July 2010


Fine-Scale Drug Distribution in Lung Tissue Slices via Imaging Mass Spectrometry

Unraveling the mystery of why some potential drugs succeed, while the great majority fail during develpment, will help lower the huge cost (hundreds of millions of dollars) required for developing a sucessful drug. A common mystery, one of many, is why a drug that is retained in a specific tissue or organ for a long time can nevertheless turn out to be ineffective.

In some circumstances, it could be due to way scientists currently measure drug concentrations in tissues. They commonly extract a chunk of tissue, homogenize it, and determine the average concentration of the drug within the entire homogenate.

Following this procedure, you'd never know if the drug in question may have localized within an unintended compartment of the tissue (rendering it ineffective). Homogenizing a large chunk of tissue eliminates information on fine-scale drug spatial distribution within it, thereby eliminating data that may explain the inefficacy mystery.

Ideally, one would be able to combine histological images of tissue slices (taken with a standard microscope) with quantitative data on drug distribution within the tissue section, eliminating the need for tissue homogenization. Per Andrén (Uppsula University, Sweden) and coworkers have utilized imaging mass spectrometry for just this purpose.

Imaging tiotropium bromide in lung tissue slices.

The scientists carried out their drug quantitation research in rat lung tissue. They administered the drug tiotropium bromide as an aerosol, depositing 50 micrograms of the drug in their lungs.

Tiotropium bromide is a drug that increases air flow in the lungs. It is commonly used as a regular treatment of chronic obstructive pulmonary disease, which is most commonly caused by smoking and can be fatal if left untreated.

Via mass spectrometry, the scientists found molecular fragments in their tissue samples that correspond to tiotropium bromide. As enabled by subsequent histological imaging of the same tissue section, these molecular fragments were most highly concentrated in the alveoli (gas exchange compartments) of the lungs.

This level of data cannot be obtained via homogenization. They then quantitated drug concentrations in the tissue, and found that it closely followed known drug concentrations obtained by directly spotting the drug on the tissue (demonstrating the accuracy of their mass spectrometry data).

The scientists could accurately quantitate drug concentrations at levels observed within most regions of their tissue slices, even in three-dimensional sections, with a resolution of approximately 200 micrometers (i.e roughly the size of a human cell). The quantitation should therefore provide data relevant to medical applications.

Furthermore, mass spectrometry also enabled the scientists to detect and quantitate important physiological molecules (e.g phosphatidylcholine) within their tissue sections. They found that some of these molecules were localized within well-defined regions, and others were more generally distributed.

However, they haven't yet spent much time determining the identity of these molecules; there were approximately 200 molecular fragments within a mass-to-charge ratio between 400 and 2200. This issue can certainly be pursued in the future.

Overall evaluation.

Combining a fine-scale drug quantitation technique with standard histological imaging yields a powerful approach for evaluating drug distribution within tissue slices. Current technology in principle will allow future scientists to perform analogous experiments within individual cells, far surpassing conventional drug quantitation techniques.

ResearchBlogging.org for more information:
Nilsson, A., Fehniger, T. E., Gustavsson, L., Andersson, M., Kenne, K., Marko-Varga, G., & Andrén, P. E. (2010). Fine Mapping the Spatial Distribution and Concentration of Unlabeled Drugs within Tissue Micro-Compartments Using Imaging Mass Spectrometry PLoS ONE, 5 (7) DOI: 10.1371/journal.pone.0011411