Terbium offers 4 clinically interesting radioisotopes with complementary physical decay characteristics: ¹⁴⁹Tb, ¹⁵²Tb, ¹⁵⁵Tb, and ¹⁶¹Tb. The identical chemical characteristics of these radioisotopes allow the preparation of radiopharmaceuticals with identical pharmacokinetics useful for PET (¹⁵²Tb) and SPECT diagnosis (¹⁵⁵Tb) and for α- (¹⁴⁹Tb) and β⁻-particle (¹⁶¹Tb) therapy. The goal of this proof-of-concept study was to produce all 4 terbium radioisotopes and assess their diagnostic and therapeutic features in vivo when labeled with a folate-based targeting agent. Methods: ¹⁶¹Tb was produced by irradiation of ¹⁶⁰Gd targets with neutrons at Paul Scherrer Institute or Institut Laue-Langevin. After neutron capture, the short-lived ¹⁶¹Gd decays to ¹⁶¹Tb. ¹⁴⁹Tb, ¹⁵²Tb, and ¹⁵⁵Tb were produced by proton-induced spallation of tantalum targets, followed by an online isotope separation process at ISOLDE/CERN. The isotopes were purified by means of cation exchange chromatography. For the in vivo studies, we used the DOTA–folate conjugate cm09, which binds to folate receptor (FR)–positive KB tumor cells. Therapy experiments with ¹⁴⁹Tb-cm09 and ¹⁶¹Tb-cm09 were performed in KB tumor–bearing nude mice. Diagnostic PET/CT (¹⁵²Tb-cm09) and SPECT/CT (¹⁵⁵Tb-cm09 and ¹⁶¹Tb-cm09) studies were performed in the same tumor mouse model. Results: Carrier-free terbium radioisotopes were obtained after purification, with activities ranging from approximately 6 MBq (for ¹⁴⁹Tb) to approximately 15 GBq (for ¹⁶¹Tb). The radiolabeling of cm09 was achieved in a greater than 96% radiochemical yield for all terbium radioisotopes. Biodistribution studies showed high and specific uptake in FR-positive tumor xenografts (23.8% ± 2.5% at 4 h after injection, 22.0% ± 4.4% at 24 h after injection, and 18.4% ± 1.8% at 48 h after injection). Excellent tumor-to-background ratios at 24 h after injection (tumor to blood, ∼15; tumor to liver, ∼5.9; and tumor to kidney, ∼0.8) allowed the visualization of tumors in mice using PET (¹⁵²Tb-cm09) and SPECT (¹⁵⁵Tb-cm09 and ¹⁶¹Tb-cm09). Compared with no therapy, α- (¹⁴⁹Tb-cm09) and β⁻-particle therapy (¹⁶¹Tb-cm09) resulted in a marked delay in tumor growth or even complete remission (33% for ¹⁴⁹Tb-cm09 and 80% for ¹⁶¹Tb-cm09) and a significantly increased survival. Conclusion: For the first time, to our knowledge, 4 terbium radionuclides have been tested in parallel with tumor-bearing mice using an FR targeting agent. Along with excellent tumor visualization enabled by ¹⁵²Tb PET and ¹⁵⁵Tb SPECT, we demonstrated the therapeutic efficacy of the α-emitter ¹⁴⁹Tb and β⁻-emitter ¹⁶¹Tb.

Based on the clinical success of platinum-based anti-cancer drugs such as cisplatin, carboplatin and oxaliplatin, a variety of other metal-based anti-cancer compounds are being investigated. In particular, a number of ruthenium-based compounds have been identified which exhibit unique biochemical properties and reduced toxicity profiles compared to the clinically used platinum-based drugs. We have developed a series of organometallic ruthenium(II)-arene complexes that were shown to exert anti-metastatic activity with relatively minor activity on primary tumor growth. Here, we show that the prototype compound, [Ru(η⁶-p-cymene)Cl₂(pta)], where pta = 1,3,5-triaza-7-phosphaadamantane (RAPTA-C), reduces the growth of primary tumors in preclinical models for ovarian and colorectal carcinomas. When administered daily at relatively low doses (0.2 mg kg⁻¹), RAPTA-C was shown to significantly reduce the growth of the A2780 ovarian carcinoma transplanted onto the chicken chorioallantoic membrane model. Similar activity was observed in LS174T colorectal carcinoma in athymic mice, albeit at a higher dose. In both models, a clear inhibition of microvessel density was observed, confirming the previously discovered anti-angiogenic mechanism of RAPTA-C. Biodistribution studies with radiolabeled (¹⁰³Ru) RAPTA-C indicate that the compound is rapidly cleared from the organs and the bloodstream through excretion by the kidneys. As such, RAPTA-C is a promising compound for translation to clinical evaluation.

Summary: Dietary restriction (DR) extends lifespan and increases resistance to multiple forms of stress, including ischemia reperfusion injury to the brain and heart in rodents. While maximal effects on lifespan require long‐term restriction, the kinetics of onset of benefits against acute stress is not known. Here, we show that 2–4 weeks of 30% DR improved survival and kidney function following renal ischemia reperfusion injury in mice. Brief periods of water‐only fasting were similarly effective at protecting against ischemic damage. Significant protection occurred within 1 day, persisted for several days beyond the fasting period and extended to another organ, the liver. Protection by both short‐term DR and fasting correlated with improved insulin sensitivity, increased expression of markers of antioxidant defense and reduced expression of markers of inflammation and insulin/insulin‐like growth factor‐1 signaling. Unbiased transcriptional profiling of kidneys from mice subject to short‐term DR or fasting revealed a significant enrichment of signature genes of long‐term DR. These data demonstrate that brief periods of reduced food intake, including short‐term daily restriction and fasting, can increase resistance to ischemia reperfusion injury in rodents and suggest a rapid onset of benefits of DR in mammals.

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 ¹⁶¹Tb (T_1/2 = 6.89 days; Eβ^͞_av = 154 keV) in combination with PSMA-617 as a potentially more effective therapeutic alternative to ¹⁷⁷Lu-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile.

In recent years, ⁴⁷Sc has attracted attention because of its favorable decay characteristics (half-life, 3.35 d; average energy, 162 keV; Eγ, 159 keV) for therapeutic application and for SPECT imaging. The aim of the present study was to investigate the suitability of ⁴⁷Sc for radionuclide therapy in a preclinical setting. For this purpose a novel DOTA-folate conjugate (cm10) with an albumin-binding entity was used. Methods: ⁴⁷Sc was produced via the ⁴⁶Ca(n,γ)⁴⁷Ca ⁴⁷Sc nuclear reaction at the high-flux reactor at the Institut Laue-Langevin. Separation of the ⁴⁷Sc from the target material was performed by a semi-automated process using extraction chromatography and cation exchange chromatography. ⁴⁷Sc-labeled cm10 was tested on folate receptor–positive KB tumor cells in vitro. Biodistribution and SPECT imaging experiments were performed in KB tumor–bearing mice. Radionuclide therapy was conducted with two groups of mice, which received either ⁴⁷Sc-cm10 (10 MBq) or only saline. Tumor growth and survival time were compared between the two groups of mice. Results: Irradiation of ⁴⁶Ca resulted in approximately 1.8 GBq of ⁴⁷Ca, which subsequently decayed to ⁴⁷Sc. Separation of ⁴⁷Sc from ⁴⁷Ca was obtained with 80% yield in only 10 min. The ⁴⁷Sc was then available in a small volume (∼500 μL) of an ammonium acetate/HCl (pH 4.5) solution suitable for direct radiolabeling. ⁴⁷Sc-cm10 was prepared with a radiochemical yield of more than 96% at a specific activity of up to 13 MBq/nmol. In vitro ⁴⁷Sc-cm10 showed folate receptor–specific binding and uptake into KB tumor cells. In vivo SPECT/CT images allowed the visualization of accumulated radioactivity in KB tumors and in the kidneys. The therapy study showed a significantly delayed tumor growth in mice, which received ⁴⁷Sc-cm10 (10 MBq, 10 Gy) resulting in a more than 50% increase in survival time, compared with untreated control mice. Conclusion: With this study, we demonstrated the suitability of using ⁴⁷Sc for therapeutic purposes. On the basis of our recent results obtained with ⁴⁴Sc-folate, the present work confirms the applicability of ⁴⁴Sc/⁴⁷Sc as an excellent matched pair of nuclides for PET imaging and radionuclide therapy.

The folate receptor (FR) has proven a valuable target for nuclear imaging using folic acid radioconjugates. However, using folate-based radiopharmaceuticals for therapy has long been regarded as an unattainable goal because of their considerable renal accumulation. Herein, we present a novel strategy in which a DOTA–folate conjugate with an albumin-binding entity (cm09) was designed with the aim of prolonging circulation in the blood and therewith potentially improving tumor-to-kidney ratios. Methods: The folate conjugate cm09 was radiolabeled with ¹⁷⁷LuCl₃, and stability experiments were performed in plasma. Cell uptake studies were performed on FR-positive KB tumor cells, and an ultrafiltration assay was used to determine the plasma protein–binding properties of ¹⁷⁷Lu-cm09. In vivo, ¹⁷⁷Lu-cm09 was tested in KB tumor–bearing mice using SPECT/CT. The therapeutic anticancer effect of ¹⁷⁷Lu-cm09 (20 MBq) applied as a single injection or as fractionated injections was investigated in different groups of mice (n = 5) by monitoring tumor size and the survival time of treated mice, compared with untreated controls. Results: Compound cm09 was radiolabeled at a specific activity of 40 MBq/nmol, a radiochemical yield of more than 98%, and a stability of more than 99% over 5 d in plasma. Ultrafiltration revealed significant binding of ¹⁷⁷Lu-cm09 to serum proteins (∼91%) in plasma, compared with folate radioconjugate without an albumin-binding entity. Cell uptake and internalization of ¹⁷⁷Lu-cm09 was FR-specific and comparable to other folate radioconjugates. In vivo studies resulted in high tumor uptake (17.56 percentage injected dose per gram [%ID/g] at 4 h after injection), which was almost completely retained for at least 72 h. Renal accumulation was significantly reduced (28 %ID/g at 4 h after injection), compared with folate conjugates that lack an albumin-binding entity (∼70 %ID/g at 4 h after injection). These circumstances enabled SPECT imaging of excellent quality. Radionuclide therapy (1 × 20 MBq) revealed complete remission of tumors in 4 of 5 cases and a significantly prolonged survival time, compared with untreated controls. Conclusion: The modification of a folate radioconjugate with an albumin-binding entity resulted in a significant increase of the tumor-to-kidney ratio of radioactivity, enabling for the first time, to our knowledge, the preclinical application of folic acid–targeted radionuclide therapy in mice.