Research Project
7110531
[unreadable] DESCRIPTION (provided by applicant): Development of technologies enabling early drug absorption profiling for novel drug candidates is one of the crucial issues facing modern drug discovery research. Current approaches are low-throughput and suffer from difficulties with poor reproducibility and poor compatibility with existing instrumentation. To overcome these barriers, we propose to develop a surface plasmon resonance imaging (SPR/)-based microarray assay for drug absorption profiling in a standardized format. The basis for this novel assay is mixture of amphiphilic polymers that can extract membrane proteins and lipids from natural membranes by formation of stable micelle-membrane component complexes (PM-Mem). Such micelles can be effectively immobilized on a SPRi biosensor surface via polymeric tethers. Each SPRi biosensor chip can accommodate multiple spots with biological membrane components extracted from various tissues. This technology provides significant benefits over traditional liposome sensor coatings due to the stability of PM-Mem. The research plan for this Phase I SBIR application includes: 1) optimization of the composition of the polymeric micelles, the extraction procedure from model natural cell membranes using the polymeric micelles, and the immobilization of the PM-Mem on the surface of SPRi biosensor chips; 2) development of a reliable protocol for detecting drug absorption (binding) of different concentrations of a model drug to the SPRi biosensor surface; 3) validation of the principle of our microarray approach by using SPRi biosensor chips coated with PM-Mem formed from the membrane components of model natural membrane preparations (1) to compare binding of single model drug to model cell membranes in two membrane formulations (hybrid bilayers and PM-Mem) and (2) to screen a panel of six drugs with different absorption profiles to establish a correlation between each drug's fraction absorbed (Fa) quotient and its partitioning into the biosensor chip surface. Relevance of the proposed research to the public health: The proposed research is highly relevant to the public health because the methods we propose to develop may provide a break-through in drug discovery research. Using the approaches described in this application may enable researchers to predict quickly, efficiently, and cost-effectively how well the body will likely absorb a potential new drug before animal testing. Our future research plans extend to examining how a potential new drug would be distributed throughout the various tissues in the body. [unreadable] [unreadable] [unreadable]
