## 4 Past and Ongoing Biomedical Activities at ISOLDE/Biomedical Research Performed at ISOLDE
### Ongoing Research  
Present bio-medical activities at ISOLDE are focused on further tests of the feasibility of the Tb isotopes for tumor imaging and radionuclide therapy, as well as fundamental research in the field of bioinorganic and conjugation chemistry and the relationship between molecule parameters and the biological response or heavy metal toxicity.  
In 2012, two independent research groups studied the feasibility of using different Tb isotopes (\({}^{149}\)Tb, \({}^{152}\)Tb, \({}^{155}\)Tb and \({}^{161}\)Tb) for imaging and tumor targeted systemic therapy. [PERSON] and co-workers examined the _in vivo_ distribution of the \({}^{152}\)Tb labelled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-RM6 conjugate in severe combined immunodeficiency (SCID) mice bearing the human prostate cancer PC-3. The results of these studies will be published elsewhere. [PERSON] _et al_. [25,26] carried out the proof-of-concept study of all four Tb isotopes in order to evaluate their possible diagnostic and therapeutic aspects. For the purpose of these studies \({}^{149}\)Tb, \({}^{152}\)Tb and \({}^{155}\)Tb were produced from the Ta-foil target at ISOLDE. The isotopes were implanted into a zinc-coated foil. \({}^{161}\)Tb was produced either by 2-3 weeks of irradiation of the highly enriched \({}^{160}\)Gd targets with neutrons at the spallation neutron source (SINQ) at the Paul Scherrer Institute (PSI) in Villigen, Switzerland, or by one week of irradiation at the high-flux nuclear reactor at the Institut Laue-Langevin (ILL) in Grenoble, France. All isotopes were then purified by cation-exchange chromatography column and linked to the DOTA-folate conjugate, cm09, and injected into KB-tumor bearing nude mice. The results obtained during these studies confirm excellent tumor visualization in PET (\({}^{152}\)Tb) and SPECT (\({}^{155}\)Tb), as well as the good therapeutic effectiveness of \({}^{149}\)Tb and \({}^{161}\)Tb for \(\alpha\)- and \(\beta\)-therapy, respectively.  
The first biophysics activities at ISOLDE are dated to more than 20 years ago, when in November, 1990, [PERSON] and [PERSON] performed preliminary experiments with \({}^{199m}\)Hg bound to ascorbate oxidase and increase using the perturbed angular correlation of \(\gamma\)-rays (PAC) spectroscopy technique [27]. \({}^{199m}\)Hg was collected into ice hosted by a small Cu sample-holder and kept at approximately 100 K in order to guarantee the vacuum in the beam line. After the implantation, the activated ice was thawed slowly in the fume hood located in the off-line laboratory and added to a solution containing the proteins. The obtained results demonstrated unambiguously that PAC spectroscopy can be applied to study biological samples [28,29]. These studies were then followed by several successful experimental campaigns, and the research was extended to other isotopes, such as \({}^{111m}\)Cd [30, 31, 32, 33]. In early 2006, the project was taken over by the biophysics and bioinorganic chemistry groups from the University of Copenhagen, Denmark, led by [PERSON]. The major focus of the research was continuously kept on investigating the metal ion behavior at the molecular level and under physiological conditions and on the heavy-metal ion toxicity of Hg(II), Pb(II) and Cd(II) metal ions [34, 35, 36]. In addition, the year 2012 was particularly successful for the biophysics collaboration, because a new apparatus allowing for \(\beta\)-NMR experiments on liquid samples was finally established at ISOLDE and tried in the world's first experiments in an ionic liquid. The results of this study will soon be published elsewhere [37].