In pursuit of a preventive therapeutic for maternal autoantibody‐related (MAR) autism, we assessed the toxicity, biodistribution, and clearance of a MAR specific peptide‐functionalized dextran iron oxide nanoparticle system in pregnant murine dams. We previously synthesized ~15 nm citrate‐coated dextran iron oxide nanoparticles (DIONPs), surface‐modified with polyethylene glycol and MAR peptides to produce systems for nanoparticle‐based autoantibody reception and entrapments (SNAREs). First, we investigated their immunogenicity and MAR lactate dehydrogenase B antibody uptake in murine serum in vitro. To assess biodistribution and toxicity, as well as systemic effects, we performed in vivo clinical and post mortem pathological evaluations. We observed minimal production of inflammatory cytokines—interleukin 10 (IL‐10) and IL‐12 following in vitro exposure of macrophages to SNAREs. We established the maximum tolerated dose of SNAREs to be 150 mg/kg at which deposition of iron was evident in the liver and lungs by histology and magnetic resonance imaging but no concurrent evidence of liver toxicity or lung infarction was detected. Further, SNAREs exhibited slower clearance from the maternal blood in pregnant dams compared to DIONPs based on serum total iron concentration. These findings demonstrated that the SNAREs have a prolonged presence in the blood and are safe for use in pregnant mice as evidenced by no associated organ damage, failure, inflammation, and fetal mortality. Determination of the MTD dose sets the basis for future studies investigating the efficacy of our nanoparticle formulation in a MAR autism mouse model.

中文翻译：

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表位功能化葡聚糖氧化铁纳米颗粒在妊娠鼠模型中的生物分布和毒性。

为了寻求母体自身抗体相关 (MAR) 自闭症的预防性治疗方法，我们评估了 MAR 特异性肽功能化葡聚糖氧化铁纳米颗粒系统在怀孕鼠类中的毒性、生物分布和清除率。我们之前合成了~15 nm 柠檬酸盐包被的葡聚糖氧化铁纳米粒子 (DIONPs)，用聚乙二醇和 MAR 肽进行表面修饰，以生产基于纳米粒子的自身抗体接收和捕获 (SNARE) 系统。首先，我们在体外研究了它们的免疫原性和 MAR 乳酸脱氢酶 B 抗体在鼠血清中的吸收。为了评估生物分布和毒性以及全身效应，我们进行了体内临床和死后病理评估。我们观察到体外巨噬细胞暴露于 SNARE 后，炎症细胞因子——白细胞介素 10 (IL-10) 和 IL-12 的产生极少。我们将 SNARE 的最大耐受剂量确定为 150 mg/kg，通过组织学和磁共振成像在肝和肺中明显存在铁沉积，但未检测到肝毒性或肺梗塞的并发证据。此外，与基于血清总铁浓度的 DIONPs 相比，SNAREs 从怀孕母猪的母血中清除速度较慢。这些发现表明 SNARE 在血液中的存在时间较长，并且可以安全地用于怀孕小鼠，这证明没有相关的器官损伤、衰竭、炎症和胎儿死亡。