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Targeted radionuclide therapy with 177Lu- and 90Y-labeled radioconjugates is a clinically-established treatment modality for metastasized cancer. 47Sc is a therapeutic radionuclide that decays with a half-life of 3.35 days and emits medium-energy β−-particles. In this study, 47Sc was investigated, in combination with a DOTA-folate conjugate, and compared to the therapeutic properties of 177Lu-folate and 90Y-folate, respectively. In vitro, 47Sc-folate demonstrated effective reduction of folate receptor-positive ovarian tumor cell viability similar to 177Lu-folate, but 90Y-folate was more potent at equal activities due to the higher energy of emitted β−-particles. Comparable tumor growth inhibition was observed in mice that obtained the same estimated absorbed tumor dose (~21 Gy) when treated with 47Sc-folate (12.5 MBq), 177Lu-folate (10 MBq), and 90Y-folate (5 MBq), respectively. The treatment resulted in increased median survival of 39, 43, and 41 days, respectively, as compared to 26 days in untreated controls. There were no statistically significant differences among the therapeutic effects observed in treated groups. Histological assessment revealed no severe side effects two weeks after application of the radiofolates, even at double the activity used for therapy. Based on the decay properties and our results, 47Sc is likely to be comparable to 177Lu when employed for targeted radionuclide therapy. It may, therefore, have potential for clinical translation and be of particular interest in tandem with 44Sc or 43Sc as a diagnostic match, enabling the realization of radiotheragnostics in future., Pharmaceutics, 11 (8)

Folate receptor (FR)-targeted radionuclide therapy using folate radioconjugates is of interest due to the expression of the FR in a variety of tumor types. The high renal accumulation of radiofolates presents, however, a risk of radionephropathy. A potential option to address this challenge would be to use radioprotectants, such as amifostine. Methods for early detection of kidney damage that—in this case—cannot be predicted based on dose estimations, would facilitate the development of novel therapies. The aim of this study was, therefore, to assess potentially changing levels of plasma and urine biomarkers and to determine DNA damage at an early stage after radiofolate application. The identification of an early indicator for renal damage in mice would be useful since histological changes become apparent only several months after treatment. Mice were injected with different quantities of 177Lu-folate (10 MBq, 20 MBq and 30 MBq), resulting in mean absorbed kidney doses of ~23 Gy, ~46 Gy and ~69 Gy, respectively, followed by euthanasia two weeks (>85% of the mean renal radiation dose absorbed) or three months later. Whereas all investigated biomarkers remained unchanged, the number of γ-H2AX-positive nuclei in the renal cortex showed an evident dose-dependent increase as compared to control values two weeks after treatment. Comparison with the extent of kidney injury determined by histological changes five to eight months after administration of the same 177Lu-folate activities suggested that the quantitative assessment of double-strand breaks can be used as a biological indicator for long-term radiation effects in the kidneys. This method may, thus, enable faster assessment of radiopharmaceuticals and protective measures by preventing logistically challenging long-term investigations to detect kidney damage., Pharmaceuticals, 10 (2), ISSN:1424-8247

Folic-acid-based radioconjugates have been developed for nuclear imaging of folate receptor (FR)-positive tumors; however, high renal uptake was unfavorable in view of a therapeutic application. Previously, it was shown that pre-injection of pemetrexed (PMX) increased the tumor-to-kidney ratio of radiofolates several-fold. In this study, PMX was combined with the currently best performing radiofolate ([177Lu]cm13), which is outfitted with an albumin-binding entity. Biodistribution studies were carried out in mice bearing KB or IGROV-1 tumor xenografts, both FR-positive tumor types. SPECT/CT was performed with control mice injected with [177Lu]folate only and with mice that received PMX in addition. Control mice showed high uptake of radioactivity in KB and IGROV-1 tumor xenografts, but retention in the kidneys was also high, resulting in tumor-to-kidney ratios of ~0.85 (4 h p.i.) and ~0.60 (24 h p.i.) or ~1.17 (4 h p.i.) and ~1.11 (24 h p.i.) respectively. Pre-injection of PMX improved the tumor-to-kidney ratio to values of ~1.13 (4 h p.i.) and ~0.92 (24 h p.i.) or ~1.79 (4 h p.i.) and ~1.59 (24 h p.i.), respectively, due to reduced uptake in the kidneys. It was found that a second injection of PMX—3 h or 7 h after administration of the radiofolate—improved the tumor-to-kidney ratio further to ~1.03 and ~0.99 or ~1.78 and ~1.62 at 24 h p.i. in KB and IGROV-1 tumor-bearing mice, respectively. SPECT/CT scans readily visualized the tumor xenografts, whereas accumulation of radioactivity in the kidneys was reduced in mice that received PMX. In this study, it was shown that PMX had a positive impact in terms of reducing the kidney uptake of albumin-binding radiofolates; hence, the administration of PMX resulted in ~1.3–1.7-fold higher tumor-to-kidney ratios. This is, however, a rather moderate effect in comparison to the previously shown effect of PMX on conventional radiofolates (without albumin binder), which led to 5–6-fold increased tumor-to-kidney ratios. An explanation for this result may be the different pharmacokinetic profiles of PMX and long-circulating radiofolates, respectively. Despite the promising potential of this concept, it is believed that a clinical translation would be challenging, particularly when PMX had to be injected more than once., Molecules, 23 (6), ISSN:1420-3049

Purpose It was previously demonstrated that radiation effects can enhance the therapy outcome of immune checkpoint inhibitors. In this study, a syngeneic breast tumor mouse model was used to investigate the effect of [Lu-177]Lu-DOTA-folate as an immune stimulus to enhance anti-CTLA-4 immunotherapy. Methods In vitro and in vivo studies were performed to characterize NF9006 breast tumor cells with regard to folate receptor (FR) expression and the possibility of tumor targeting using [Lu-177]Lu-DOTA-folate. A preclinical therapy study was performed over 70 days with NF9006 tumor-bearing mice that received vehicle only (group A); [Lu-177]Lu-DOTA-folate (5 MBq; 3.5 Gy absorbed tumor dose; group B); anti-CTLA-4 antibody (3 x 200 mu g; group C), or both agents (group D). The mice were monitored regarding tumor growth over time and signs indicating adverse events of the treatment. Results [Lu-177]Lu-DOTA-folate bound specifically to NF9006 tumor cells and tissue in vitro and accumulated in NF9006 tumors in vivo. The treatment with [Lu-177]Lu-DOTA-folate or an anti-CTLA-4 antibody had only a minor effect on NF9006 tumor growth and did not substantially increase the median survival time of mice (23 day and 19 days, respectively) as compared with untreated controls (12 days). [Lu-177]Lu-DOTA-folate sensitized, however, the tumors to anti-CTLA-4 immunotherapy, which became obvious by reduced tumor growth and, hence, a significantly improved median survival time of mice (> 70 days). No obvious signs of adverse effects were observed in treated mice as compared with untreated controls. Conclusion Application of [Lu-177]Lu-DOTA-folate had a positive effect on the therapy outcome of anti-CTLA-4 immunotherapy. The results of this study may open new perspectives for future clinical translation of folate radioconjugates., European Journal of Nuclear Medicine and Molecular Imaging, 48 (4), ISSN:1619-7070, ISSN:1619-7089