Auger electron-emitting EGFR-targeted and non-targeted [197Hg]Hg-gold nanoparticles for treatment of glioblastoma multiforme (GBM)
Abstract Background We describe here radiation nanomedicines for glioblastoma multiforme (GBM) composed of gold nanoparticles (AuNPs) that integrate the Auger electron-emitter, 197Hg. [197Hg]Hg-AuNPs were conjugated to anti-epidermal growth factor receptor (EGFR) panitumumab or were non-targeted. Ou...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
SpringerOpen
2025-07-01
|
| Series: | EJNMMI Radiopharmacy and Chemistry |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s41181-025-00367-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849332429885538304 |
|---|---|
| author | Madeline K. Brown Zhongli Cai Constantine J. Georgiou Shaohuang Chen Yumeela Ganga-Sah Valery Radchenko James T. Rutka Raymond M. Reilly |
| author_facet | Madeline K. Brown Zhongli Cai Constantine J. Georgiou Shaohuang Chen Yumeela Ganga-Sah Valery Radchenko James T. Rutka Raymond M. Reilly |
| author_sort | Madeline K. Brown |
| collection | DOAJ |
| description | Abstract Background We describe here radiation nanomedicines for glioblastoma multiforme (GBM) composed of gold nanoparticles (AuNPs) that integrate the Auger electron-emitter, 197Hg. [197Hg]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-[197Hg]Hg-AuNPs and non-targeted [197Hg]Hg-AuNPs on U251-Luc human GBM cells and estimate their cellular dosimetry. We further aimed to compare the biodistribution in vivo of panitumumab-[197Hg]Hg-AuNPs and [197Hg]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 [197Hg]Hg-AuNPs (26.8 ± 6.4 nm) were produced with a radiochemical yield of 98 ± 1% by incorporating 197Hg into the Turkevich synthesis method, forming a mercury-gold amalgam. Panitumumab-[197Hg]Hg-AuNPs exhibited high affinity (KD = 1.8 × 10–9 mol/L) binding to EGFR-positive U251-Luc cells. The binding of panitumumab-[197Hg]Hg-AuNPs to U251-Luc cells was 15-fold higher than [197Hg]Hg-AuNPs, and internalization and nuclear uptake were 12-fold and 18-fold greater, respectively. Panitumumab-[197Hg]Hg-AuNPs caused 84-fold more DNA double-strand breaks (DSBs) in U251-Luc cells than [197Hg]Hg-AuNPs. Panitumumab-[197Hg]Hg-AuNPs were ninefold more effective at reducing the clonogenic survival of U251-Luc cells than [197Hg]Hg-AuNPs. Panitumumab-[197Hg]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-[197Hg]Hg-AuNPs or [197Hg]Hg-AuNPs were 8.8 ± 2.9 Gy and 0.6 ± 0.1 Gy, respectively. SPECT/CT imaging showed that panitumumab-[197Hg]Hg-AuNPs and [197Hg]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-[197Hg]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 [197Hg]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-[197Hg]Hg-AuNPs vs. 0.6% of the tumour for non-targeted [197Hg]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-[197Hg]Hg-AuNPs and [197Hg]Hg-AuNPs, respectively. Conclusion Radiation nanomedicines incorporating the AE-emitter, 197Hg administered by CED are a promising approach to treatment of GBM. Panitumumab-[197Hg]Hg-AuNPs are particularly attractive due to their EGFR-mediated binding, internalization and nuclear importation in GBM cells, which amplifies their in vitro cytotoxicity. |
| format | Article |
| id | doaj-art-72c8e111adf84bf8a62b793a8611cb92 |
| institution | Kabale University |
| issn | 2365-421X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | EJNMMI Radiopharmacy and Chemistry |
| spelling | doaj-art-72c8e111adf84bf8a62b793a8611cb922025-08-20T03:46:12ZengSpringerOpenEJNMMI Radiopharmacy and Chemistry2365-421X2025-07-0110112010.1186/s41181-025-00367-2Auger electron-emitting EGFR-targeted and non-targeted [197Hg]Hg-gold nanoparticles for treatment of glioblastoma multiforme (GBM)Madeline K. Brown0Zhongli Cai1Constantine J. Georgiou2Shaohuang Chen3Yumeela Ganga-Sah4Valery Radchenko5James T. Rutka6Raymond M. Reilly7Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of TorontoDepartment of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of TorontoDepartment of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of TorontoLife Sciences Division, TRIUMFLife Sciences Division, TRIUMFLife Sciences Division, TRIUMFDivision of Neurosurgery, The Hospital for Sick ChildrenDepartment of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of TorontoAbstract Background We describe here radiation nanomedicines for glioblastoma multiforme (GBM) composed of gold nanoparticles (AuNPs) that integrate the Auger electron-emitter, 197Hg. [197Hg]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-[197Hg]Hg-AuNPs and non-targeted [197Hg]Hg-AuNPs on U251-Luc human GBM cells and estimate their cellular dosimetry. We further aimed to compare the biodistribution in vivo of panitumumab-[197Hg]Hg-AuNPs and [197Hg]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 [197Hg]Hg-AuNPs (26.8 ± 6.4 nm) were produced with a radiochemical yield of 98 ± 1% by incorporating 197Hg into the Turkevich synthesis method, forming a mercury-gold amalgam. Panitumumab-[197Hg]Hg-AuNPs exhibited high affinity (KD = 1.8 × 10–9 mol/L) binding to EGFR-positive U251-Luc cells. The binding of panitumumab-[197Hg]Hg-AuNPs to U251-Luc cells was 15-fold higher than [197Hg]Hg-AuNPs, and internalization and nuclear uptake were 12-fold and 18-fold greater, respectively. Panitumumab-[197Hg]Hg-AuNPs caused 84-fold more DNA double-strand breaks (DSBs) in U251-Luc cells than [197Hg]Hg-AuNPs. Panitumumab-[197Hg]Hg-AuNPs were ninefold more effective at reducing the clonogenic survival of U251-Luc cells than [197Hg]Hg-AuNPs. Panitumumab-[197Hg]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-[197Hg]Hg-AuNPs or [197Hg]Hg-AuNPs were 8.8 ± 2.9 Gy and 0.6 ± 0.1 Gy, respectively. SPECT/CT imaging showed that panitumumab-[197Hg]Hg-AuNPs and [197Hg]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-[197Hg]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 [197Hg]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-[197Hg]Hg-AuNPs vs. 0.6% of the tumour for non-targeted [197Hg]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-[197Hg]Hg-AuNPs and [197Hg]Hg-AuNPs, respectively. Conclusion Radiation nanomedicines incorporating the AE-emitter, 197Hg administered by CED are a promising approach to treatment of GBM. Panitumumab-[197Hg]Hg-AuNPs are particularly attractive due to their EGFR-mediated binding, internalization and nuclear importation in GBM cells, which amplifies their in vitro cytotoxicity.https://doi.org/10.1186/s41181-025-00367-2Glioblastoma multiforme (GBM)Gold nanoparticles197HgAuger electronsPanitumumabEpidermal growth factor receptors (EGFR) |
| spellingShingle | Madeline K. Brown Zhongli Cai Constantine J. Georgiou Shaohuang Chen Yumeela Ganga-Sah Valery Radchenko James T. Rutka Raymond M. Reilly Auger electron-emitting EGFR-targeted and non-targeted [197Hg]Hg-gold nanoparticles for treatment of glioblastoma multiforme (GBM) EJNMMI Radiopharmacy and Chemistry Glioblastoma multiforme (GBM) Gold nanoparticles 197Hg Auger electrons Panitumumab Epidermal growth factor receptors (EGFR) |
| title | Auger electron-emitting EGFR-targeted and non-targeted [197Hg]Hg-gold nanoparticles for treatment of glioblastoma multiforme (GBM) |
| title_full | Auger electron-emitting EGFR-targeted and non-targeted [197Hg]Hg-gold nanoparticles for treatment of glioblastoma multiforme (GBM) |
| title_fullStr | Auger electron-emitting EGFR-targeted and non-targeted [197Hg]Hg-gold nanoparticles for treatment of glioblastoma multiforme (GBM) |
| title_full_unstemmed | Auger electron-emitting EGFR-targeted and non-targeted [197Hg]Hg-gold nanoparticles for treatment of glioblastoma multiforme (GBM) |
| title_short | Auger electron-emitting EGFR-targeted and non-targeted [197Hg]Hg-gold nanoparticles for treatment of glioblastoma multiforme (GBM) |
| title_sort | auger electron emitting egfr targeted and non targeted 197hg hg gold nanoparticles for treatment of glioblastoma multiforme gbm |
| topic | Glioblastoma multiforme (GBM) Gold nanoparticles 197Hg Auger electrons Panitumumab Epidermal growth factor receptors (EGFR) |
| url | https://doi.org/10.1186/s41181-025-00367-2 |
| work_keys_str_mv | AT madelinekbrown augerelectronemittingegfrtargetedandnontargeted197hghggoldnanoparticlesfortreatmentofglioblastomamultiformegbm AT zhonglicai augerelectronemittingegfrtargetedandnontargeted197hghggoldnanoparticlesfortreatmentofglioblastomamultiformegbm AT constantinejgeorgiou augerelectronemittingegfrtargetedandnontargeted197hghggoldnanoparticlesfortreatmentofglioblastomamultiformegbm AT shaohuangchen augerelectronemittingegfrtargetedandnontargeted197hghggoldnanoparticlesfortreatmentofglioblastomamultiformegbm AT yumeelagangasah augerelectronemittingegfrtargetedandnontargeted197hghggoldnanoparticlesfortreatmentofglioblastomamultiformegbm AT valeryradchenko augerelectronemittingegfrtargetedandnontargeted197hghggoldnanoparticlesfortreatmentofglioblastomamultiformegbm AT jamestrutka augerelectronemittingegfrtargetedandnontargeted197hghggoldnanoparticlesfortreatmentofglioblastomamultiformegbm AT raymondmreilly augerelectronemittingegfrtargetedandnontargeted197hghggoldnanoparticlesfortreatmentofglioblastomamultiformegbm |