Project 2 Pharmacokinetics and Pharmacodynamics of C60 and MWCNTs in non-pregnant

项目2 C60和多壁碳纳米管在非妊娠期的药代动力学和药效学

• 批准号: 8675238
• 负责人: SUSAN J SUMNER
• 金额: $ 77.59万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8675238
• 关键词: 8-hydroxy-2' -deoxyguanosine; Adult; Affect; Animals; Applications Grants; Arteries; Autoradiography; Biological Markers; Blood; Blood Circulation; Blood Pressure; Blood Vessels; C14 isotope; Carbon; Carbon nanoparticle; Cardiac; Cardiac Output; Cardiovascular Physiologic Processes; Cardiovascular system; Charge; Colostrum; Data; Defect; Deposition; Development; Dose; Drug Formulations; Drug Kinetics; Engineering; Equilibrium; Evaluation; Excretory function; Exposure to; Feces; Female; Fetus; Fullerenes; Glass; Health; Hormones; Human; Immune system; In Vitro; Inflammatory; Injection of therapeutic agent; Intravenous; Investigation; Iron; Kinetics; Label; Lactation; Learning; Life; Liquid substance; Lung; Measurement; Measures; Mesentery; Metabolic; Metabolism; Metals; Methods; Milk; Modeling; Modification; Mus; Nanotubes; National Institute of Environmental Health Sciences; Neonatal; Oral; Oropharyngeal; Outcome; Oxidative Stress; Parents; Perinatal Exposure; Pharmacodynamics; Phase; Physiological; Physiology; Placenta; Predisposition; Pregnancy; Preparation; Procedures; Process; Production; Property; Radioactivity; Radiolabeled; Rattus; Reaction; Reproduction; Reproductive system; Research; Risk; Risk Estimate; Rodent; Role; Route; Sampling; Scintillation Counting; Serum; Site; Staging; Suspension substance; Suspensions; Tail; Time; Tissue Sample; Tissues; Transmission Electron Microscopy; Tube; Ultrasonography; Urine; Veins; Work; absorption; abstracting; adverse outcome; analog; base; cellular imaging; cytokine; dosage; fullerene C60; in vivo; inflammatory marker; intravenous administration; intravenous injection; mouse model; multi walled carbon nanotube; nanomaterials; nanoparticle; neonate; offspring; oxidation; oxidative damage; particle; pharmacodynamic model; pharmacokinetic model; pregnant; pup; radioactivity analysis; radiotracer; reproductive; reproductive development; response; uptake

Abstract Important components in estimating risks associated with exposure to nanomaterials include understanding the uptake, distribution, and elimination; the mode of action; and the pharmacodynamics of the effects of nanoparticles. Pregnancy and lactation are physiological states in which the distribution and effects of nanomaterials have not been extensively investigated. This project will investigate the absorption, distribution, metabolism, and excretion of several nanoparticles with different size and charge properties. Investigations will be conducted with fullerene 060 and forms of multi-walled carbon nanotubes in female rats and mice, pregnant rats and mice, and in lactating rats and mice. The nanoparticles will be carbon-14 uniformly labeled by the RTI Synthesis and Characterization Core for conduct of these studies. Using three different routes of administration in female rats and mice (oropharyngeal aspiration, oral gavage, and intravenous [i.v.] injection) will provide information regarding the uptake and distribution processes for nanoparticles. Administration of the labeled nanoparticles to pregnant rats and mice by i.v, injection at different times in pregnancy will provide information about the ability of the nanoparticles to cross the placenta and result in fetal exposure. Analogously, i.v. administration to lactating rats and mice will enable evaluation ofthe secretion of nanoparticles into milk, resulting in exposure to offspring. The determination of the mass balance of radiolabel in urine, feces, blood tissues, and carcass at 5 time points over a period of 30 days following dosing will provide an enhanced understanding of the long-term fate of nanoparticles in the body. Quantitative whole body autoradiography will enable detailed characterization of the distribution of the nanoparticles. Examination of tissue samples with transmission electron microscopy will provide information on the subcellular localization of the nanomaterials. The effects of exposure to the carbon nanomaterials by oropharyngeal aspiration and i.v. administration will be investigated in the non-pregnant and pregnant (i.v. only) rodent by measuring arterial vascular reactivity, blood pressure, and cardiac ultrasound. The determination of markers of inflammation (cytokines), reproduction and development (hormones), and oxidative stress (8-hydroxydeoxyguanosine; 8- OHdG) will be conducted. The data obtained from Project 2 will be used in the development ofthe physiologically based pharmacokinetic and pharmacodynamic models constructed in Project 3.

摘要 评估与暴露于纳米材料相关的风险的重要组成部分包括了解纳米颗粒的吸收、分布和消除;作用方式;以及纳米颗粒作用的药效学。怀孕和哺乳是生理状态，其中纳米材料的分布和影响尚未得到广泛研究。该项目将研究具有不同尺寸和电荷特性的几种纳米颗粒的吸收、分布、代谢和排泄。将在雌性大鼠和小鼠、妊娠大鼠和小鼠以及哺乳期大鼠和小鼠中使用富勒烯060和多壁碳纳米管形式进行调查。纳米颗粒将由RTI合成和表征核心均匀标记碳-14，以进行这些研究。在雌性大鼠和小鼠中使用三种不同的给药途径（口咽抽吸、经口灌胃和静脉内[i. v.]注射）将提供关于纳米颗粒的摄取和分布过程的信息。 在怀孕的不同时间通过静脉注射将标记的纳米颗粒给予怀孕的大鼠和小鼠将提供关于纳米颗粒穿过胎盘并导致胎儿暴露的能力的信息。类似地，对哺乳期大鼠和小鼠静脉注射将能够评估纳米颗粒分泌到乳汁中，导致后代暴露。在给药后30天内的5个时间点测定尿液、粪便、血液组织和尸体中放射性标记物的质量平衡，将加深对纳米颗粒在体内的长期命运的理解。定量全身放射自显影将能够详细表征纳米颗粒的分布。用透射电子显微镜检查组织样本将提供有关纳米材料亚细胞定位的信息。将通过测量动脉血管反应性、血压和心脏超声，在非妊娠和妊娠（仅静脉注射）啮齿动物中研究通过口咽抽吸和静脉注射给药暴露于碳纳米材料的影响。将测定炎症（细胞因子）、生殖和发育（激素）以及氧化应激（8-羟基脱氧鸟苷; 8- OHdG）标志物。从项目2中获得的数据将用于开发项目3中构建的基于生理学的药代动力学和药效学模型。