Whole-body PET tracking of a D-dodecapeptide and its radiotheranostic potential for PD-L1 overexpressing tumors

Peptides that are composed of dextrorotary (D)-amino acids have gained increasing attention as a potential therapeutic class. However, our understanding of the in vivo fate of D-peptides is limited. This highlights the need for whole-body, quantitative tracking of D-peptides to better understand how they interact with the living body. Here, we used mouse models to track the movement of a programmed death-ligand 1 (PD-L1)-targeting D-dodecapeptide antagonist (DPA) using positron emission tomography (PET). More specifically, we profiled the metabolic routes of [Cu-64]DPA and investigated the tumor engagement of [Cu-64/Ga-68]DPA in mouse models. Our results revealed that intact [Cu-64/Ga-68]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors. Moreover, a single dose of [Cu-64]DPA effectively delayed tumor growth and improved the survival of mice. Collectively, these results not only deepen our knowledge of the in vivo fate of D-peptides, but also underscore the utility of D-peptides as radiopharmaceuticals. (C) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.