A Polymer-Halloysite Formulation for Postnatal Methylmercury Delivery

用于产后甲基汞输送的聚合物埃洛石配方

• 批准号: 8773322
• 负责人: Marshall CHRISTOPHER NEWLAND
• 金额: $ 7.36万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-24 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8773322
• 关键词: Adverse effects; Behavioral; Binding; Biological Availability; Biological Models; Body Temperature; Brain; Cerebellum; Cerebral cortex; Chronic; Complex; Development; Discipline of Nursing; Dose; Drug Formulations; Drug or Chemical; Environmental Pollution; Experimental Models; Exposure to; Gel; Growth; Human; Injectable; Injection of therapeutic agent; Kaolin; Kinetics; Laboratories; Life; Liquid substance; Mercury; Metals; Methylmercury Compounds; Milk; Modeling; Mus; Neocortex; Neonatal; Nervous system structure; Nutrient; Organism; Perinatal Exposure; Phase; Physiologic pulse; Physiological; Placenta; Polymers; Prefrontal Cortex; Pregnancy; Risk Factors; Rodent; Rodent Model; Route; Saline; Scientist; Socioeconomic Factors; Source; Structure; Syringes; Techniques; Temperature; Third Pregnancy Trimester; Time; age group; base; critical period; design; developmental neurotoxicity; drinking water; exposed human population; halloysite; methylmercury exposure; neonate; neurotoxicity; postnatal; public health relevance; pup; toxicant; uptake

DESCRIPTION (provided by applicant): Postnatal Methylmercury Delivery Using a Polymer and Halloysite Formulation The developing nervous system is especially sensitive to exposure to methylmercury (MeHg), a significant environmental contaminant. Experimental models are required to characterize human exposure, but modeling the full human gestational period in a rodent requires ex- posure both during gestation and during the rodent's early postnatal period. This is because regions that are sensitive to MeHg, including the prefrontal cortex and cerebellum, show significant development during the last trimester of human gestation, and show similar development during the first 7-10 days of rodent life. Unfortunately, the bioavailability of MeHg in milk is very low so it is not possible to produce significant postnatal exposure by exposing the lactating dam. A convenient technique for producing postnatal exposure simply, reliably, inexpensively, and a sustained, low-dose manner would facilitate the study of critical periods of exposure. In the proposed studies, an injectable polymer-based formulation will be developed that can be used to provide chronic, low-dose exposure to MeHg in the post-natal rodent. If successful, the approach could be used for any age group and possibly for other metals. MeHg will be bound to halloysite and this MeHg/halloysite complex will then be dispersed in a polymer matrix. Two different approaches will be examined, one based on a thermoresponsive gel and a second on a thermoplastic material. Both will be in a liquid form at cool temperatures so they can be injected easily with a syringe but, upon exposure to the mouse's warmer body temperature, will become more viscous and therefore will release MeHg slowly. The studies will be conducted in four phases. First, benchtop studies will be conducted to identify candidate formulations for administration to a mouse pup. Second, dose-ranging studies will be conducted to determine the relation between MeHg loading on to the halloysite and brain MeHg after five days. Third, postnatal kinetic studies will be conducted to determine the rate of uptake and elimination of MeHg after injection on postnatal day 1. Finally, the kinetics of pre + postnatal exposure will be examined to determine the smoothness of the transition from fetal exposure via maternal drinking water to postnatal exposure via the formulation. A successful formulation will greatly facilitate the study of MeHg exposure during the crucial postnatal period. Current techniques, such as daily dosing, are highly labor intensive and more primitive approaches, such as injection of MeHg in saline, produce an unrealistic MeHg pulse that decreases with time.

描述（由申请人提供）：使用聚合物和子宫岩配方的产后甲基汞递送。发育的神经系统对暴露于甲基汞（MEHG）（一种严重的环境污染物）特别敏感。需要实验模型来表征人类暴露，但是在啮齿动物中对整个人妊娠期进行建模需要在妊娠期间和啮齿动物的早期产后时期。这是因为对MEHG敏感的地区，包括前额叶皮层和小脑，在人类妊娠的最后三个月中显示出重大发展，并在啮齿动物寿命的前7-10天中显示出相似的发展。不幸的是，牛奶中MEHG的生物利用度非常低，因此不可能通过暴露泌乳大坝来产生大量的产后暴露。一种方便的技术，可简单，可靠，廉价地产生产后暴露，持续，低剂量的方式将有助于研究关键时期。 在拟议的研究中，将开发一种可注射聚合物的配方，可用于在产后啮齿动物中向MEHG提供慢性，低剂量的暴露。如果成功，该方法可用于任何年龄段，可能用于其他金属。 Mehg将被绑定到Halloysite，而这个Mehg/Halloysite Complex将被散布在聚合物矩阵中。将检查两种不同的方法，一种基于热重凝胶，一秒钟基于热塑性材料。两者都将在凉爽的温度下以液体形式以液体形式，因此可以轻松地注射注射器，但是在暴露于小鼠温暖的体温后，它们会变得更加粘稠，因此会缓慢释放MEHG。 研究将分为四个阶段。首先，将进行台式研究，以确定用于给小鼠幼犬给药的候选公式。其次，将进行剂量范围的研究，以确定五天后MEHG加载与Halloysite和Brain MeHG之间的关系。第三，将进行产后动力学研究，以确定产后第1天注射后注射后的摄取速率和消除MEHG的速率。最后，将检查 +产后暴露的动力学，以确定通过孕妇饮用水从胎儿暴露到通过配方的胎儿暴露于胎儿暴露的胎儿暴露过渡的平稳性。 成功的表述将极大地促进在关键的产后研究中MEHG暴露的研究。当前的技术（例如日常剂量）是高度劳动密集型和更原始的方法，例如在盐水中注射MEHG，会产生一种不切实际的MEHG脉冲，随着时间的推移会减少。