GOALI: Nanoparticle Immunotoxicology Assessment using High-Throughput Biomimicry (NIAHTB)

该奖项是根据2009年美国复苏和再投资法案（公法111 - 5）资助的。0930170SealNanoparticles（NP）在治疗领域显示出巨大的潜力，由于其较小的尺寸和独特的物理化学性质相比，其粗糙的对应部分。 然而，目前关于NP与人类免疫学相互作用的知识体系中存在裂缝。 必须立即注意这一差距，以确定潜在的环境威胁。 对环境惰性的材料如氧化铝、二氧化钛、二氧化铈或氧化锆可能在纳米级尺寸范围内对生物细胞具有反应性和毒性。 这种行为的根本原因可以归因于几个物理和化学参数，例如尺寸、形状、相、表面积、官能化端基、活性/反应性电子构型、还原/氧化电位、工程表面缺陷、增强的UV或IR吸收或加工污染。 因此，重要的是将纳米颗粒的免疫反应与其材料化学、尺寸和表面性质相关联，以设计和加工安全使用。 这项研究提案是根据NSF GOALI计划与UCF和佛罗里达州奥兰多的VaxDesign公司一起提交的，将建立纳米颗粒的各种物理化学性质与其先天性和适应性免疫反应之间的关系。 由此，他们将能够开发一个可量化和可靠的纳米材料毒性数据库。 将开发基于疫苗接种位点（VS）、类肉瘤组织等效物（LTE）和功能测定模块的模拟人类免疫系统的功能等效免疫生理模型（MIMIC），以模拟治疗性NP在人体中的作用，并在大型供体库中测试纳米颗粒制剂的反应原性和免疫原性。拟议的研究将有助于实现对纳米毒理学理解的知识洞察，从而允许设计安全的纳米治疗药物。 它将通过体外免疫学模型建立具体的证据，将纳米颗粒的物理，化学和表面性质与其免疫反应的类别联系起来。这些参数的成功量化和整合将为研究人员提供物理相关的模板，该模板可用于在发现的早期阶段快速评估免疫纳米毒性制剂，使他们能够以更有效和更具成本效益的方式开发具有上级性能的产品。该提案侧重于从合成氧化物纳米颗粒到其表征以及随后在生理条件下进行测试以确定其对生物细胞的毒性反应的完整产品周期。 具体目标基于假设（金属氧化物纳米颗粒可以通过基于大小、形状、电荷和反应性的复杂过程刺激人体免疫系统，产生活性氧和氮物质。 这些参数的成功量化和整合将为研究人员提供物理模板（人体模型的生理自体），其可用于在其发现阶段的早期快速评估制剂，从而能够更有效和成本有效地选择具有上级性能和缩短的上市时间的产品。 它还将提供关于对人体具有毒性的纳米材料的不良免疫后果的信息。 开发这样一种新的工具，可以创建一个知识库，可以使用类似的平台转化并应用于许多NP，通过评估消费行业安全使用的潜在纳米材料，将对科学界产生深远的影响。预计这项工作将导致开发一个合理的模型，可以将免疫反应与纳米颗粒的物理化学性质相关联。 这一模型将填补纳米材料的毒性反应与其免疫反应之间日益扩大的差距，从而提高研究界对纳米材料评估的基本认识。 这个模型将识别并在我们对身体的理解方面取得重大进展？的反应存在于环境中的NP。 研究生和本科生将有机会定期在VaxDesign实验室工作，包括少数民族和代表性不足的学生通过UCF的REU计划。 与VaxDesign的工业合作伙伴关系提供技术转让，扩大制造，商业化和实习方面的技术咨询和培训。 该提案旨在建立具体证据，将纳米颗粒的物理、化学和表面属性与纳米毒性中的免疫反应类型联系起来。

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).0930170SealNanoparticles (NP) show tremendous potential in the area of therapeutics due to their smaller size and unique physicochemical properties as compared to their coarse counter parts. However, there exists a fissure in the current body of knowledge pertaining to NP interactions with human immunology. Immediate attention to this gap is necessary to define potential environmental threats. Materials which are environmentally inert such as alumina, titania, ceria or zirconia may turn reactive and toxic to biological cells in the nanoscale size domain. The root cause of this behavior may be ascribed to several physical and chemical parameters such as size, shape, phase, surface area, functionalized terminal groups, active/reactive electronic configuration, reduction/oxidation potential, engineered surface defects, enhanced UV or IR absorption, or processing contamination. Hence, it is important to correlate the immune response of nanoparticles with their material chemistry, size and surface properties to engineer and process safe usage. This research proposal, submitted under the NSF GOALI program in conjunction with UCF and VaxDesign Corporation of Orlando, Fl, will establish the relation between various physico-chemical properties of the nanoparticles with their innate and adaptive immune responses. From this they will be able to develop a quantifiable and reliable database of nanomaterial toxicity. A functionally equivalent immuno-physiological model (MIMIC) to mimic the human immune system based on Vaccination Site (VS), Lymphoid Tissue Equivalent (LTE) and Functional Assay modules will be developed to simulate the effect of therapeutic NPs in the human body and test the reactogenicity and immunogenicity of nanoparticle formulation across a large donor pool. The proposed study will help to achieve intellectual insight into the understanding of nanotoxicology and in turn allow for design of safe nanotherapeutics. It will establish concrete evidence to relate the physical, chemical, and surface properties of nanoparticles with the category of their immune response through in vitro immunological models. A successful quantification and integration of these parameters will provide researchers with a physically relevant template that can be used for rapid assessment of the immuno nanotoxicity formulations at the earlier stage of discovery, enabling them to develop products with superior performance in a more efficient and cost effective way. This proposal focuses on a complete product cycle from synthesizing oxide nanoparticles to their characterization and subsequent testing in physiological conditions to determine their toxic response to biological cells. The specific objectives based on the hypothesis (metal oxide NPs can stimulate the human immune system through a complex process based on size, shape, charge and reactivity to produce reactive oxygen and nitrogen species. The successful quantification and integration of these parameters will provide researchers with a physical template (physiological autologous of human model) that can be used for rapid assessment of the formulations earlier in their discovery stage enabling more efficient and cost effective selection of products with superior performance and decreased time to market. It will also provide information on adverse immunological consequences of nanomaterials which exhibit toxicity to the human body. Developing such a new tool which can create a knowledgebase that can be transformed and applied to a host of NPs using a similar platform will have far reaching implications in the scientific community by assessing potential nanotherapeutic materials for safe usage in consumer industries. The proposed work is expected to result in developing a sound model that can correlate the immune response to physico-chemical properties of NPs. Such a model will fill the widening gap between the toxicity response of nanomaterials and their immune response, thereby increasing the fundamental understanding of the research community engaged in assessment of NPs. This model will identify and make significant strides in our understanding of the body?s response to NPs present in the environment. Graduate and undergraduate students will have an opportunity to work at VaxDesign laboratories on a regular basis, including minorities and underrepresented students through UCF's REU program. The industrial partnership with VaxDesign provides technical advice and training in technology transfer, scale-up manufacturing, commercialization and internships. This proposal is aimed to establish concrete evidence to relate the physical, chemical and surface attributes of NPs with the type of immune response in nanotoxicity.