Auger electron-emitting EGFR-targeted and non-targeted [197Hg]Hg-gold nanoparticles for treatment of glioblastoma multiforme (GBM)
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".