Purpose
The prostate-specific membrane antigen (PSMA) has emerged as an interesting target for radionuclide therapy of metastasized castration-resistant prostate cancer (mCRPC). The aim of this study ...was to investigate
161
Tb (T
1/2
= 6.89 days; Eβ
͞
av
= 154 keV) in combination with PSMA-617 as a potentially more effective therapeutic alternative to
177
Lu-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile.
Methods
161
Tb was used for the radiolabeling of PSMA-617 at high specific activities up to 100 MBq/nmol.
161
Tb-PSMA-617 was tested in vitro and in tumor-bearing mice to confirm equal properties, as previously determined for
177
Lu-PSMA-617. The effects of
161
Tb-PSMA-617 and
177
Lu-PSMA-617 on cell viability (MTT assay) and survival (clonogenic assay) were compared in vitro using PSMA-positive PC-3 PIP tumor cells.
161
Tb-PSMA-617 was further investigated in therapy studies using PC-3 PIP tumor-bearing mice.
Results
161
Tb-PSMA-617 and
177
Lu-PSMA-617 displayed equal in-vitro properties and tissue distribution profiles in tumor-bearing mice. The viability and survival of PC-3 PIP tumor cells were more reduced when exposed to
161
Tb-PSMA-617 as compared to the effect obtained with the same activities of
177
Lu-PSMA-617 over the whole investigated concentration range. Treatment of mice with
161
Tb-PSMA-617 (5.0 MBq/mouse and 10 MBq/mouse, respectively) resulted in an activity-dependent increase of the median survival (36 vs 65 days) compared to untreated control animals (19 days). Therapy studies to compare the effects of
161
Tb-PSMA-617 and
177
Lu-PSMA-617 indicated the anticipated superiority of
161
Tb over
177
Lu.
Conclusion
161
Tb-PSMA-617 showed superior in-vitro and in-vivo results as compared to
177
Lu-PSMA-617, confirming theoretical dose calculations that indicate an additive therapeutic effect of conversion and Auger electrons in the case of
161
Tb. These data warrant more preclinical research for in-depth investigations of the proposed concept, and present a basis for future clinical translation of
161
Tb-PSMA-617 for the treatment of mCRPC.
Synthetic molecular machines hold tremendous potential to revolutionize chemical and materials sciences. Their autonomous motion controlled by external stimuli allows to develop smart materials whose ...properties can be adapted on command. For the realisation of more complex molecular machines, it is crucial to design building blocks whose properties can be controlled by multiple orthogonal stimuli. A major challenge is to reversibly switch from forward to backward and again forward light-driven rotary motion using external stimuli. Here we report a push-pull substituted photo-responsive overcrowded alkene whose function can be toggled between that of a unidirectional 2
generation rotary motor and a molecular switch depending on its protonation and the polarity of its environment. With its simplicity in design, easy preparation, outstanding stability and orthogonal control of distinct forward and backward motions, we believe that the present concept paves the way for creating more advanced molecular machines.
The aim of this review is to make the reader familiar with currently available radiometals, their production modes, capacities, and quality concerns related to their medical use, as well as new ...emerging radiometals and irradiation technologies from the perspective of their diagnostic and theranostic applications. Production methods of 177Lu serve as an example of various issues related to the production yield, specific activity, radionuclidic and chemical purity, and production economy. Other radiometals that are currently used or explored for potential medical applications, with particular focus on their theranostic value, are discussed. Using radiometals for diagnostic imaging and therapy is on the rise. The high demand for radiometals for medical use prompts investigations towards using alternative irradiation reactions, while using existing nuclear reactors and accelerator facilities. This review discusses these production capacities and what is necessary to cover the growing demand for theranostic nuclides.
Using radiometals for diagnostic imaging and therapy is on the rise. New emerging radiometals and irradiation technologies are expected to cover the growing demand for theranostic nuclides.
Abstract
We report on the delithiation of LiCoO
2
thin films using oxalic acid (C
2
H
2
O
4
) with the goal of understanding the structural degradation of an insertion oxide associated with Li ...chemical extraction. Using a multi-technique approach that includes synchrotron radiation X-ray diffraction, scanning electron microscopy, micro Raman spectroscopy, photoelectron spectroscopy and conductive atomic force microscopy we reveal the balance between selective Li extraction and structural damage. We identify three different delithiation regimes, related to surface processes, bulk delithiation and damage generation. We find that only a fraction of the grains is affected by the delithiation process, which may create local inhomogeneities. However, the bulk delithiation regime is effective to delithiate the LCO film. All experimental evidence collected indicates that the delithiation process in this regime mimics the behavior of LCO upon electrochemical delithiation. We discard the formation of Co oxalate during the chemical extraction process. In conclusion, the chemical route to Li extraction provides additional opportunities to investigate delithiation while avoiding the complications associated with electrolyte breakdown and simplifying in-situ measurements.
Purpose
The β
¯
-emitting terbium-161 also emits conversion and Auger electrons, which are believed to be effective in killing single cancer cells. Terbium-161 was applied with somatostatin receptor ...(SSTR) agonists that localize in the cytoplasm (DOTATOC) and cellular nucleus (DOTATOC-NLS) or with a SSTR antagonist that localizes at the cell membrane (DOTA-LM3). The aim was to identify the most favorable peptide/terbium-161 combination for the treatment of neuroendocrine neoplasms (NENs).
Methods
The capability of the
161
Tb- and
177
Lu-labeled somatostatin (SST) analogues to reduce viability and survival of SSTR-positive AR42J tumor cells was investigated in vitro. The radiopeptides’ tissue distribution profiles were assessed in tumor-bearing mice. The efficacy of terbium-161 compared to lutetium-177 was investigated in therapy studies in mice using DOTATOC or DOTA-LM3, respectively.
Results
In vitro,
161
TbTb-DOTA-LM3 was 102-fold more potent than
177
LuLu-DOTA-LM3; however,
161
Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their
177
Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that
161
TbTb-DOTA-LM3 was significantly more effective in delaying tumor growth than
177
LuLu-DOTA-LM3, thereby, prolonging survival of the mice. A therapeutic advantage of terbium-161 over lutetium-177 was also manifest when applied with DOTATOC. Since the nuclear localizing sequence (NLS) compromised the in vivo tissue distribution of DOTATOC-NLS, it was not used for therapy.
Conclusion
The use of membrane-localizing DOTA-LM3 was beneficial and profited from the short-ranged electrons emitted by terbium-161. Based on these preclinical data,
161
TbTb-DOTA-LM3 may outperform the clinically employed
177
LuLu-DOTATOC for the treatment of patients with NENs.
Terbium-149 (T
= 4.1 h, E
= 3.98 MeV (16.7%), 28 µm range in tissue) is a radionuclide with potential for targeted alpha therapy. Due to the negligible emission of α-emitting daughter nuclides, ...toxicity to healthy tissue may be reduced in comparison with other α-particle emitters. In this study, terbium-149 was produced via 1.4 GeV proton irradiation of a tantalum target at the CERN-ISOLDE facility. The spallation products were mass separated and implanted on zinc-coated foils and, later, radiochemically processed. Terbium-149 was separated from the co-produced isobaric radioisotopes and the zinc coating from the implantation foil, using cation-exchange and extraction chromatographic techniques, respectively. At the end of separation, up to 260 MBq terbium-149 were obtained with > 99% radionuclidic purity. Radiolabeling experiments were performed with DOTATATE, achieving 50 MBq/nmol apparent molar activity with radiochemical purity > 99%. The chemical purity was determined by inductively coupled plasma-mass spectrometry measurements, which showed lead, copper, iron and zinc only at ppb level. The radiolabeling of the somatostatin analogue DOTATATE with
TbTbCl
and the subsequent in vivo PET/CT scans conducted in xenografted mice, showing good tumor uptake, further demonstrated product quality and its ability to be used in a preclinical setting.
Developments throughout the history of nuclear medicine have involved improvements in both instrumentation and radionuclides, which have been intertwined. Instrumentation developments always occurred ...during the search to improving devices' sensitivity and included advances in detector technology (with the introduction of cadmium zinc telluride and digital Positron Emission Tomography-PET-devices with silicon photomultipliers), design (total body PET) and configuration (ring-shaped, Single-Photon Emission Computed Tomography (SPECT), Compton camera). In the field of radionuclide development, we observed the continual changing of clinically used radionuclides, which is sometimes influenced by instrumentation technology but also driven by availability, patient safety and clinical questions. Some areas, such as tumour imaging, have faced challenges when changing radionuclides based on availability, when this produced undesirable clinical findings with the introduction of unclear focal uptakes and unspecific uptakes. On the other end of spectrum, further developments of PET technology have seen a resurgence in its use in nuclear cardiology, with rubidium-82 from strontium-82/rubidium-82 generators being the radionuclide of choice, moving away from SPECT nuclides thallium-201 and technetium-99m. These continuing improvements in both instrumentation and radionuclide development have helped the growth of nuclear medicine and its importance in the ever-evolving range of patient care options.
The favorable decay characteristics of 161Tb attracted the interest of clinicians in using this novel radionuclide for radioligand therapy (RLT). 161Tb decays with a similar half-life to 177Lu, but ...beyond the emission of β−-particles and γ-rays, 161Tb also emits conversion and Auger electrons, which may be particularly effective to eliminate micrometastases. The aim of this study was to compare the dosimetry and therapeutic efficacy of 161Tb and 177Lu in tumor-bearing mice using SibuDAB and PSMA-I&T, which differ in their blood residence time and tumor uptake. Methods: 161TbTb-SibuDAB and 161TbTb-PSMA-I&T were evaluated in vitro and investigated in biodistribution, imaging, and therapy studies using PC-3 PIP tumor–bearing mice. The 177Lu-labeled counterparts served for dose calculations and comparison of therapeutic efficacy. The tolerability of RLT in mice was monitored on the basis of body mass, blood plasma parameters, blood cell counts, and the histology of relevant organs and tissues. Results: The prostate-specific membrane antigen (PSMA)–targeting radioligands, irrespective of whether labeled with 161Tb or 177Lu, showed similar in vitro data and comparable tissue distribution profiles. As a result of the albumin-binding properties, 161TbTb/177LuLu-SibuDAB had an enhanced blood residence time and higher tumor uptake (62%–69% injected activity per gram at 24 h after injection) than 161TbTb/177LuLu-PSMA-I&T (30%–35% injected activity per gram at 24 h after injection). 161TbTb-SibuDAB inhibited tumor growth more effectively than 161TbTb-PSMA-I&T, as can be ascribed to its 4-fold increased absorbed tumor dose. At any of the applied activities, the 161Tb-based radioligands were therapeutically more effective than their 177Lu-labeled counterparts, as agreed with the approximately 40% increased tumor dose of 161Tb compared with that of 177Lu. Under the given experimental conditions, no obvious adverse events were observed. Conclusion: The data of this study indicate the promising potential of 161Tb in combination with SibuDAB for RLT of prostate cancer. Future clinical studies using 161Tb-based RLT will shed light on a potential clinical benefit of 161Tb over 177Lu.
44Sc is a promising radionuclide for positron emission tomography (PET) in nuclear medicine. As a part of the implementation of a production site for 44Sc, precise knowledge of the activity of the ...product is necessary. At the Paul Scherrer Institute (PSI) and the University of Bern (UniBE), 44Sc is produced by enriched 44CaO-target irradiation with a cyclotron. The two sites use different techniques for activity measurement, namely a dose calibrator at the PSI and a gamma-ray spectrometry system at UniBE and PSI. In this work, the 44Sc was produced at the PSI, and samples of the product were prepared in dedicated containers for onsite measurements at PSI, UniBE, and the Institute of Radiation Physics (IRA) in Lausanne for precise activity measurement using primary techniques and for the calibration of the reference ionization chambers. An accuracy of 1% was obtained for the activity measurement, allowing for a precise calibration of the dose calibrator and gamma-ray spectrometry of the two production sites. Each production site now has the capability of measuring 44Sc activity with an accuracy of 2%.
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