Genetic Engineering & Biotechnology News

DEC 2017

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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Genetic Engineering & Biotechnology News | GENengnews.com | DECEMBER 2017 | 13 determining tissue distribution of the par- ent drug and its metabolites are quantitative whole-body autoradiography (QWBA) and liquid chromatography–mass spectrometry (LC–MS), but these don't provide a complete distribution picture. QWBA studies are ex- pensive and cannot distinguish parent drug from metabolite, presenting severe limita- tions for researchers looking for early insight into biochemical pathways and mechanisms. LC–MS analysis is performed on ex- tracts from tissue homogenates which inher- ently do not convey any spatial information and, just as importantly, can be misleading. For example, if a metabolite is localized to very small compartments, average amount in tissue reported by LC–MS doesn't accu- rately represent the true distribution and a researcher could draw incorrect conclusions about toxicity. MALDI–MSI has emerged as a test that provides quantitative, spatially resolved data on the tissue distribution of drugs, drug metabolites, and other endogenous species. MALDI–MSI is helping developers under- stand the spatial distribution and tissue physiology of a candidate drug and related metabolites before costly QWBA experi- ments, thereby allowing for informed deci- sions whether to move the candidate to the next development stage. A range of mass spectrometers are uti- lized for MALDI-MSI, depending on ap- plication needs. MALDI-TOF systems, for example, offer highest throughput while magnetic resonance mass spectrometers (MALDI-MRMS) provides the ultimate in measurement accuracy and mass resolving power. Additionally, MALDI-MRMS can often yield unique molecular formula identi- fication for compounds imaged. In MALDI-MS imaging (MALDI-MSI), a conventional, fresh-frozen tissue section is treated with a solution of MALDI matrix solution, which extracts molecules from the tissue but retains the spatial relationships found in the underlying tissue. MALDI-MSI analysis generates a panel of label-free inten- sity/distribution maps of compounds detect- ed from the sample. MALDI-MSI does not destroy underlying cellular features, which can subsequently be histologically stained to facilitate co-registration of histology with the MSI images for histopathological context. Images shown in Figure 1 illustrate the potential of this new technology for provid- ing deeper insight into ADME/TOX mecha- nisms. In an early work by Castellino et al., 3 lapatinib-dosed dog liver was analyzed by MSI at 50 µm spatial resolution. A corre- lation with histology revealed a metabolite having molecular weight of 649.14 Daltons localized to areas of inflammation. In another recent publication from the same group, 4 MALDI-MSI was able to an- swer a question that had eluded convention- al LC-MS analysis. Studying nephrotoxicity of the anticancer drug Dabrafenib in juvenile rats, tubular deposits were observed in kid- ney sections that did not present in kidneys of adult rats. MALDI-MSI was used to di- rectly analyze the crystals and determined them to be calcium phosphate, providing a more complete risk assessment of Dab- rafenib than would have been possible using traditional LC–MS or QWBA. Conclusion New technology and innovative ap- proaches built around MALDI-MS are emerging that facilitate more rapid filling of discovery pipelines with new candidates, as well as the ability to probe ADME/TOX of these candidates at earlier stages in a more cost-effective manner. Already, many phar- ma companies have recognized the value in these new technologies and have invested in the latest instrumentation. With new appli- cations being published monthly, anticipa- tion is high that MALD-MS technology will provide additional insight and a deeper un- derstanding of candidate compounds early in the discovery process. References 1. Pharmaprojects, "Pharma R&D Annual Review 2017," (Janu- ary 2017), https://pharmaintelligence.informa.com/~/media/ Informa-Shop-Window/Pharma/Files/PDFs/whitepapers/ RD-Review-2017.pdf, accessed November 10, 2017. 2. P. Marshall et al., "Ultra-High-Throughput Drug Discovery Screening by MALDI–TOF Mass Spectrometry—Exceeding One Million Samples per Week," Presentation ASMS 2016 in San Antonio, TX (June 2016). 3. S. Castellino, M.R. Groseclose, and D. Wagner, "MALDI Imag- ing Mass Spectrometry: Bridging Biology and Chemistry in Drug Developments," Bioanalysis 21, 2427–2441 (2011). 4. M.R. Groseclose et al., "Imaging MS in Toxicology: An Investigation of Juvenile Rat Nephrotoxicity Associated with Dabrafenib Administration," J. Am. Soc. 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