@misc{oai:repo.qst.go.jp:00082983,
 author = {Kuan, Hu and Lin, Xie and Zhang, Yiding and Masayuki, Hanyu and Zhang, Ming-Rong and Kuan, Hu and Lin, Xie and Zhang, Yiding and Masayuki, Hanyu and Zhang, Ming-Rong},
 month = {Jun},
 note = {Introduction: D-peptides are hyper-resistant to proteolytic degradation in L-homochiral living subjects, making them remarkedly increased gut, blood plasma, and intracellular half-lives. D-peptides are theoretically ideal drug candidates, however, there still exist many uncertainties associated with D-peptides regarding their in vivo fate and metabolism profiles. No research thus far paid special attention on exploring the authentic in vivo profiles of D-peptides. In this work, we report the tracking of a programmed death-ligand 1 (PD-L1) targeting D-dodecapeptide antagonist (DPA) and its target engagement inside normal and tumor-bearing mice using PET. 
Methods: To monitor the in vivo behavior of [64Cu]DPA in the living animal, we performed dynamic PET in normal C57BL/6J mice from 0 to 60 min following intravenous injection (i.v.) of [64Cu]DPA. To comprehensively profile the in vivo distribution of the tracer, ex vivo distribution was carried out in C57BL/6J mice. After that, we used [64Cu]DPA to image PD-L1 in B16F10 tumor-bearing mice. We also performed PET imaging in glioblastoma tumors to generalize [64Cu]DPA PET for gauging PD-L1 expression. To examine the therapeutic effect of [64Cu]DPA in U87MG tumors, we administrated [64Cu]DPA (⁓2 mCi per mouse) to mice intravenously on day 6 of post tumor inoculation. Finally, to assess the toxicity of [64Cu]DPA, we injected normal mice with a single dose of 3 mCi per mouse.
Results: [64Cu]DPA is very hydrophilic based on its cLogD. The PET and ex vivo biodistribution studies revealed that intact [64Cu]DPA is majorly excreted by the kidney. Strong tracer accumulation in B16F10 tumors was observed in both small and large tumors at 30, 60, and 80 min p.i. The highest radioactivity in both groups appeared in the kidney and bladder, and non-striking radioactivity was noticed in other tissues, such as the liver and lung. In the U87MG model, a strong tracer accumulation in the tumor was observed at 60 min p.i. The mice bearing U87MG tumors treated with [64Cu]DPA displayed remarkably delayed tumor growth compared to the control group. Specifically, on day 13 of postinjection, the average tumor volume of mice in the treated cohort (431.9 mm3) was significantly smaller than that in the control cohort (1393.1 mm3; p<0.0001). Simultaneously, the survival of mice treated with [64Cu]DPA was largely improved. Tumor tissues from the [64Cu]DPA treated mice revealed a significantly lower Ki67 positive rate (5%) than that from the control mice (67%). Mice treated with 3 mCi [64Cu]DPA per mouse showed no body weight loss and hematological changes. No sign of tissue injury was observed in the heart, lung, liver, and spleen from H&E staining.
Conclusion: We have studied the metabolism profile, target engagement, and therapeutic potential of [64Cu]DPA in living animals. These results dramatically deepen our understanding of the in vivo properties of D-peptides. This study also provides a paradigmatic model that is generally applicable to other D-peptides to explore their in vivo behavior. The acquired insights into DPA’s in vivo performance offer valuable reference to design ideal D-peptide drugs. Moreover, our study paves the way for exploiting D-peptides as radiopharmaceuticals to manage cancer, both as PET tracers and radiotheranostics agents., SNMMI2021},
 title = {Whole-body PET Tracking of a D-dodecapeptide and its Radiotheranostic Potential for PD-L1 overexpressed tumors},
 year = {2021}
}