Development of Novel ¹⁹¹Pt-Labeled Hoechst33258: ¹⁹¹Pt Is More Suitable than ¹¹¹In for Targeting DNA

Abstract

This study aims to establish new labeling methods for no-carrieradded radio-Pt ( 191 Pt) and to evaluate the in vitro properties of 191 Pt-labeled agents compared with those of agents labeled with the common emitter 111 In. 191 Pt was complexed with the DNA-targeting dye Hoechst33258 via diethylenetriaminepentaacetic acid (DTPA) or the sulfur-containing amino acid cysteine (Cys). The intranuclear fractions of 191 Pt-and 111 In-labeled Hoechst33258 were comparable, indicating that the labeling for 191 Pt via DTPA or Cys and the labeling for 111 In via DTPA worked equally well. 191 Pt showed a DNA-binding/cellular uptake ratio of more than 1 order of magnitude greater than that of 111 In. [ 191 Pt]Pt-Hoechst33258 labeled via Cys showed a higher cellular uptake than that labeled via DTPA, resulting in a very high DNA-binding fraction of [ 191 Pt]Pt-Cys-Hoechst33258 and extensive DNA damage. Our labeling methods of radio-Pt, especially via Cys, promote the development of radio-Pt-based agents for use in Auger electron therapy targeting DNA.

Novel Auger-Electron-Emitting 191Pt-Labeled Pyrrole–Imidazole Polyamide Targeting MYCN Increases Cytotoxicity and Cytosolic dsDNA Granules in MYCN-Amplified Neuroblastoma

“…High radiochemical yields and purities were achieved for the current 191 Pt-labeled compounds (Figure 2a). In a previous study, we obtained only a low radiochemical yield and purity for another 191 Pt-labeled compound via Cys because of the high reactivity of Pt toward the thiol group and the multivalent coordination of 191 Pt [11]. However, in the present study, changing the position of Cys in the compounds led to high radiochemical yields and purities for 191 Pt-MYCN-PIP and 191 Pt-GCC-PIP.…”

“…This ability has realized the Pt-based antineoplastic drugs widely used to treat various types of cancer [10]. A previous study observed that 191 Pt-labeled DNA intercalator Hoechst33258 exhibited better DNA-binding and damaging characteristics than 111 In-labeled Hoechst33258 as a common radionuclide [11]. Taken together, 191 Pt-labeled agents have a substantial advantage for use in DNA-targeting drugs.…”

“…We here designed a 191 Pt-labeled conjugate, 191 Pt-MYCN-PIP, based on the MYCN-targeting PIP as described above. The conjugate consists of the MYCN-targeting PIP [23] conjugated with cysteine (Cys) as the labeling site of 191 Pt [11], tri-arginine (R3) as a cell penetration module [24], and the fluorescent compound coumarin (Figure 1). 191 Pt-MYCN-PIP was synthesized, and its in vitro properties were evaluated in MYCN-amplified and -unamplified neuroblastoma models.…”

Targeted Molecular Imaging and Therapy Based on Nuclear and Optical Technologies

“…DNA damage can be induced by binding the Auger emitter Pt-191 directly to DNA. 15) Because Auger electrons have an extremely short radiation range, organellespecific damage can be induced.…”

Searching for a Paradigm Shift in Auger-Electron Cancer Therapy with Tumor-Specific Radiopeptides Targeting the Mitochondria and/or the Cell Nucleus

“…The influence of the proximity to DNA and accumulation in the cell nucleus on DNA damage and other radiobiological effects was thoroughly investigated for several other AE emitters, namely SPECT radiometals in clinical use such as 67 Ga, 111 In or 99m Tc or less common but more efficient AE emitters such as 195m Pt and 191 Pt [14,15]. For instance, Terry's group demonstrated how the DNA damage induced by 67 Ga and 111 In depends on their proximity to the DNA using a cell-free plasmid DNA assay [16,17].…”