期刊
MOLECULAR PHARMACEUTICS
卷 15, 期 9, 页码 3946-3952出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.8b00399
关键词
PD-1; NSCLC; peptide; TNBC; immune checkpoint therapy
资金
- Allegheny Health Network Johns Hopkins Cancer Research Fund
- NIH [R01CA16631, P30 CA006973, R01CA236616, P41 EB024495]
Tumors create and maintain an immunosuppressive microenvironment that promotes cancer cell escape from immune surveillance. The immune checkpoint protein programmed death-ligand 1 (PD-L1) is expressed in many cancers and is an important contributor to the maintenance of the immunosuppressive tumor microenvironment. PD-L1 is a prominent target for cancer immunotherapy. Guidance of anti-PD-L1 therapy is currently effected through measurement of PD-L1 through biopsy and immunohistochemistry. Here, we report a peptide-based imaging agent, [Ga-68]WL2, to detect PD-L1 expression in tumors noninvasively by positron emission tomography (PET). WL12, a cyclic peptide comprising 14 amino acids, binds to PD-L1 with high affinity (IC50 approximate to 23 nM). Synthesis of [Ga-68]WL12 provided radiochemical purity >99% after purification. Biodistribution in immunocompetent mice demonstrated 11.56 +/- 3.18, 4.97 +/- 0.8, 1.9 +/- 0.1, and 1.33 +/- 0.21 percentage of injected dose per gram (%ID/g) in hPD-L1, MDAMB231, SUM149, and CHO tumors, respectively, at 1 h postinjection, with high binding specificity noted with coinjection of excess, nonradiolabeled WL12. PET imaging demonstrated high tissue contrast in all tumor models tested.
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