Evolution of Quantitative MALDI-TOF Mass Spectrometry for Clinical Applications

Abstract

The nearly simultaneous discoveries of electrospray ionization (ESI)2 (1) and MALDI (2) 27 years ago removed the volatility barrier for mass spectrometry (MS). ESI-MS developed very rapidly, at least partly due to the ease of interfacing with commercially available quadrupole and trap instruments widely used for analytical applications. TOF is particularly well suited to MALDI with pulsed ion sources compatible with pulsed laser desorption, but applications developed more slowly, at least in part because higher-performance instruments were not initially available. The potential of MALDI has stimulated development of improved TOF instrumentation particularly tailored for this ionization technique. Laser ionization MS has been extensively studied for >60 years, but until the introduction of an appropriate matrix for absorbing the laser energy was introduced, biological applications were very limited (3). Karas and Hillenkamp (2) found that the use of a suitable matrix could reduce the required photon intensity for desorption by an order of magnitude and coined the description of the process as “matrix-assisted laser desorption ionization.” Further development of the time-of-flight instrument enabled the observation of proteins of masses >100 kDa, such as β-d-galactosidase at approximately 117 kDa reported by Hillenkamp (4) at the Bordeaux International Mass Spectrometry meeting in 1988. This signaled the beginning of a new era in biological MS. The resolving power obtained in this initial work was rather low, and it was quickly realized that a major limitation was due to ion fragmentation in flight. The first practical MALDI-TOF mass spectrometer for high m / z was built by Beavis and Chait within a few months of the discovery of MALDI (5). This was a simple linear TOF with a static single field source, drift tube, and detector. A major advantage of the linear analyzer is that ions dissociating in flight arrive at nearly …