Dual-Receptor-Targeted (DRT) Radiation Nanomedicine Labeled with <sup>177</sup>Lu Is More Potent for Killing Human Breast Cancer Cells That Coexpress HER2 and EGFR Than Single-Receptor-Targeted (SRT) Radiation Nanomedicines
Notice bibliographique
Résumé
Resistance to HER2-targeted therapies in breast cancer (BC) is associated in some cases with an increased expression of epidermal growth factor receptors (EGFR). We describe a dual-receptor-targeted (DRT) radiation nanomedicine for local intratumoral (i.t.) treatment of BC composed of 15 nm sized gold nanoparticles (AuNPs) modified with trastuzumab (TmAb) to target HER2 and panitumumab (PmAb) to target EGFR. The AuNPs were modified with poly(ethylene glycol) (PEG 3k ) linked to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators to complex the β-particle emitter, 177 Lu. Our aim was to compare the properties of these DRT-AuNP- 177 Lu with single-receptor-targeted (SRT)-TmAb-AuNP- 177 Lu or PmAb-AuNP- 177 Lu or nontargeted (NT)-AuNP- 177 Lu using human BC cells that expressed HER2, EGFR, or both receptors. To construct these radiation nanomedicines, PEG 5K was linked to TmAb or PmAb, while PEG 3k was linked to DOTA. These polymers were conjugated to AuNP via two Au–thiol bonds using a terminal lipoic acid (LA) group on the polymers. NT-AuNP- 177 Lu were constructed without modification with TmAb or PmAb. MDA-MB-231-H2N, MDA-MB-468, and BT-474 human BC cells were designated as HER2 mod /EGFR mod, EGFR high /HER2 neg, and HER2 high /EGFR low, respectively, based on the expression of these receptors. Specific binding to HER2 and/or EGFR was assessed by incubating BC cells with DRT-AuNP- 177 Lu or TmAb-AuNP- 177 Lu or PmAb-AuNP- 177 Lu, or NT-AuNP- 177 Lu in the absence or presence of an excess of TmAb or PmAb or both competitors. Binding and internalization of AuNP by BC cells were assessed by dark-field microscopy. Cell fractionation studies were conducted to quantify AuNP- 177 Lu bound and internalized. The cytotoxicity of DRT-AuNP- 177 Lu was determined in clonogenic survival (CS) assays after an exposure of 5 × 10 5 BC cells to 3 MBq (1.4 × 10 12 AuNP) for 16 h and then seeding and culturing the cells for 7−15 days. CS was compared to exposure to TmAb-AuNP- 177 Lu and PmAb-AuNP- 177 Lu or NT-AuNP- 177 Lu. The absorbed doses to the nucleus in these CS assays were estimated. DRT-AuNP- 177 Lu were specifically bound by BC cells that expressed HER2 or EGFR or both receptors. In contrast, SRT-TmAb-AuNP- 177 Lu and PmAb-AuNP- 177 Lu were bound and internalized only by BC cells that expressed HER2 or EGFR, respectively. NT-AuNP- 177 Lu exhibited very low binding to BC cells. DRT-AuNP- 177 Lu and SRT-TmAb-AuNP- 177 Lu or PmAb-AuNP- 177 Lu were internalized by BC cells in accordance with the receptor expression. Importantly, DRT-AuNP- 177 Lu were more potent in vitro than PmAb-AuNP- 177 Lu for killing MDA-MB-231-H2N cells that coexpress HER2 and EGFR (CS = 18.8 ± 1.0 vs 51.5 ± 10.4%; P = 0.006). Furthermore, DRT-AuNP- 177 Lu were more potent for killing BT-474 cells with high HER2 but low EGFR expression than TmAb-AuNP- 177 Lu (CS = 8.9 ± 3.3 vs 20.7 ± 2.4%; P = 0.007) or PmAb-AuNP- 177 Lu (CS = 63.9 ± 1.7%; P < 0.0001). Even for MDA-MB-468 cells that overexpress EGFR but have negligible HER2, DRT-AuNP- 177 Lu were more potent for cell killing than PmAb-AuNP- 177 Lu (CS = 3.2 ± 3.0 vs 7.5 ± 1.8%; P = 0.001) or TmAb-AuNP- 177 Lu (63.2 ± 3.2%; P = 0.0002). All targeted forms of AuNP- 177 Lu were more cytotoxic to BC cells than those of NT-AuNP- 177 Lu. High absorbed doses (36–119 Gy) were deposited in the nucleus of BC cells by DRT-AuNP- 177 Lu. We conclude that a DRT radiation nanomedicine is more potent for killing BC cells that coexpress HER2 and EGFR than SRT radiation nanomedicines. These results are promising for further evaluation of these DRT-AuNP- 177 Lu in vivo for the local radiation treatment of human BC tumors that coexpress HER2 and EGFR in mice following i.t. injection, especially tumors that are resistant to HER2-targeted therapies.
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 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) | 0,001 | 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 source (Gemma direct ou Codex distillé), 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 ».