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(申请人提供)：来自许多环境来源的超细/纳米颗粒(NPs)，包括由纳米技术爆炸性领域产生的那些，可能出现在职业和环境环境中，对人类既有暴露又有毒性。更大的问题是纳米医学领域的不断扩大。目前的研究还没有将孕妇或胎儿作为主要焦点。我们计划在体外检查NPs是否能通过人类胎盘进入胎儿。由于它们的体积小，单位面积的表面积大，所以NPs具有很高的生物相互作用的倾向。吸入的NPs离开呼吸道进入循环，并分布到肺外组织。当NPs进入血流时，它们会被血清蛋白包裹，这可能会影响这些组织识别它们的方式。两种蛋白质，特别是免疫球蛋白和白蛋白，被选择性地识别并被胎盘转运(免疫球蛋白)或分解代谢(白蛋白)。假设：在人类中，母血中的NPs可以穿过胎盘进入胎儿循环，这种转移依赖于NPs的蛋白表面涂层和大小。特异性目的1：用包被人F105Ig G或血清白蛋白的5 nm金(Au)颗粒，测定NPs在体外灌流的人胎盘中蓄积并转移到胎儿回路的能力；特异性目的2：确定在同样包被50 nm Au纳米颗粒的灌流条件下，较大的NPs是否从母体回路转移到胎儿回路。具体目标3：通过动态功能、形态、生化和内分泌评估，确定暴露于NPs是否会导致人类胎盘功能障碍。这些研究将确定人类胎盘是否会根据大小和蛋白质涂层积聚Au NPs，B.将这些Au NPs选择性地从母体循环转移到胎儿循环，以及C.由于与这些NPs配方中的任何一种相互作用而变得急性中毒。这些实验的一个主要目标是启动一个模型的开发，该模型将有助于评估纳米材料在母体循环中的发育影响。未来方向：利用这些纳米粒子模型，本项目的结果将成为后续研究目标的基础，使用其他类型的纳米粒子，例如部分可溶和可生物降解的纳米粒子和具有不同表面电荷和大小的纳米粒子，以确定a)胎盘纳米粒子的转移机制以及不仅依赖于大小和蛋白质涂层，而且还依赖于电荷、溶解度和其他物理化学特性，以及b)纳米粒子在不同妊娠阶段在人类胎盘中的去向、作用和潜在机制。这项工作将确定胚胎/胎儿直接接触不同环境NPs的可能性，以及胎盘受到影响的可能性。 公共卫生相关性：这项研究将确定不同大小和蛋白质涂层的纳米颗粒是否会在体外利用双重灌流的人类胎盘小叶穿过胎盘并进入胎儿循环。

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