Abstract
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Introduction: Glioblastoma Multiforme (GBM) is a highly aggressive and lethal brain tumor. GBM has high recurrence rates post-surgery due to residual tumor at the surgical margins. Patients with recurrent GBM have a poor prognosis (median survival 3-9 months). Radionuclides such as [197Hg]Hg (t1/2=64h) which emit abundant DNA-damaging Auger electrons (AEs) complexed to gold nanoparticles (AuNPs) endocytosed by GBM cells is a potential treatment to eradicate residual GBM. Epidermal growth factor receptor (EGFR) targeting by conjugation of [197Hg]Hg-AuNPs to anti-EGFR monoclonal antibody, panitumumab promotes internalization by GBM cells, amplifying the cytotoxic effects of the AEs. Convection-enhanced delivery (CED) circumvents the blood-brain-barrier and enables local delivery of [197Hg]Hg-AuNPs directly to GBM tumors. Our aim was to synthesize EGFR-targeted and non-targeted [197Hg]Hg-AuNPs and compare their biodistribution after CED to orthotopic human GBM tumors in the brains of NRG mice.
Methods: [197Hg]Hg-AuNPs (25.1 ± 5.3 nm) were synthesized by trisodium citrate reduction of tetrachloroauric acid (25 mM) refluxed at 100ºC for 10 mins at pH=3.0. 197Hg was incorporated into the reaction to form a 197Hg-Au amalgam. [197Hg]Hg-AuNPs were stabilized with 0.006% Tween-20 and coated with lipoic acid-polyethylene glycol. [197Hg]Hg-AuNPs were transferred to 1M citric acid pH 4 to bind panitumumab (1 µg/µL), then the pH was adjusted to 9 with 1M NaHCO3. EGFR-targeted and non-targeted [197Hg]Hg-AuNPs were recovered by centrifuging at 10,000xg for 1.25 h. An orthotopic human GBM mouse tumor xenograft model was established by stereotaxic inoculation of 2x105 U251-Luc cells into the right hemisphere of the brain in NRG mice. Two weeks later when tumors (~2 mm) were detected by bioluminescence imaging, EGFR-targeted or non-targeted [197Hg]Hg-AuNPs (~0.7 MBq; 7x1010AuNPs; 5 mL) were stereotaxically infused by CED into the brain. Whole body SPECT/CT images were obtained at 1 and 3 d post-infusion (p.i.) using the 77 keV γ-photon of 197Hg. At 7 d p.i.197Hg uptake (%ID/g) in the brain and tissues was measured. The brain was examined visually ex vivo for deposition of AuNPs.
Results: [197Hg]Hg-AuNPs were prepared with a labeling efficiency = 99.0 ± 0.1%. SPECT/CT images showed focal retention in the brain tumor for both EGFR-targeted and non-targeted [197Hg]Hg-AuNPs (Fig. 1A,B). Ex vivo examination showed more diffuse distribution of non-targeted AuNPs in the brain. Biodistribution at 7 d p.i. of EGFR-targeted [197Hg]Hg-AuNPs revealed 484.5 ± 145.6 %ID/g in the tumor-bearing right brain vs. 2.8 ± 1.4 and 0.8 ± 0.4 %ID/g in the normal left brain and cerebellum, respectively. Uptake of non-targeted [197Hg]Hg-AuNPs in the tumor-bearing right brain was 423.9 ± 168.3 %ID/g vs. 5.04 ± 2.61, 6.68 ± 7.22 %ID/g, respectively, for left brain and cerebellum. Normal tissue uptake was low and there were no significant differences (P>0.05) between EGFR-targeted and non-targeted [197Hg]Hg-AuNPs (Fig. 2). At 7 d p.i. the brain retained 71.1 ± 17.5% and 64.7 ± 23.8% of EGFR-targeted and non-targeted [197Hg]Hg-AuNPs.
Conclusions: Both EGFR-targeted and non-targeted [197Hg]Hg-AuNPs were strongly retained in U251-Luc tumors in the brain in NRG mice after CED. Our study is the first to report 197Hg complexed to AuNPs as a potential AE-emitting radiation nanomedicine treatment for GBM that could improve patient outcome
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