Treatment of Human Glioblastoma Multiforme in NRG Mice by Convection-Enhanced Delivery of EGFR-Targeted or Nontargeted Auger Electron-Emitting (197g)Hg-Labeled Gold Nanoparticles.

内容摘要

The effectiveness and safety of Auger electron (AE)-emitting epidermal growth factor receptor (EGFR)-targeted panitumumab-197gHg-gold nanoparticles (AuNPs) or nontargeted 197gHg-AuNPs for treating glioblastoma multiforme (GBM) were studied after convection-enhanced delivery (CED) in NOD-Rag1nullIL2rgnull (NRG) mice with orthotopic GBM tumors. We hypothesized that EGFR binding, internalization, and nuclear importation of panitumumab-197gHg-AuNPs would make these radiation nanomedicines more effective than nontargeted 197gHg-AuNPs because of the subcellular range of AEs, but that both would be safe because of their confined localization at the infusion site in the brain after CED. Methods: Localization of 197gHg in NRG mice after CED was assessed by SPECT/CT imaging. Toxicity was evaluated after CED of 1.8 × 1011 to 2.3 × 1011 panitumumab-197gHg-AuNPs (0.9 ± 0.5 MBq) or nontargeted 197gHg-AuNPs (2.6 ± 0.8 MBq) by hematology, blood biochemistry, and body weight monitoring. Mice with U251-Luc tumors were treated with panitumumab-197gHg-AuNPs (1.3 ± 0.3 MBq) or 197gHg-AuNPs (1.1 ± 0.4 MBq), panitumumab-AuNPs or AuNPs, or 0.9% NaCl. Tumor response was assessed by MRI and Kaplan-Meier median survival. Self-absorbed doses in the nucleus of tumor cells from AEs were estimated. Toxicity to the brain was assessed by MRI and ex vivo histologic examination. Results: Both panitumumab-197gHg-AuNPs and 197gHg-AuNPs were confined to the infusion site with no redistribution to healthy brain or other organs. There was no hematologic, liver, or kidney toxicity and no decrease in body weight. MRI at 21 d and 34 d revealed that tumors in mice treated with panitumumab-197gHg-AuNPs or 197gHg-AuNPs were significantly smaller than tumors in mice treated with panitumumab-AuNPs, AuNPs, or 0.9% NaCl. Median survival in mice treated with panitumumab-197gHg-AuNPs (59 d) was significantly longer than that in mice treated with nontargeted 197gHg-AuNPs (43 d) or control treatments (31-33 d). The self-radiation absorbed dose in the nucleus of GBM tumor cells from AEs was 3.2-fold higher for panitumumab-197gHg-AuNPs (40.2 Gy) than for 197gHg-AuNPs (12.2 Gy). Conclusion: EGFR-targeted panitumumab-197gHg-AuNPs were more effective than nontargeted 197gHg-AuNPs for treating U251-Luc human GBM tumors in NRG mice. This approach may offer a safe and effective treatment for GBM that could improve patient survival.