nl7b03813_si_001.pdf (3.62 MB)
Molecular Imaging of Cancer Using X‑ray Computed Tomography with Protease Targeted Iodinated Activity-Based Probes
journal contribution
posted on 2018-02-22, 17:05 authored by Hanmant
K. Gaikwad, Darya Tsvirkun, Yael Ben-Nun, Emmanuelle Merquiol, Rachela Popovtzer, Galia BlumX-ray computed tomography
(CT) is a robust, precise, fast, and
reliable imaging method that enables excellent spatial resolution
and quantification of contrast agents throughout the body. However,
CT is largely inadequate for molecular imaging applications due mainly
to its low contrast sensitivity that forces the use of large concentrations
of contrast agents for detection. To overcome this limitation, we
generated a new class of iodinated nanoscale activity-based probes
(IN-ABPs) that sufficiently accumulates at the target site by covalently
binding cysteine cathepsins that are exceptionally highly expressed
in cancer. The IN-ABPs are comprised of a short targeting peptide
selective to specific cathepsins, an electrophilic moiety that allows
activity-dependent covalent binding, and tags containing dendrimers
with up to 48 iodine atoms. IN-ABPs selectively bind and inhibit activity
of recombinant and intracellular cathepsin B, L, and S. We compared
the in vivo kinetics, biodistribution, and tumor accumulation of IN-ABPs
bearing 18 and 48 iodine atoms each, and their control counterparts
lacking the targeting moiety. Here we show that although both IN-ABPs
bind specifically to cathepsins within the tumor and produce detectable
CT contrast, the 48-iodine bearing IN-ABP was found to be optimal
with signals over 2.1-fold higher than its nontargeted counterpart.
In conclusion, this study shows the synthetic feasibility and potential
utility of IN-ABPs as potent contrast agents that enable molecular
imaging of tumors using CT.