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超细/纳米颗粒（NP），包括由纳米技术爆炸领域产生的那些，可能出现在职业和环境环境中，并对人类造成暴露和毒性。更大的问题是纳米医学领域的不断扩大。目前的研究尚未将孕妇或胎儿作为主要焦点。我们计划在体外研究纳米颗粒是否可以通过人胎盘进入胎儿体内。由于纳米颗粒尺寸小且单位面积表面积大，因此它们发生生物相互作用的可能性很高。吸入的纳米粒子离开呼吸道进入循环系统并分布到肺外组织。当纳米颗粒进入血流时，它们会被血清蛋白包裹，这可能会影响它们被这些组织识别的方式。特别是两种蛋白质，IgG 和白蛋白，被胎盘选择性识别并转运（IgG）或分解代谢（白蛋白）。假设：在人类中，母体血液中的纳米粒子可以穿过胎盘并进入胎儿循环，并且纳米粒子的这种转移取决于蛋白质表面涂层和纳米粒子的大小。具体目标 1：使用涂有人 F105 IgG 或血清白蛋白的 5 nm 金 (Au) 颗粒，确定 NP 在体外通过灌注人胎盘积累和转移到胎儿回路的能力，具体目标 2：确定较大的 NP 是否转运使用类似涂层的 50 nm Au NP 在灌注条件下从母体到胎儿回路。具体目标 3：通过动态功能、形态、生化和内分泌评估确定接触纳米粒子是否会导致人胎盘功能障碍。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累 Au NP，b．将这些金纳米颗粒选择性地从母体循环转移至胎儿循环，以及c．由于与任何这些纳米颗粒制剂相互作用而严重中毒。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：使用这些模型 Au NP，该项目的结果将成为使用其他类型 NP 的后续研究目标的基础，例如部分可溶和可生物降解的 NP 以及具有不同表面电荷和尺寸的 NP，以确定 a) 胎盘的机制纳米颗粒的转移，不仅取决于尺寸和蛋白质涂层，还取决于电荷、溶解度和其他物理化学特征，以及 b) 纳米颗粒的命运、影响和潜在机制不同妊娠阶段人胎盘中的纳米颗粒。这项工作将确定胚胎/胎儿直接暴露于不同环境纳米粒子以及胎盘受到影响的可能性。 公共健康相关性：本研究将确定不同尺寸和蛋白质涂层的纳米颗粒是否会在体外利用双重灌注的人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