Nanotechnology: Advancing Toxicity Testing

纳米技术：推进毒性测试

• 批准号: 8035837
• 负责人: Kristi Lynn Haik
• 金额: $ 40.58万
• 依托单位: NORTHERN KENTUCKY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035837
• 关键词: Academic Research Enhancement Awards; Accounting; Affect; Animal Model; Antineoplastic Agents; Apoptosis; Apoptotic; Area; Astrocytes; Biological Assay; Blood; Blood - brain barrier anatomy; Brain; Brain Diseases; Bromides; Cell Culture Techniques; Cell Line; Cell membrane; Cells; Cerebrum; Characteristics; Charge; Chemicals; Chemistry; Development; Disease; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug vehicle; Endothelial Cells; Exhibits; Faculty; Funding; Gene Expression; Genes; Glioblastoma; Homeostasis; In Vitro; Injury; Institution; Kentucky; Lactate Dehydrogenase; Lipids; Measures; Membrane; Membrane Lipids; Methods; Mitochondria; Modeling; Molecular; Molecular Profiling; Molecular and Cellular Biology; Nanotechnology; Outcome; Oxidative Stress; Pathway interactions; Penetration; Pharmaceutical Preparations; Phase; Polysorbate 80; Procedures; Production; Property; Publishing; Reporting; Research; Research Personnel; Screening procedure; Stream; Stress; Students; Surface; Testing; Tissues; Toxic effect; Toxicity Tests; Toxin; United States National Institutes of Health; Universities; Up-Regulation; Work; base; combat; cytotoxicity; functional group; gene repression; interdisciplinary approach; membrane model; monolayer; nanodrug; nanomaterials; nanoparticle; nervous system disorder; pressure; prevent; programs; surfactant; tool

DESCRIPTION (provided by applicant): Nanotechnology provides an opportunity to develop drug delivery systems that cross the blood brain barrier (BBB). However, as the production and discovery of new nanomaterials increases, identification of the toxic effects of nanomaterials is essential. Factors affecting toxicity include size of the nanoparticle (NP) as well as core material, drugs within the core, external functional groups, and surfactants. A standardized procedure to assess the toxicity of newly created nano-drug vehicles is highly desirable. This work will utilize an interdisciplinary approach to in vitro studies, providing a more comprehensive and accurate screening tool for toxicity. Specifically, the studies proposed will compare cellular toxicity measures, specific genes related to toxicity, and biophysical characteristics of NP interactions with model BBB membranes. This will enable the development of a standard panel of toxicity tests that can be conducted in a timely and relatively inexpensive fashion to investigate the toxicity of any type and number of NPs. In this work we will utilize the toxicity panel to characterize the effects of different charged surfactants on the toxicity of poly (butylcyanoacrylate) (PBCA) NPs, which have been shown to deliver drugs to the brain in animal models. While much research has been conducted on PBCA NPs, issues of toxicity have not been fully elucidated. Specific aims of this application include: (1) testing the toxicity of NPs using a two-cell culture model of the BBB; (2) examining a subset of genes related to (a) apoptosis and (b) stress and toxicity using PCR arrays; and (3) evaluating the biophysical characterization of NP-BBB model membrane interactions. This project fits well with the Academic Research Enhancement Award (AREA) R15 mechanism. Northern Kentucky University (NKU) is a primarily undergraduate institution but has not been a major recipient of NIH funding. The investigators and project faculty have strong active undergraduate research programs where students have the opportunity to present and publish their research. PUBLIC HEALTH RELEVANCE: More than one billion people across the world suffer with brain diseases, disorders, or injuries. To combat these maladies, researchers have been working hard to develop potential therapies, a majority of which may only be administered by injecting them directly into the brain. Nanotechnology has shown promise in delivering drugs to the brain that previously had not had access. The purpose of this application is to compare cellular toxicity measures, specific genes related to toxicity, and biophysical characteristics of model BBB membranes that have been exposed to a variety of nanoparticles. This will enable the development of a much needed standard panel of toxicity tests that can be conducted in a timely and relatively inexpensive fashion to investigate the toxicity of any type and number of nanoparticles.

描述（由申请人提供）：纳米技术提供了开发穿过血脑屏障（BBB）的药物递送系统的机会。然而，随着新纳米材料的生产和发现的增加，确定纳米材料的毒性效应至关重要。影响毒性的因素包括纳米颗粒（NP）的大小以及核心材料、核心内的药物、外部官能团和表面活性剂。一个标准化的程序来评估新创建的纳米药物载体的毒性是非常可取的。这项工作将利用跨学科的方法进行体外研究，为毒性提供更全面和准确的筛选工具。具体而言，拟议的研究将比较细胞毒性措施，与毒性相关的特定基因，以及NP与模型BBB膜相互作用的生物物理特征。这将使得能够开发一个标准的毒性测试小组，可以以及时和相对便宜的方式进行，以研究任何类型和数量的NP的毒性。在这项工作中，我们将利用毒性面板来表征不同电荷的表面活性剂对聚（氰基丙烯酸丁酯）（PBCA）纳米颗粒的毒性的影响，这些纳米颗粒已被证明可以在动物模型中将药物输送到大脑。虽然已经对PBCA NP进行了大量研究，但毒性问题尚未完全阐明。本申请的具体目的包括：（1）使用BB B的双细胞培养模型测试NP的毒性;（2）使用PCR阵列检查与（a）细胞凋亡和（B）应激和毒性相关的基因子集;和（3）评估NP-BB B模型膜相互作用的生物物理表征。该项目非常符合学术研究促进奖（AREA）R15机制。北方肯塔基州大学（NKU）是一所主要的本科院校，但并不是NIH资助的主要接受者。研究人员和项目教师有很强的活跃的本科研究项目，学生有机会展示和发表他们的研究。 公共卫生相关性：全世界有超过10亿人患有脑部疾病、紊乱或损伤。为了对抗这些疾病，研究人员一直在努力开发潜在的治疗方法，其中大部分只能通过直接注射到大脑中来进行。纳米技术在将药物输送到大脑方面显示出了希望，而这在以前是无法实现的。本申请的目的是比较暴露于各种纳米颗粒的模型BBB膜的细胞毒性测量、与毒性相关的特定基因和生物物理特性。这将使开发一个非常需要的标准毒性测试小组成为可能，可以及时和相对便宜的方式进行，以研究任何类型和数量的纳米颗粒的毒性。