| In this thesis, imaging time-of-flight secondary ion mass spectrometry (ToF-SIMS) is applied to the high-throughput analysis of combinatorially synthesized organic molecules, which are normally referred to as libraries. Two issues need to be addressed for a library: the occurrence and structure of the library components and their bioactivity toward certain targets. Since bioassay can be rapidly handled with a variety of strategies, here we focus on identifying the library members using mass spectrometric methodologies.; We establish parallel analysis protocols for combinatorial libraries synthesized both in solution phase and on solid phase, such as polymer resin particles. By acquiring molecule-specific images of the analytes densely arrayed either in picoliter-volume silicon vials for liquid samples or on arraying chips for polymer beads, analysis rates of 10 analytes/second on model systems has been achieved with imaging ToF-SIMS. The challenges lie in the development of appropriate treatments for diverse samples or samples presented in complex matrixes. For liquid samples, glass substrates modified with functional groups are employed to separate the analytes from a mixture solution through selective binding. As a result, SIMS sensitivity is greatly enhanced.; Solid-bound libraries comprise of an intricate system because of the wide varieties of linker moieties and polymer matrixes involved in the synthesis. We examined the influence of three classes of linkers—acid or base labile linkers, a thermally labile linker and a photochemically cleavable linker, all of which are used to anchor one end of the analyte to the polymer resin. With data obtained using both SIMS, X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM), we conclude that an effective treatment of the resin needs to include cleaving the linker and extracting the unbound analyte to the resin surface. We also demonstrate that the hydrophilicity of the polymeric constituents of a resin particle affects the experiments by changing the location of the analyte molecules during resin treatment. In addition, the spatial localization of the released analytes could be controlled by introducing a hydrophobic supporting substrate such as Teflon tape that confines the diffusion of the cleaving reagent.; Encoding a library with tags is necessary when direct mass analysis fails to yield conclusive results due to mass redundancy and inadequate sensitivity. Two different encoding strategies and corresponding tags are designed, synthesized and examined with imaging ToF-SIMS. The dual recursive deconvolution (DRED) strategy differentiates the resins based on the varying concentrations of bromine and chlorine-derivatized polystyrene in their polymer matrixes. The resins are subsequentially decoded using isotopic signal intensities measured with SIMS. This scheme obviates the need for extra synthetic steps and cleaving reactions, thus is highly compatible with high-throughput analysis using imaging ToF-SIMS. (Abstract shortened by UMI.)... |
