Treatment of Orthotopic U251 Human Glioblastoma Multiforme Tumors in NRG Mice by Convection-Enhanced Delivery of Gold Nanoparticles Labeled with the β-Particle-Emitting Radionuclide, 177Lu
Abstract:In this study, we investigated convection-enhanced delivery (CED) of 23 ± 3 nm gold nanoparticles (AuNPs) labeled with the β-particle-emitting radionuclide 177 Lu ( 177 Lu-AuNPs) for treatment of orthotopic U251-Luc human glioblastoma multiforme (GBM) tumors in NRG mice. The cytotoxicity in vitro of 177 Lu-AuNPs (0.0−2.0 MBq, 4 × 10 11 AuNPs) on U251-Luc cells was also studied by a clonogenic survival assay, and DNA double-strand breaks (DSBs) caused by β-particle emissions of 177 Lu were measured by confocal … Show more
“…CED of 177 Lu-labeled metallofullerenes (0.25–1.35 MBq) into orthotopic U87MG tumors in nude mice improved median survival with > 80% of mice treated with 1.35 MBq surviving > 100 d, while untreated mice survived < 29 d. Moreover, tumours in treated mice were smaller assessed by ex vivo histological staining (Wilson et al 2012 ). Together, the results of these studies confirm our findings (Georgiou et al 2023 ) that radiation nanomedicines administered by CED deposit high absorbed doses in GBM tumours in animal models that result in strong tumour growth-inhibitory effects, but are not toxic to normal tissues including normal brain, due to the restricted diffusion within the brain or redistribution to organs outside the brain mediated by the anchoring effects of NPs.…”
Section: Main Textsupporting
confidence: 90%
“…10 ) (Woodall et al 2021 ) These imaging results in patients with GBM administered 188 Re-labeled nanoliposomes by CED are very similar to those that we reported for [ 177 Lu]Lu-MCP-AuNPs infused by CED in NRG mice with orthotopic human GBM tumours (Fig. 9 b) (Georgiou et al 2023 ). Fig.…”
Section: Main Textsupporting
confidence: 85%
“…Local infusion of radiation nanomedicines by convection enhanced delivery (CED) into the surgical cavity post-resection may eradicate residual tumour at the margins and prevent recurrence, potentially improving survival. We studied a radiation nanomedicine for treatment of GBM by stereotaxically infusing 1.1 MBq [ 177 Lu]Lu-MCP-AuNPs (~ 23 nm; 4 × 10 11 AuNPs) by CED into small (~ 2 mm) luciferase-transfected U251-Luc human GBM tumours in the brain in NRG mice (Georgiou et al 2023 ) (Fig. 9 a).…”
Background
Radiation nanomedicines are nanoparticles labeled with radionuclides that emit α- or β-particles or Auger electrons for cancer treatment. We describe here our 15 years scientific journey studying locally-administered radiation nanomedicines for cancer treatment. We further present a view of the radiation nanomedicine landscape by reviewing research reported by other groups.
Main body
Gold nanoparticles were studied initially for radiosensitization of breast cancer to X-radiation therapy. These nanoparticles were labeled with 111In to assess their biodistribution after intratumoural vs. intravenous injection. Intravenous injection was limited by high liver and spleen uptake and low tumour uptake, while intratumoural injection provided high tumour uptake but low normal tissue uptake. Further, [111In]In-labeled gold nanoparticles modified with trastuzumab and injected iintratumourally exhibited strong tumour growth inhibition in mice with subcutaneous HER2-positive human breast cancer xenografts. In subsequent studies, strong tumour growth inhibition in mice was achieved without normal tissue toxicity in mice with human breast cancer xenografts injected intratumourally with gold nanoparticles labeled with β-particle emitting 177Lu and modified with panitumumab or trastuzumab to specifically bind EGFR or HER2, respectively. A nanoparticle depot (nanodepot) was designed to incorporate and deliver radiolabeled gold nanoparticles to tumours using brachytherapy needle insertion techniques. Treatment of mice with s.c. 4T1 murine mammary carcinoma tumours with a nanodepot incorporating [90Y]Y-labeled gold nanoparticles inserted into one tumour arrested tumour growth and caused an abscopal growth-inhibitory effect on a distant second tumour. Convection-enhanced delivery of [177Lu]Lu-AuNPs to orthotopic human glioblastoma multiforme (GBM) tumours in mice arrested tumour growth without normal tissue toxicity. Other groups have explored radiation nanomedicines for cancer treatment in preclinical animal tumour xenograft models using gold nanoparticles, liposomes, block copolymer micelles, dendrimers, carbon nanotubes, cellulose nanocrystals or iron oxide nanoparticles. These nanoparticles were labeled with radionuclides emitting Auger electrons (111In, 99mTc, 125I, 103Pd, 193mPt, 195mPt), β-particles (177Lu, 186Re, 188Re, 90Y, 198Au, 131I) or α-particles (225Ac, 213Bi, 212Pb, 211At, 223Ra). These studies employed intravenous or intratumoural injection or convection enhanced delivery. Local administration of these radiation nanomedicines was most effective and minimized normal tissue toxicity.
Conclusions
Radiation nanomedicines have shown great promise for treating cancer in preclinical studies. Local intratumoural administration avoids sequestration by the liver and spleen and is most effective for treating tumours, while minimizing normal tissue toxicity.
“…CED of 177 Lu-labeled metallofullerenes (0.25–1.35 MBq) into orthotopic U87MG tumors in nude mice improved median survival with > 80% of mice treated with 1.35 MBq surviving > 100 d, while untreated mice survived < 29 d. Moreover, tumours in treated mice were smaller assessed by ex vivo histological staining (Wilson et al 2012 ). Together, the results of these studies confirm our findings (Georgiou et al 2023 ) that radiation nanomedicines administered by CED deposit high absorbed doses in GBM tumours in animal models that result in strong tumour growth-inhibitory effects, but are not toxic to normal tissues including normal brain, due to the restricted diffusion within the brain or redistribution to organs outside the brain mediated by the anchoring effects of NPs.…”
Section: Main Textsupporting
confidence: 90%
“…10 ) (Woodall et al 2021 ) These imaging results in patients with GBM administered 188 Re-labeled nanoliposomes by CED are very similar to those that we reported for [ 177 Lu]Lu-MCP-AuNPs infused by CED in NRG mice with orthotopic human GBM tumours (Fig. 9 b) (Georgiou et al 2023 ). Fig.…”
Section: Main Textsupporting
confidence: 85%
“…Local infusion of radiation nanomedicines by convection enhanced delivery (CED) into the surgical cavity post-resection may eradicate residual tumour at the margins and prevent recurrence, potentially improving survival. We studied a radiation nanomedicine for treatment of GBM by stereotaxically infusing 1.1 MBq [ 177 Lu]Lu-MCP-AuNPs (~ 23 nm; 4 × 10 11 AuNPs) by CED into small (~ 2 mm) luciferase-transfected U251-Luc human GBM tumours in the brain in NRG mice (Georgiou et al 2023 ) (Fig. 9 a).…”
Background
Radiation nanomedicines are nanoparticles labeled with radionuclides that emit α- or β-particles or Auger electrons for cancer treatment. We describe here our 15 years scientific journey studying locally-administered radiation nanomedicines for cancer treatment. We further present a view of the radiation nanomedicine landscape by reviewing research reported by other groups.
Main body
Gold nanoparticles were studied initially for radiosensitization of breast cancer to X-radiation therapy. These nanoparticles were labeled with 111In to assess their biodistribution after intratumoural vs. intravenous injection. Intravenous injection was limited by high liver and spleen uptake and low tumour uptake, while intratumoural injection provided high tumour uptake but low normal tissue uptake. Further, [111In]In-labeled gold nanoparticles modified with trastuzumab and injected iintratumourally exhibited strong tumour growth inhibition in mice with subcutaneous HER2-positive human breast cancer xenografts. In subsequent studies, strong tumour growth inhibition in mice was achieved without normal tissue toxicity in mice with human breast cancer xenografts injected intratumourally with gold nanoparticles labeled with β-particle emitting 177Lu and modified with panitumumab or trastuzumab to specifically bind EGFR or HER2, respectively. A nanoparticle depot (nanodepot) was designed to incorporate and deliver radiolabeled gold nanoparticles to tumours using brachytherapy needle insertion techniques. Treatment of mice with s.c. 4T1 murine mammary carcinoma tumours with a nanodepot incorporating [90Y]Y-labeled gold nanoparticles inserted into one tumour arrested tumour growth and caused an abscopal growth-inhibitory effect on a distant second tumour. Convection-enhanced delivery of [177Lu]Lu-AuNPs to orthotopic human glioblastoma multiforme (GBM) tumours in mice arrested tumour growth without normal tissue toxicity. Other groups have explored radiation nanomedicines for cancer treatment in preclinical animal tumour xenograft models using gold nanoparticles, liposomes, block copolymer micelles, dendrimers, carbon nanotubes, cellulose nanocrystals or iron oxide nanoparticles. These nanoparticles were labeled with radionuclides emitting Auger electrons (111In, 99mTc, 125I, 103Pd, 193mPt, 195mPt), β-particles (177Lu, 186Re, 188Re, 90Y, 198Au, 131I) or α-particles (225Ac, 213Bi, 212Pb, 211At, 223Ra). These studies employed intravenous or intratumoural injection or convection enhanced delivery. Local administration of these radiation nanomedicines was most effective and minimized normal tissue toxicity.
Conclusions
Radiation nanomedicines have shown great promise for treating cancer in preclinical studies. Local intratumoural administration avoids sequestration by the liver and spleen and is most effective for treating tumours, while minimizing normal tissue toxicity.
“…Luciferase-transfected KS-1-Luc#19 glioblastoma cells were implanted into the right cerebral hemisphere of 6-week-old female NOD/Shi-scid, IL-2RgKO (NOG) mice. For the procedure [ 21 , 22 ], the mice were anesthetized with 3 % isoflurane. A 1 cm midline incision was made in the skin and a burr hole was created using a 25G needle.…”
“…One possible tool to combat recurrence and to prolong the survival of patients could be the infusion of 197m/g Hg labelled gold nanoparticles (AuNPs) into the surgical cavity after tumor resection. Efforts employing AuNP labelled with 177 Lu show promising results [8].…”
Meitner-Auger-electron emitters have a promising potential for targeted radionuclide therapy of cancer because of their short range and the high linear energy transfer of Meitner-Auger-electrons (MAE). One promising MAE candidate is 197m/gHg with its half-life of 23.8 h and 64.1 h, respectively, and high MAE yield. Gold nanoparticles (AuNPs) that are labelled with 197m/gHg could be a helpful tool for radiation treatment of glioblastoma multiforme when infused into the surgical cavity after resection to prevent recurrence. To produce such AuNPs, 197m/gHg was embedded into pristine AuNPs. Two different syntheses were tested starting from irradiated gold containing trace amounts of 197m/gHg. When sodium citrate was used as reducing agent, no 197m/gHg labelled AuNPs were formed, but with tannic acid, 197m/gHg labeled AuNPs were produced. The method was optimized by neutralizing the pH (pH = 7) of the Au/197m/gHg solution, which led to labelled AuNPs with a size of 12.3 ± 2.0 nm as measured by transmission electron microscopy. The labelled AuNPs had a concentration of 50 μg (gold)/mL with an activity of 151 ± 93 kBq/mL (197gHg, time corrected to the end of bombardment).
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