Trithiol ligand provides tumor-targeting <sup>191</sup>Pt-complexes with high molar activity and promising in vivo properties.
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2025-07
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The Auger electron-emitting radionuclide 191Pt is a promising candidate for radiopharmaceutical therapy. Herein, we explored novel labeling methods for 191Pt using thiol-containing ligands to improve the in vivo stability and targeting ability of 191Pt-labeled complexes.Methods
We synthesized dithiol-containing N2S2 and NS2 ligands, and a trithiol ligand, and then compared their radiochemical reactivity with 191Pt. [191Pt]Pt-trithiol was synthesized and its biodistribution was evaluated in mice and compared with free 191Pt. Finally, a 191Pt-trithiol complex targeting prostate-specific membrane antigen (PSMA): [191Pt]Pt-trithiol-PSMA was developed and evaluated in mice bearing tumor xenografts and compared with a 191Pt-complex labeled via monothiol-containing Cys ([191Pt]Pt-Cys-PSMA).Results
A comparison of N2S2, NS2, and trithiol showed that the trithiol ligand is the best for producing 191Pt-labeled compounds in high yield and as a single peak in preparative HPLC. Notably, the trithiol ligand made 191Pt-labeled compounds and precursors separatable, achieving 191Pt-labeled products with a high molar activity: 200-400 mCi/μmol (7.4-14.8 GBq/μmol) at EOS. Additionally, [191Pt]Pt-trithiol and [191Pt]Pt-trithiol-PSMA were stable in vivo with rapid clearance compared with free 191Pt and [191Pt]Pt-Cys-PSMA. [191Pt]Pt-trithiol-PSMA resulted in a low uptake in most normal organs and a high uptake in the kidneys and prostate cancer with PSMA expression.Conclusions
This study demonstrated that a labeling method with trithiol for Pt radionuclides achieves 191Pt-labeled products with high molar activity. 191Pt-trithiol-PSMA showed promising in vivo stability and tumor-targeting specificity, which should facilitate the pharmaceutical development of Pt radionuclides for radiopharmaceutical therapy, especially Auger electron cancer therapy.Type
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Obata, Honoka, Atsushi B Tsuji, Yutian Feng, Yongxiang Zheng, Hitomi Sudo, Aya Sugyo, Werner Tornow, Sean W Finch, et al. (2025). Trithiol ligand provides tumor-targeting <sup>191</sup>Pt-complexes with high molar activity and promising in vivo properties. Nuclear medicine and biology, 146-147. p. 109043. 10.1016/j.nucmedbio.2025.109043 Retrieved from https://hdl.handle.net/10161/34036.
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Scholars@Duke
Werner Tornow
My research interests are in experimental nuclear physics studies performed with beams of neutrons, photons and neutrinos. While the early focus was on polarization phenomena in few-body systems studied mainly with polarized neutrons first at the University of Tuebingen and later at TUNL (Triangle Universities Nuclear Laboratory at Duke University), subsequent activities include experiments in the broad field of weak-interaction nuclear physics.
In 1998 TUNL joined the KamLAND collaboration in Japan to pursue reactor antineutrino oscillation measurements. Supported by the U.S. Department of Energy (DOE), I was the principle investigator (PI) of TUNL’s effort in building the veto detector of KamLAND. At about the same time I became one of the four originators of the Majorana zero-neutrino double-beta decay experiment on 76Ge, which later received DOE funding and is now known as the MAJORANA DEMONSTRATOR. Simultaneously, my group performed two-neutrino double-beta decay experiments to excited states in the daughter nucleus at TUNL and at the Kimballton mine in Virginia. In 2011, the KamLAND detector was modified to search for the zero-neutrino double-beta decay of 136Xe, resulting in the currently most stringent lower limit of larger than 3.8 x 1026 years for the decay half-life time for any zero-neutrino double-beta decay candidate nucleus, corresponding to an effective neutrino mass in the range of 28 to 125 meV, depending on the adopted nuclear matrix element calculations.
When I started my 10-year tenure as Director of TUNL in 1996, the Duke University Free-Electron Laser Laboratory (DFFLL), funded at the time by the U.S. Air Force Medical Free-Electron Laser Program, was already collaborating with nuclear physics faculty at TUNL In November 1996 I was fortunate enough to detect the first high-energy photons produced via Compton backscattering of free-electron laser low-energy photons from electrons circulating in the Duke 1.1 GeV electron storage ring. This was the beginning of HIGS, the High-Intensity Gamma-ray Source (strictly speaking the notation “Gamma-ray” is somewhat misleading; the “Gamma-Rays” produced at HIGS are actually high-energy photons and do not originate from nuclei, as gamma-rays do). After years of work sufficient funding was raised from DOE and Duke University to upgrade HIGS and convert it into a Nuclear Physics research facility operated by TUNL. As a result, I had to enlarge my nuclear physics portfolio to now include many-body physics as well, in order to manage the research opportunity provided by this worldwide unique facility. Here, nuclear structure experiments performed with mono-energetic incident photons in the 2 to 15 MeV energy range were of special interest for the many users from all around the world.
After retiring from teaching at Duke University in 2011, my research focus at TUNL’s Tandem Accelerator Laboratory was on experiments with mono-energetic neutron beams in the 0.5 to 30 MeV energy range. Here, nuclear fission studies have played a major role for about 12 years. In addition, my research group performed measurements to help quantify the neutron-induced background in zero-neutrino double-beta decay searches on 76Ge, 130Te and 136Xe as well as in associated shielding materials, including 40Ar. Furthermore, we studied reactions of importance for the National Ignition Facility (NIF) to help better understand the complicated physics governing the plasma generated in inertial confinement fusion laser shots at Lawrence Livermore National Laboratory. All these activities were supported by the Stewardship Science Academic Alliances Program of DOE’s National Nuclear Security Administration (NNSA).
Michael Rod Zalutsky
The overall objective of our laboratory is the development of novel radioactive compounds for improving the diagnosis and treatment of cancer. This work primarily involves radiohalo-genation of biomolecules via site-specific approaches, generally via demetallation reactions. Radionuclides utilized for imaging include I-123, I-124 and F-18, the later two being of particular interest because they can be used for the quantification of biochemical and physiological processes in the living human through positron emission tomography. For therapy, astatine-211 decays by the emission of alpha-particles, a type of radiation considerably more cytotoxic that the beta-particles used in conventional endoradiotherapy. The range of At-211 alpha particles is only a few cell diameters, offering the possibility of extremely focal irradiation of malignant cells while leaving neighboring cells intact. Highlights of recent work include: a)
development of reagents for protein and peptide radioiodination that decrease deiodination in vivo by up to 100-fold, b) demonstration that At-211 labeled monoclonal antibodies are effective in the treatment of a rat model of neoplastic meningitis, c) synthesis of a thymidine analogue labeled with At-211 and the demonstration that this molecule is taken up in cellular DNA with highly cytotoxicity even at levels of only one atom bound per cell and d) development of
radiohalobenzylguanidines which are specifically cytotoxic for human neuroblastoma cells.
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