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Optical Biopsies: Utilizing Light to Improve Decision Making from the Cell to the Clinic

Zane Arp, PhD

One of the keys to success for drug development is early identification of whether a drug has reached and engaged its target. In most instances this target engagement is observed through ancillary information using a variety of different techniques including, but not limited to, fluorescent labeling, chemical biomarkers, or morphologic changes to the system. In complex biological systems the reliability of each of these markers is often an issue. Although these markers are validated, it is impossible to fully understand the impacts that drugs or fluorescent markers may have on such a complex system. For example biomarkers and morphology are tools to observe downstream changes after drug/target engagement. In many situations a change or lack of change may be observed as there are off-target interactions or potentially redundancies within the biological system which prevent easy detection of drug/target interaction. In order to better elucidate drug/target engagement, better tools are needed that will directly observe the chemistry that occurs when a drug finds its target. The focus of this talk will be on GlaxoSmithKlines efforts to develop methods to help address these needs. Optical tools such as Raman, Coherent anti-Stokes Raman (CARS), and Fluorescence Lifetime Microscopy (FLIM) are non-invasive, non-damaging, and non-tagged techniques which can be used to better elucidate whether a drug has reached its target by directly observing either drug location or the chemistry that takes place when a drug engages a target using their inherent optical or spectral properties. As these methods have very high spatial resolution it is possible to elucidate the location of a drug and its effects at the sub-cellular level. In this talk examples will be shown that demonstrate the capability to use optical method to follow drug penetration and activity in a variety of different systems of interest to the pharmaceutical industry. Using the data from these new methods it is now possible to directly detect a drugs penetration and target engagement using endogenous signals from the system, greatly improving the reliability of detecting a drugs disposition at the sub-cellular level.

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