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This technology improves the entire drug cycle— from discovery through human studies
In the pharmaceutical industry, accurately identifying the components of a mixture can be the difference between life and death. Mass spectrometry delivers that capability and more. According to Jonathan L. Josephs, director, pharma/biopharma, life sciences mass spectrometry at Thermo Fisher Scientific (San Jose, Calif.), “Mass spectrometry plays many key roles in the pharmaceutical industry, from the very early stages of drug discovery through to late-stage development and clinical trials.” Looking for a biomarker to target a particular disease pathway? Mass spec might be just what you need. “When new therapeutic agents are first ‘synthesized,’ be they small molecules or large proteins, their structural composition must be determined/confirmed,” says Josephs. “Mass spectrometry plays a key role in these determinations.” Want to see how a compound impacts a pathway? MS again. The technology is used in so many aspects of the pharmaceutical process that it’s hard to name them all.
MS can reveal a compound’s efficacy and toxicology. It can be used to study a compound’s pharmacokinetics—its distribution in the body over time. “The unique degree of sensitivity and selectivity in complex matrices that is afforded by mass spectrometry makes it the technique of choice for these extensive experiments that take place from drug discovery, where animal studies are conducted, through clinical trials, where these parameters are determined in humans,” Josephs says. The technique can also disclose if a drug causes health problems or is broken down into compounds that do.
Various drugs, such as the cancer drug Trastuzumab shown here, can be analyzed with mass spectrometry. (Image courtesy of Thermo Fisher Scientific.)After a drug is tested and approved, companies use MS to make sure that a manufacturing process makes the right compound and that dangerous chemicals from packaging don’t end up in the drug.
Minding the mass
At the Waters mass spectrometry headquarters (Wilmslow, U.K.), chemists work with quadrupole time-of-flight platforms in a customer demonstration lab. (Image courtesy of Waters.)MS platforms used for pharmaceutical work fall into one of two categories: nominal mass and accurate mass. A nominal mass spectrometer measures isotopes in the sample to about 1 Dalton, while an accurate mass spectrometer measures Daltons to 3–4 decimal places. For less demanding applications, accurate mass is not required.
Nominal MS, says Diane Diehl, director of small molecule pharmaceutical marketing at Waters (Milford, Mass.), “spans the range of drug discovery and development.” In drug discovery, medicinal chemists use nominal MS to make sure they are synthesizing the right molecules. “Our ACQUITY QDa mass detector can be used here,” Diehl says. Pharmaceutical scientists also use this single-quadrupole MS technology in drug development to check for impurities in a synthesized compound.
Easier-to-use devices, like the Waters ACQUITY QDa detector, expand the use of mass spectrometry in the pharmaceutical sciences. (Image courtesy of Waters.)Other factors come into play. “These instruments may then be further characterized by whether they are capable of measuring only mass or if they can isolate an ion of particular mass-to-charge ratio, and then fragment it prior to mass determination,” Josephs explains. The latter is tandem mass spectrometry, and this form of accurate MS is required to elucidate structures. The Thermo Scientific Orbitrap mass analyzer observes “the image current created by the oscillation of ions accelerated into and trapped by an electrostatic field,” says Josephs, adding that the Orbitrap Fusion Lumos tribrid mass spectrometer produces very high-resolution accurate mass (HRAM) spectra and offers multiple modes of tandem mass spectrometry. Such configurations, he points out, “are very powerful for structural elucidation of unknowns and for peptide sequencing, and have become the gold standard in the industry for these applications…. The advent of HRAM has simplified the automated assignments of structures and metabolic soft spots, greatly increasing the throughput of these assays.”
Expanding utility
MS shows increasing applications in disease-related research. Scientists from Merck (Rahway, N.J.), Kings College (London, England) and Waters tested the ACQUITY QDa MS platform in drug discovery and development and reported: “Overall, the compact mass detector has proven to be a valuable and reliable mass detection and compound confirmation tool for the open access environment in the pharmaceutical discovery and development space where speed and uptime is crucial, unit mass resolution is a necessity and sample availability is rarely a concern.” They added, “The benefits of the compact mass detector for use in a wide variety of applications including standard small molecule analysis [high-throughput screening] and QC type analyses, as well as biological samples and quantitation studies have been demonstrated” (Gao, J. et al. Journal of Pharmaceutical and Biomedical Analysis; Jan. 2016, doi:10.1016/j.jpba.2016.01.017).
An October 2015 article in Antimicrobial Agents and Chemotherapy (Page-Sharp, M. et al., doi:10.1128/AAC.01740-15) reports on the use of dried blood spots in antibiotic assays analyzed with liquid chromatography followed by tandem MS. The researchers concluded that this technique could be used to determine a drug’s pharmacokinetics (how the drug affects the body) and pharmacodynamics (how the body affects the drug).
Metabolomics-based MS and gas and liquid chromatography were used to analyze the phenotypes of four cancer cell lines—two from colon cancer and two from ovarian cancer. Halama et al., writing in a July 2015 article in the Journal of Translational Medicine (doi: 10.1186/ s12967-015-0576-z), said, “Our study provides a panel of distinct metabolic fingerprints between colon and ovarian cancer cell lines. These may serve as potential drug targets, and now can be evaluated further in primary cells, biofluids and tissue samples for biomarker purposes.”
As the pharmaceutical industry continues its search for critical targets and develops evermore sophisticated compounds, MS will make it possible for researchers to look at increasingly finer levels of molecular detail.
Mike May is a freelance writer and editor living in Ohio. He can be reached at [email protected].