoxiang |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Youxin |e verfasserin |4 aut | |
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