Imaging Fractional Occupancy to Quantitate Drug Delivery
In vivo pharmacology is an enormously complex process with a 95% clinical failure rate in oncology of drugs that were advanced after successful preclinical studies. To be effective drug must reach the target tissue or organ, bind to the target protein or nucleic acid, and remain bound long enough to alter cellular processes. However, determining when, where and how much drug reaches the target remains difficult, too often leading to drugs advancing through development that do not behave the way we expect or targets erroneously deemed ineffective. To measure drug delivery and target engagement we have developed an approach to image and quantitate the fraction of cognate target occupancy within single cells. This approach allows us to study heterogeneity of target occupancy in cancer models, determine drug susceptibility to efflux pumps and quantitate binding rates in cells. Currently we are extending our approach to measure the dynamics of nanoparticle drug delivery at the cellular level.
J. Matt Dubach is a faculty member of the Center for Systems Biology and the Institute for Innovation in Imaging at MGH and Harvard Medical School. After time as a member of the technical staff at Draper Laboratories he obtained his PhD in Bioengineering from Northeastern University with Heather Clark as an NSF IGERT fellow in Nanomedicine. Matt then became a NIH T32 postdoctoral fellow at MGH under the guidance of Ralph Weissleder. His current research focuses on developing novel, optical approaches to measure the unmeasurable in biomedicine.