Word (http://tools.niehs.nih.gov/portfolio/sc/detail_doc.cfm?appl_id=7271230&ext=.doc)
|
Excel (http://tools.niehs.nih.gov/portfolio/sc/detail_xls.cfm?appl_id=7271230&ext=.xls)
|
PDF (http://tools.niehs.nih.gov/portfolio/sc/detail_doc.cfm?appl_id=7271230&pdf=1&ext=.pdf)
Integrated Biochip for In-Vitro Toxicology
Principal Investigator
Dordick, Jonathan
Institute Receiving Award
Solidus Biosciences,, Inc.
Location
Troy, NY
Grant Number
R42ES012619
Funding Organization
National Institute of Environmental Health Sciences
Award Funding Period
01 Sep 2003to31 Jul 2009
DESCRIPTION (provided by applicant): Solidus Biosciences, Inc. is developing a proprietary Metabolizing Enzyme Toxicology Assay Chip (MetaChip), along with a xenobiotic metabolism and toxicity screening device that uses these chips (the MetaReader), for high- throughput analysis of drug metabolism and toxicity. The MetaChip integrates the high-throughput metabolite- generating capability of P450 catalysis with human cell-based screening on a single microscale platform. As a result, P450-generated drug-candidate metabolites can be generated and screened against human cell lines even if the metabolites are unstable. The MetaChip platform along with the MetaReader provides Solidus Biosciences with an enabling technology that will have myriad applications in both early stage and preclinical toxicology testing. Solidus is therefore developing the first technology and associated products that can rapidly replicate human metabolism and perform in vitro toxicity testing in a single, automated, high-throughput manner. Consequently, Solidus' products have significant commercial potential and the promise to greatly benefit human health. The proposed Phase II program will focus on the full optimization of the MetaChip and on the design, preparation, and operation of the MetaReader, both of which can be readily combined with other in vitro toxicology and metabolite profiling approaches that deal with ADME (adsorption, distribution, metabolism, and excretion) of xenobiotics. The specific aims and milestones for the Phase II STTR are to: 1. Optimize P450 loading, activity, and stability within sol-gel matrices and generate sol-gels with physicochemical properties that accurately and reproducibly mimic the human liver; 2. Perform rapid P450 inhibition assays on the MetaChip using well-known inhibitors of the different human P450 isoforms; 3. Complete development of the collagen gel and other 3D cell culture techniques for growth inhibition assays on the MetaChip; 4. Expand the repertoire of metabolic enzymes to include phase II drug metabolism enzymes. This also includes addition of glutathione for conjugation to metabolites generated in the MetaChip; 5. Co-develop (with an industrial collaborator) the MetaReader to streamline the application of sample, the enzymatic reaction and assay steps, and image analysis in a simple operating scheme; 6. Use the fully operational MetaChip platform to correlate in vitro toxicity results to in vivo toxicity results. This aim involves components of the ICCVAM validation process. The end result of the Phase II study will be a fully operational and integrated device, the MetaReader, that will become an important tool in early-stage testing of drug and drug-candidate toxicity, and in the development of in vitro models that mimic human metabolism.
Crisp Terms/Key Words: high throughput technology, microarray technology, genetic screening, combinatorial chemistry, cell line, technology /technique development, cytotoxicity, cytochrome P450, growth inhibitor, enzyme inhibitor, drug screening /evaluation, drug metabolism, biotechnology
|