Nanotechnology: Advancing Toxicity Testing

描述(申请人提供)：纳米技术为开发跨越血脑屏障(BBB)的药物输送系统提供了机会。然而，随着新纳米材料的生产和发现的增加，识别纳米材料的毒性效应是至关重要的。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发明的纳米药物载体的毒性是非常必要的。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。具体地说，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。这将使建立一个标准的毒性测试小组成为可能，该小组可以以及时和相对廉价的方式进行，以调查任何类型和数量的核燃料的毒性。在这项工作中，我们将利用毒性小组来表征不同带电表面活性剂对聚氰基丙烯酸丁酯(PBCA)纳米颗粒毒性的影响，这些纳米颗粒已被证明在动物模型中可以将药物输送到大脑。虽然对PBCA纳米粒进行了大量的研究，但其毒性问题还没有完全阐明。这一应用的具体目的包括：(1)使用血脑屏障的两细胞培养模型测试NPs的毒性；(2)使用PCR阵列检测与(A)细胞凋亡和(B)应激和毒性相关的基因子集；以及(3)评估NP-BBB模型膜相互作用的生物物理特征。该项目与学术研究促进奖(AREA)R15机制非常吻合。北肯塔基大学(NKU)主要是一所本科院校，但并不是NIH资金的主要接受者。研究人员和项目教师拥有强大的活跃的本科生研究项目，学生有机会展示和发表他们的研究成果。 与公共卫生相关：全世界有10多亿人患有脑部疾病、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，其中大部分可能只能通过直接将它们注射到大脑中来实施。纳米技术在将以前无法获得的药物输送到大脑方面显示出了希望。这一应用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以及生物物理特性。这将使开发一个急需的毒性测试标准小组成为可能，该小组可以及时和相对便宜的方式进行，以调查任何类型和数量的纳米颗粒的毒性。

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.