|
内容記述 |
Aim/Introduction: Pt-191-labeled agents are promising candidates for DNA-targeted Auger electron cancer therapy, but there has yet to be an established drug design that enables targeting tumor DNA efficiently in vivo. Herein, we explored linker structures for 191Pt-labeled complexes targeting both tumor antigen and genomic DNA, and demonstrated DNA binding of novel 191Pt-labeled complexes in targeted tumors in vivo.Materials and Methods: We synthesized six different conjugates composed of a trithiol ligand for 191Pt labeling, Hoechst for DNA binding, and a glutamic acid–urea–lysine moiety for targeting prostate-specific membrane antigen (PSMA) (Trithiol-Hoechst-PSMA: THP1, 2-4, 2-8, 3-4, 3-8, 4). They contain different structures and lengths of linkers between either side of the trithiol ligand and Hoechst/the PSMA-targeted moiety. After 191Pt labeling, the DNA binding ability and PSMA targeting specificity of the [191Pt]Pt-THP complexes were evaluated in cell experiments, and their biodistribution was investigated in mice bearing tumors with/without PSMA expression. Finally, tumor DNA binding of [191Pt]Pt-THP3-4 and 3-8 was evaluated in vivo.Results: All six [191Pt]Pt-THP complexes were obtained with radiochemical yields of 60–80%, and 191Pt-labeled products were successfully separated from their precursors. [191Pt]Pt-THP3-4 and 3-8, in which Hoechst is on one side of the trithiol ligand across a linear PEG linker and the PSMA-targeted moiety on another side across a C4 linker, maintained PSMA targeting specificity and DNA binding ability in cultured cells than the other complexes. In vivo experiments for [191Pt]Pt-THP3-4 and 3-8 showed rapid drug clearance from normal organs and long retention in the kidneys and tumors expressing PSMA. Notably, the two complexes exhibited almost the same DNA binding ratio in PSMA-positive tumors in vivo as in the cultured cells.Conclusion: This study demonstrated that two novel 191Pt-labeled agents efficiently bind the genomic DNA of PSMA-positive tumors in vivo. Comparison of six different [191Pt]Pt-THP complexes suggests that two linkers (1) a PEG linker between the trithiol ligand and the Hoechst compound and (2) a C4 linker between the trithiol ligand and the PSMA ligand were crucial for delivering 191Pt-labeled complexes to tumor DNA. These findings would facilitate drug development using Pt radionuclide for radiopharmaceutical therapy, especially DNA-targeted Auger electron cancer therapy. |
