posted on 2020-06-19, 14:33authored byMengzhe Wang, Hui Wang, Crystal Q. Niu, Tao Zhang, Zhanhong Wu, Zibo Li
Targeted imaging
via peptides has been extensively investigated
for both diagnostic and therapeutic applications. However, peptides
can be cleared out from the blood circulation quickly, leading to
only moderate to low accumulation in regions of interest. Previously, 18F-sTCO-DiPhTz-RGDyK demonstrated relatively high blood retention
with increased tumor uptake at the late time point (5.3 ± 0.4
and 8.9 ± 0.5%ID/g tumor uptake at 1 h p.i. and 4 h p.i., respectively).
In this study, we aim to develop a novel platform based on TCO/tetrazine
ligation that could be used not only to label the peptides with F-18
for PET but also to lead to increased or persistent tumor uptake potentially
due to enhanced blood circulation of the labeled peptides. We first
constructed systems containing different combinations of TCOs/tetrazines
and found that the tetrazine moiety played a more important role to
facilitate the enhanced blood circulation compared with TCO moiety.
Four clinically relevant peptides including NT20.3, RGD, BBN, and
exendin-4 were then evaluated, and the increased tumor uptake at a
late time point was demonstrated by the combination of 18F-sTCO-DiPhTz system to NT20.3, RGD, and exendin-4. The plasma binding
components of the PET agents were investigated by electrophoresis
and autoradiography and indicated that transferrin and hemopexin could
be the major proteins in blood plasma for binding with 18F-sTCO-DiPhTz conjugates. In summary, we have discovered a TCO/tetrazine
system that could not only be used for PET probe construction but
also potentially improve the tumor uptake and retention of fast-clearing
peptides. Although additional binding experiments are still needed
for some of the constructs, the promising preliminary result suggested
that this strategy may be used to convert fast-clearing bioligands
into relatively long circulating agents with enhanced tumor uptake/retention
for either imaging or therapy applications.