Micro- and Nanotechnologies
Novel sampling strategies and highly miniaturized systems for mass spectrometric analysis
Recently, a new bioanalytical platform based on the coupling of acoustic droplet ejection (ADE) and open pore probe (OPP) technologies to mass spectrometry with standard electrospray ionization (ESI) ion source was introduced. Extraordinary performance has been demonstrated with this new platform, including plate-reader sampling speed, label free detection with MS, simplicity of assay development, just to name a few. As the pioneers to develop and apply this technology, our group have demonstrated the instrument capability and shared several seminal proof-of-concept studies supporting different areas of drug discovery including functional HTS, Drug-Drug Interaction (DDI), and other ADME applications in previous SLAS conference. With the commercialization of this new platform coming along, the technology had been further enhanced especially around system integration, automation, and robustness. We will be happy to report back the recent technology advancements, as well as the recent studies of the different screens Pfizer team have been working on to support live projects.
One lipid based HTS assay have been developed and successfully applied for hits triage and SAR support. Challenges of the lipid sampling and handling will be highlighted, and solutions and performance highlights will be provided. Both false positive and false negative hits identified from other HTS means were effectively teased out taking advantage of the high selective of MS detection. With the integration of liquid handling workstation (Beckman I7) and other key peripherals to the ADE-OPP-MS instrument and implementation of automation solutions, ultra-high throughput screening with mass spec became a reality and can provide up to hundreds of thousands of compounds per day throughput. Besides pharmacology advancements, high throughput parallel medicinal chemistry applications enabled by this ADE-OPP-MS technology will be shared. Ultra-low sample requirements provide by ADE technology enabled readouts with as little as 1uL reaction, making 100X cost savings for the reagent and enabled much bigger chemical libraries to be made. Chemical reactions can be thoroughly evaluated with OPP-high resolution MS (HRMS) at second/reaction speed, 60-100X faster than the current paradigm. Such large and high-quality dataset enables generation of big data around chemical reactions to feed in machine learning/artificial intelligence builds. Finally, biomarker analysis is another direction that we are interested as another big advantage of ADE-OPP-MS platform is that it can handle dirty sample matrixes with minimum sample preparation. We will show some recent example such as detecting N-methyl nicotinamide (NMN) from human urine samples or plasma pharmacokinetics (PK) studies where high-quality data (and equivalent to those obtained by conventional LC/MS method) were acquired without no sample preparation or just one step dilution; while the analysis time was effectively cut from multiple hours to a few minutes.