Nanoparticles in the Human Placenta:Toxicokinetics

人胎盘中的纳米颗粒：毒代动力学

• 批准号: 7885351
• 负责人: Richard Kermit Miller
• 金额: $ 7.57万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7885351
• 关键词: Affect; Albumins; Animals; Area; Biochemical; Blood; Blood Circulation; Breathing; Cadmium; Capsid Proteins; Catabolism; Cells; Characteristics; Charge; Data; Dependence; Development; Diffusion; Drug Formulations; Endocrine; Endocytosis; Endothelium; Exposure to; Fetus; Functional disorder; Future; Gold; Human; Immunoglobulin G; Immunoglobulins; In Vitro; Kinetics; Ligands; Lobule; Mediating; Metals; Modeling; Mothers; Nanotechnology; Newborn Infant; Occupational; Perfusion; Placenta; Pregnancy; Pregnant Women; Process; Proteins; Rattus; Research; Respiratory System; Respiratory tract structure; Serum Albumin; Serum Proteins; Signal Transduction; Solubility; Source; Staging; Stream; Surface; Syncytiotrophoblast; System; Tissues; Toxic effect; Toxicokinetics; Ultrafine; Work; abstracting; base; embryo/fetus; fetal; macrophage; nanomaterials; nanomedicine; nanoparticle; particle; placental transfer; pregnant; public health relevance; receptor; research study; surface coating

DESCRIPTION (provided by applicant): Ultrafine/nanoparticles (NPs) from many environmental sources, including those produced by the exploding field of nanotechnology, can occur in occupational and environmental settings and present humans with both exposures and toxicities. Even more of an issue is the expanding field of nanomedicine. Current research has not had the pregnant woman or fetus as a major focus. We plan to examine whether NPs can cross into the fetus through the human placenta in vitro. Because of their small size and large surface area per unit area, the propensity of NPs to interact biologically is high. Inhaled NPs exit the respiratory tract into circulation with distribution to extrapulmonary tissues. When NPs enter the blood stream they become coated with serum proteins, which may influence the manner in which they are recognized by these tissues. Two proteins in particular, IgG and albumin, are selectively recognized and either transported (IgG) or catabolized (albumin) by the placenta. HYPOTHESIS: In the human, NPs in maternal blood can cross the placenta and enter into fetal circulation, and this transfer of NPs is dependent on the protein surface coating and size of the NPs. SPECIFIC AIM 1: Determine the ability of NPs to accumulate and transfer into the fetal circuit by the perfused human placenta in vitro using 5 nm gold (Au) particles coated with human F105 IgG or serum albumin, SPECIFIC AIM 2: Determine if larger NPs transit from the maternal to fetal circuits under perfusion conditions using similarly coated 50 nm Au NPs. SPECIFIC AIM 3: Determine if exposure to NPs induces dysfunction in the human placenta using dynamic functional, morphologic, biochemical and endocrine assessments. These studies will establish whether the human placenta will a. accumulate Au NPs according to size and protein coating, b. transfer these Au NPs selectively from maternal to fetal circulation, and c. become acutely intoxicated due to interaction with any of these NPs formulations. A major objective of these experiments is to initiate development of a model that will help assess the developmental effects of nanomaterials in the maternal circulation. FUTURE DIRECTIONS: Using these model Au NPs, results from this project will be the basis for subsequent research objectives using other types of NPs, e.g., partially soluble and biodegradable NPs and NPs with varying surface charge and size to identify a) the mechanisms of placental transfer of NPs and the dependence not only on size and protein coating, but also on charge, solubility, and other physicochemical characteristics, and b) the fate, effects, and underlying mechanisms of NPs in the human placenta at different stages of gestation. This work will identify the potential for the embryo/fetus to be directly exposed to different environmental NPs, and for the placenta to be affected. PUBLIC HEALTH RELEVANCE: This study will determine if nanoparticles of different sizes and protein coatings will cross the placenta and enter into the fetal circulation utilizing a dually perfused human placenta lobule in vitro.

描述（由申请人提供）：来自许多环境来源的Ultrafine/纳米颗粒（NP），包括纳米技术爆炸领域所产生的环境，可以在职业和环境环境中发生，并出现具有暴露和毒性的人类。更重要的是纳米医学的扩大领域。当前的研究没有将孕妇或胎儿作为主要重点。我们计划检查NP是否可以在体外通过人体胎盘跨入胎儿。由于它们的尺寸很小，每个单位面积的表面积较大，因此NP倾向在生物学上相互作用很高。吸入的NP将呼吸道退出循环，分布到肺外组织。当NP进入血液时，它们会被血清蛋白涂覆，这可能会影响这些组织识别它们的方式。尤其是两种蛋白质，即IgG和白蛋白，被胎盘被选择性地识别和运输（IgG）或分解代谢（白蛋白）。假设：在人类中，母体血液中的NP可以越过胎盘并进入胎儿循环，而这种NP的转移取决于NP的蛋白质表面涂层和大小。具体目标1：确定NP使用5 nm Gold（AU）颗粒在体外灌注和转移到胎儿回路中的能力，该颗粒涂有人类F105 IgG或血清白蛋白，具体目标2：确定使用类似涂层的50 NM AU NP的较大的NPS在灌注条件下从母体到胎儿回旋的较大的NPS转运。具体目标3：确定暴露于NPS是否使用动态功能，形态学，生化和内分泌评估引起人胎盘功能障碍。这些研究将确定人胎盘是否会a。根据尺寸和蛋白质涂层累积Au nps，b。选择性地从母体循环中选择性地将这些Au NPS转移到c。由于与这些NP的任何一个配方的相互作用而急性陶醉。这些实验的一个主要目的是启动开发模型，该模型将有助于评估纳米材料在母体循环中的发育效果。 FUTURE DIRECTIONS: Using these model Au NPs, results from this project will be the basis for subsequent research objectives using other types of NPs, e.g., partially soluble and biodegradable NPs and NPs with varying surface charge and size to identify a) the mechanisms of placental transfer of NPs and the dependence not only on size and protein coating, but also on charge, solubility, and other physicochemical characteristics, and b) the fate,在妊娠的不同阶段，NPS在人胎盘中的影响和基本机制。这项工作将确定胚胎/胎儿直接暴露于不同环境NP的潜力，以及胎盘受到影响。 公共卫生相关性：这项研究将确定不同尺寸和蛋白质涂层的纳米颗粒是否会越过胎盘，并在体外使用双重灌注的人胎盘小叶进入胎儿循环。

项目成果

Transfer of PAMAM dendrimers across human placenta: prospects of its use as drug carrier during pregnancy.

• DOI: 10.1016/j.jconrel.2010.11.023
• 发表时间: 2011-03-30
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Menjoge AR;Rinderknecht AL;Navath RS;Faridnia M;Kim CJ;Romero R;Miller RK;Kannan RM
• 通讯作者: Kannan RM