Auger electron-emitting EGFR-targeted and non-targeted [197Hg]Hg-gold nanoparticles for treatment of glioblastoma multiforme (GBM)
Notice bibliographique
Résumé
Abstract Background We describe here radiation nanomedicines for glioblastoma multiforme (GBM) composed of gold nanoparticles (AuNPs) that integrate the Auger electron-emitter, 197 Hg. [ 197 Hg]Hg-AuNPs were conjugated to anti-epidermal growth factor receptor (EGFR) panitumumab or were non-targeted. Our aim was to compare the cytotoxicity and DNA-damaging properties in vitro of panitumumab-[ 197 Hg]Hg-AuNPs and non-targeted [ 197 Hg]Hg-AuNPs on U251-Luc human GBM cells and estimate their cellular dosimetry. We further aimed to compare the biodistribution in vivo of panitumumab-[ 197 Hg]Hg-AuNPs and [ 197 Hg]Hg-AuNPs after convection-enhanced delivery (CED) in NRG mice with U251-Luc tumours in the brain and estimate the absorbed doses in the tumour and surrounding margins of healthy brain. Results [ 197 Hg]Hg-AuNPs (26.8 ± 6.4 nm) were produced with a radiochemical yield of 98 ± 1% by incorporating 197 Hg into the Turkevich synthesis method, forming a mercury-gold amalgam. Panitumumab-[ 197 Hg]Hg-AuNPs exhibited high affinity (K D = 1.8 × 10 –9 mol/L) binding to EGFR-positive U251-Luc cells. The binding of panitumumab-[ 197 Hg]Hg-AuNPs to U251-Luc cells was 15-fold higher than [ 197 Hg]Hg-AuNPs, and internalization and nuclear uptake were 12-fold and 18-fold greater, respectively. Panitumumab-[ 197 Hg]Hg-AuNPs caused 84-fold more DNA double-strand breaks (DSBs) in U251-Luc cells than [ 197 Hg]Hg-AuNPs. Panitumumab-[ 197 Hg]Hg-AuNPs were ninefold more effective at reducing the clonogenic survival of U251-Luc cells than [ 197 Hg]Hg-AuNPs. Panitumumab-[ 197 Hg]Hg-AuNPs were twofold more cytotoxic than non-radioactive panitumumab-AuNPs ( P = 0.04) and fivefold more cytotoxic than panitumumab ( P = 0.01). The absorbed doses in the nucleus of U251-Luc cells treated in vitro with panitumumab-[ 197 Hg]Hg-AuNPs or [ 197 Hg]Hg-AuNPs were 8.8 ± 2.9 Gy and 0.6 ± 0.1 Gy, respectively. SPECT/CT imaging showed that panitumumab-[ 197 Hg]Hg-AuNPs and [ 197 Hg]Hg-AuNPs were strongly retained at the infusion site in the brain after CED up to 7 d in NRG mice with orthotopic U251-Luc tumours. Uptake of panitumumab-[ 197 Hg]Hg-AuNPs in the tumour-bearing right hemisphere [484.5% injected dose/g (%ID/g)] was 172-fold and 579-fold greater than in the healthy left hemisphere and cerebellum, respectively. The uptake of [ 197 Hg]Hg-AuNPs (423.9% ID/g) in the tumour-bearing right hemisphere was 85-fold and 64-fold higher than the left hemisphere and cerebellum, respectively. Most normal tissue uptake was < 1% ID/g, except for kidneys (9–20% ID/g), spleen (3.5–6.6% ID/g) and liver (0.6–3.3% ID/g). Dosimetry showed that 58% of the tumour received > 190 Gy for CED of 1.0 MBq of panitumumab-[ 197 Hg]Hg-AuNPs vs. 0.6% of the tumour for non-targeted [ 197 Hg]Hg-AuNPs, but both agents deposited > 50 Gy in 95% of the tumour. Doses decreased dramatically to 1.7 and 3.3 Gy at 1–3 mm from the tumour edge for panitumumab-[ 197 Hg]Hg-AuNPs and [ 197 Hg]Hg-AuNPs, respectively. Conclusion Radiation nanomedicines incorporating the AE-emitter, 197 Hg administered by CED are a promising approach to treatment of GBM. Panitumumab-[ 197 Hg]Hg-AuNPs are particularly attractive due to their EGFR-mediated binding, internalization and nuclear importation in GBM cells, which amplifies their in vitro cytotoxicity.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».