<sup>191</sup>Pt-labeled trithiol-Hoechst-PSMA: preliminary evaluation of conjugates designed for delivery to genomic DNA of PSMA-positive cancers.

Abstract

BackgroundSeveral platinum radionuclides, including 191Pt, are promising candidates for DNA-targeted Auger electron radiotherapy; however, effective compound designs are needed for this application. In this study, we developed six novel 191Pt-labeled compounds and evaluated their DNA-targeting properties in PSMA-positive tumors.ResultsSix trithiol-Hoechst-PSMA (THP) conjugates that consist of a trithiol ligand for 191Pt labeling, Hoechst33258 for DNA binding, and a PSMA-targeted moiety were synthesized and labeled with 191Pt, achieving radiochemical yields of 60-80%. The six [191Pt]Pt-THP compounds were evaluated for DNA-binding ability and PSMA targeting specificity in vitro, and biodistribution experiments were performed with five of the compounds in mice bearing subcutaneous PSMA-positive and PSMA-negative xenografts. Among them, [191Pt]Pt-THP3-4 and [191Pt]Pt-THP3-8, in which Hoechst33258 is linked on one side of the trithiol ligand via a linear PEG linker and the PSMA-targeting moiety is linked on the other side via a C4 linker, had the best properties. These compounds maintained higher PSMA targeting specificity and DNA-binding ability both in vitro and in vivo than the other [191Pt]Pt-THP compounds, exhibiting similar DNA binding in PSMA-positive PC3 PIP tumors in vivo as in the cultured cells from which the xenograft was derived.ConclusionsThis study highlighted the importance of the linkers between the three components (trithiol-Hoechst-PSMA) and demonstrated binding of intravenously administered [191Pt]Pt-THP3-4 and [191Pt]Pt-THP3-8 to DNA in PSMA-positive tumors. Our compound designs and findings could be a useful foundation for DNA-targeted Auger electron cancer therapy, especially with Pt radionuclides.