Preclinical Development of [211At]meta- astatobenzylguanidine ([211At]MABG) as an Alpha Particle Radiopharmaceutical Therapy for Neuroblastoma.
Preclinical Development of [211At]meta- astatobenzylguanidine ([211At]MABG) as an Alpha Particle Radiopharmaceutical Therapy for Neuroblastoma.
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DOI：
10.1158/1078-0432.ccr-22-0400
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发表时间：
2022-09-15
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影响因子：
--
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中科院分区：
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[131I]meta-iodobenzylguanidine ([131I]MIBG) is a targeted radiotherapeutic administered systemically to deliver beta particle radiation in neuroblastoma. However, relapses in the bone marrow are common. [211At]meta-astatobenzylguanidine [211At]MABG is an alpha particle emitter with higher biological effectiveness and short path length which effectively sterilizes microscopic residual disease. Here we investigated the safety and antitumor activity [211At]MABG in preclinical models of neuroblastoma. We defined the maximum tolerated dose (MTD), biodistribution and toxicity of [211At]MABG in immunodeficient mice in comparison to [131I]MIBG. We compared the anti-tumor efficacy of [211At]MABG to [131I]MIBG in three murine xenograft models. Finally, we explored the efficacy of [211At]MABG after tail vein xenografting designed to model disseminated neuroblastoma. The MTD of [211At]MABG was 66.7 MBq/kg (1.8 mCi/kg) in CB17SC scid−/− mice and 51.8 MBq/kg (1.4 mCi/kg) in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Biodistribution of [211At]MABG was similar to [131I]MIBG. Long-term toxicity studies on mice administered with doses upto 41.5 MBq/kg (1.12 mCi/kg) showed the radiotherapeutic to be well tolerated. Both 66.7 MBq/kg (1.8 mCi/kg) single dose and fractionated dosing 16.6 MBq/kg/fraction (0.45 mCi/kg) × 4 over 11 days induced marked tumor regression in two of the three models studied. Survival was significantly prolonged for mice treated with 12.9 MBq/kg/fraction (0.35 mCi/kg) × 4 doses over 11 days [211At]MABG in the disseminated disease (IMR-05NET/GFP/LUC ) model (p=0.003) suggesting eradication of microscopic disease. [211At]MABG has significant survival advantage in disseminated models of neuroblastoma. An alpha-particle emitting radiopharmaceutical may be effective against microscopic disseminated disease, warranting clinical development.
影响因子：
8.8
作者：
Cunningham, S H;Mairs, R J;Wheldon, T E;Welsh, P C;Vaidyanathan, G;Zalutsky, M R
通讯作者：
Zalutsky, M R