Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Int J Hyperthermia. 2020 Dec;37(3):59-75. doi: 10.1080/02656736.2020.1776901.
Toxicity from off-target heating with magnetic hyperthermia (MHT) is generally assumed to be understood. MHT research focuses on development of more potent heating magnetic iron oxide nanoparticles (MIONs), yet our understanding of factors that define biodistribution following systemic delivery remains limited. Preclinical development relies on mouse models, thus understanding off-target heating with MHT in mice provides critical knowledge for clinical development.
Eight-week old female nude mice received a single tail vein injection of bionized nanoferrite (BNF) MIONs or a counterpart labeled with a polyclonal human antibody (BNF-IgG) at 1 mg, 3 mg or 5 mg Fe/mouse on day 1. On day 3, mice were exposed to an alternating magnetic field (AMF) having amplitude of 32, 48 or 64 kA/m at ∼145 kHz for 20 min. Twenty-four hours later, blood, livers and spleens were harvested and analyzed.
Damage to livers was apparent by histology and serum liver enzymes following MHT with BNF or BNF-IgG at doses ≥3 mg Fe and AMF amplitudes ≥48 kA/m. Differences between effects with BNF vs. BNF-IgG at a dose of 3 mg Fe were noted in all measures, with less damage and increased survival occurring in mice injected with BNF-IgG. Necropsies revealed severe damage to duodenum and upper small intestines, likely the immediate cause of death at the highest MHT doses.
Results demonstrate that the MION coating affects biodistribution, which in turn determines off-target effects. Developments to improve heating capabilities of MIONs may be clinically irrelevant without better control of biodistribution.
人们普遍认为，已经了解了磁性热疗（MHT）的脱靶加热毒性。MHT 研究的重点是开发更有效的加热磁性氧化铁纳米粒子（MION），但我们对系统给药后决定其生物分布的因素的了解仍然有限。临床前开发依赖于小鼠模型，因此，了解 MHT 在小鼠中的脱靶加热提供了临床开发的关键知识。
8 周龄雌性裸鼠在第 1 天接受单次尾静脉注射生物素化纳米铁（BNF）MION 或用多克隆人抗体标记的对应物（BNF-IgG），剂量分别为 1mg、3mg 或 5mg Fe/只。在第 3 天，将小鼠暴露于振幅为 32、48 或 64 kA/m 的交变磁场（AMF）中，频率约为 145 kHz，持续 20 分钟。24 小时后，采集血液、肝脏和脾脏并进行分析。
在 MHT 剂量≥3mg Fe 和 AMF 幅度≥48 kA/m 时，BNF 或 BNF-IgG 均会导致肝脏组织学和血清肝酶损伤。在 3mg Fe 剂量下，BNF 与 BNF-IgG 的效果存在差异，注射 BNF-IgG 的小鼠损伤较小且存活率更高。尸检显示十二指肠和上部小肠严重损伤，这可能是最高 MHT 剂量下死亡的直接原因。
结果表明，MION 涂层会影响生物分布，进而决定脱靶效应。如果不能更好地控制生物分布，改善 MION 加热能力的发展可能在临床上并不相关。
