Department of Pharmacology and Toxicology, University of Otago, Dunedin, 9016, New Zealand.
School of Chemical Sciences, Dublin City University, Glasnevin, Dublin, D09 NA55, Ireland.
Int J Nanomedicine. 2023 Jul 17;18:3897-3912. doi: 10.2147/IJN.S414438. eCollection 2023.
A nanoscale drug carrier could have a variety of therapeutic and diagnostic uses provided that the carrier is biocompatible in vivo. Carbon nano-onions (CNOs) have shown promising results as a nanocarrier for drug delivery. However, the systemic effect of CNOs in rodents is unknown. Therefore, we investigated the toxicity of CNOs following intravenous administration in female BALB/c mice.
Single or repeated administration of oxi-CNOs (125, 250 or 500 µg) did not affect mouse behavior or organ weight and there was also no evidence of hepatotoxicity or nephrotoxicity. Histological examination of organ slices revealed a significant dose-dependent accumulation of CNO aggregates in the spleen, liver and lungs (p<0.05, ANOVA), with a trace amount of aggregates appearing in the kidneys. However, CNO aggregates in the liver did not affect CYP450 enzymes, as total hepatic CYP450 as well as CYP3A catalytic activity, as meased by erythromycin N-demethylation, and protein levels showed no significant changes between the treatment groups compared to vehicle control. CNOs also failed to act as competitive inhibitors of CYP3A in vitro in both mouse and human liver microsomes. Furthermore, CNOs did not cause oxidative stress, as indicated by the unchanged malondialdehyde levels and superoxide dismutase activity in liver microsomes and organ homogenates.
This study provides the first evidence that short-term intravenous administration of oxi-CNOs is non-toxic to female mice and thus could be a promising novel and safe drug carrier.
纳米级药物载体在体内具有生物相容性的情况下，可以有多种治疗和诊断用途。碳纳米洋葱（CNO）作为药物递送的纳米载体显示出有前景的结果。然而，CNO 在啮齿动物中的全身效应尚不清楚。因此，我们研究了静脉注射 CNO 后在雌性 BALB/c 小鼠中的毒性。
单次或重复给予氧化 CNO（125、250 或 500μg）不会影响小鼠的行为或器官重量，也没有肝毒性或肾毒性的证据。器官切片的组织学检查显示，CNO 聚集体在脾脏、肝脏和肺部的积聚具有显著的剂量依赖性（p<0.05，ANOVA），在肾脏中出现少量聚集体。然而，肝脏中的 CNO 聚集体不会影响 CYP450 酶，因为总肝 CYP450 以及 CYP3A 催化活性，如红霉素 N-去甲基化所测量的，与对照组相比，各组之间的蛋白水平没有明显变化。CNO 在体外也不能作为 CYP3A 的竞争性抑制剂，无论是在小鼠还是人肝微粒体中。此外，CNO 不会引起氧化应激，因为肝微粒体和器官匀浆中的丙二醛水平和超氧化物歧化酶活性没有变化。
本研究首次证明，短期静脉内给予氧化 CNO 对雌性小鼠无毒，因此可能是一种有前途的新型安全药物载体。
