Imaging Therapeutic PARP Inhibition in Vivo through Bioorthogonally Developed Companion Imaging Agents
73331 neo1403_0169.pdf (3.287Mb)
Access StatusFull text of the requested work is not available in DASH at this time ("restricted access"). For more information on restricted deposits, see our FAQ.
Keliher, Edmund J.
Yang, Katherine S.
Kohler, Rainer H.
MetadataShow full item record
CitationReiner, Thomas, Jessica Lacy, Edmund J. Keliher, Katherine S. Yang, Adeeti Ullal, Rainer H. Kohler, Claudio Vinegoni, and Ralph Weissleder. 2012. “Imaging Therapeutic PARP Inhibition In Vivo through Bioorthogonally Developed Companion Imaging Agents.” Neoplasia 14 (3): 169–IN3. https://doi.org/10.1593/neo.12414.
AbstractA number of small-molecule poly (ADP-ribose) polymerase (PARP) inhibitors are currently undergoing advanced clinical trials. Determining the distribution and target inhibitory activity of these drugs in individual subjects, however, has proven problematic. Here, we used a PARP agent for positron emission tomography-computed tomography (PET-CT) imaging (F-18-BO), which we developed based on the Olaparib scaffold using rapid bioorthogonal conjugation chemistries. We show that the bioorthogonal F-18 modification of the parent molecule is simple, highly efficient, and well tolerated, resulting in a half maximal inhibitory concentration (IC50) of 17.9 +/- 1.1 nM. Intravital imaging showed ubiquitous distribution of the drug and uptake into cancer cells, with ultimate localization within the nucleus, all of which were inhibitable. Whole-body PET-CT imaging showed tumoral uptake of the drug, which decreased significantly, after a daily dose of Olaparib. Standard F-18-fludeoxyglucose imaging, however, failed to detect such therapy-induced changes. This research represents a step toward developing a more generic approach for the rapid codevelopment of companion imaging agents based on small-molecule therapeutic inhibitors.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41384254
- HMS Scholarly Articles