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

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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.