Dose ranging, expanded acute toxicity and safety pharmacology studies for intravenously administered functionalized graphene nanoparticle formulations.
Dose ranging, expanded acute toxicity and safety pharmacology studies for intravenously administered functionalized graphene nanoparticle formulations.
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DOI：
10.1016/j.biomaterials.2014.04.066
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发表时间：
2014-08
期刊：
影响因子：
14
通讯作者：
Sitharaman, Balaji
中科院分区：
文献类型：
--
作者：
Kanakia, Shruti;Toussaint, Jimmy D.;Chowdhury, Sayan Mullick;Tembulkar, Tanuf;Lee, Stephen;Jiang, Ya-Ping;Lin, Richard Z.;Shroyer, Kenneth R.;Moore, William;Sitharaman, Balaji
石墨烯纳米颗粒分散体显示出作为体内生物医学应用的多功能试剂的巨大潜力。在此，我们遵循药物监管指南，该指南建议安全药理学评估至少比预计治疗剂量高10 - 100倍，并提出全面的单剂量反应，扩展的急性毒理学，毒代动力学，和呼吸/心血管安全药理学结果，以1- 100 mg/kg的剂量向大鼠静脉内施用葡聚糖涂覆的氧化石墨烯纳米片（GNP-Dex）制剂。500 mg/kg。我们的研究结果表明，GNP-Dex的最大耐受剂量（MTD）为50 mg/kg ≤ MTD < 125 mg/kg，血液半衰期< 30分钟，大多数纳米颗粒在24小时内通过粪便排泄。在≥ 250 mg/kg剂量下，在心脏、肝脏、肺、脾脏和肾脏中观察到组织学变化;在< 125 mg/kg剂量下，我们未发现脑变化，并且在心血管参数或血液学因素（血液、脂质和代谢组）中未发现GNP-Dex相关影响。这些结果为按照监管机构对研究性新药（IND）申请所要求的药物非临床研究质量管理规范（GLP）进行关键性临床前单次和重复给药安全性研究开辟了途径。
Graphene nanoparticles dispersions show immense potential as multifunctional agents for in vivo biomedical applications. Herein, we follow regulatory guidelines for pharmaceuticals that recommend safety pharmacology assessment at least 10 – 100 times higher than the projected therapeutic dose, and present comprehensive single dose response, expanded acute toxicology, toxicokinetics, and respiratory/cardiovascular safety pharmacology results for intravenously administered dextran-coated graphene oxide nanoplatelet (GNP-Dex) formulations to rats at doses between 1–500 mg/kg. Our results indicate that the maximum tolerable dose (MTD) of GNP-Dex is between 50 mg/kg ≤ MTD < 125 mg/kg, blood half-life < 30 minutes, and majority of nanoparticles excreted within 24 hours through feces. Histopathology changes were noted at ≥ 250 mg/kg in the heart, liver, lung, spleen, and kidney; we found no changes in the brain and no GNP-Dex related effects in the cardiovascular parameters or hematological factors (blood, lipid, and metabolic panels) at doses < 125 mg/kg. The results open avenues for pivotal preclinical single and repeat dose safety studies following good laboratory practices (GLP) as required by regulatory agencies for investigational new drug (IND) application.
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