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- Siwowska, K., et al.
(författare)
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Therapeutic Potential of Sc-47 in Comparison to Lu-177 and Y-90: Preclinical Investigations
- 2019
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- Targeted radionuclide therapy with Lu-177- and Y-90-labeled radioconjugates is a clinically-established treatment modality for metastasized cancer. Sc-47 is a therapeutic radionuclide that decays with a half-life of 3.35 days and emits medium-energy beta(-)particles. In this study, Sc-47 was investigated, in combination with a DOTA-folate conjugate, and compared to the therapeutic properties of Lu-17-folate and Y-90-folate, respectively. In vitro, Sc-47-folate demonstrated effective reduction of folate receptor-positive ovarian tumor cell viability similar to Lu-177-folate, but Y-90-folate was more potent at equal activities due to the higher energy of emitted beta(-)particles. Comparable tumor growth inhibition was observed in mice that obtained the same estimated absorbed tumor dose (similar to 21 Gy) when treated with Sc-47-folate (12.5 MBq), Lu-177-folate (10 MBq), and Y-90-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, Sc-47 is likely to be comparable to Lu-177 when employed for targeted radionuclide therapy. It may, therefore, have potential for clinical translation and be of particular interest in tandem with Sc-44 or Sc-43 as a diagnostic match, enabling the realization of radiotheragnostics in future.
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| 2. |
- Guzik, P., et al.
(författare)
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Promising potential of Lu-177 Lu-DOTA-folate to enhance tumor response to immunotherapy-a preclinical study using a syngeneic breast cancer model
- 2021
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 48:4, s. 984-994
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Siwowska, K., et al.
(författare)
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Preclinical Comparison of Albumin-Binding Radiofolates: Impact of Linker Entities on the in Vitro and in Vivo Properties
- 2017
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 14:2, s. 523-532
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Tidskriftsartikel (refereegranskat)abstract
- Tumor targeting with folic acid radioconjugates has been proposed as a promising strategy for radionuclide therapy of folate receptor a (FR)-positive cancer. Recently, it was shown that modification of radiofolates with an albumin-binding entity increased the tumor-to-kidney ratios of accumulated radioactivity in mice. The goal of this study was to evaluate the lead compound cm10 and compare it with new albumin-binding folate conjugates. Compound cm12 was designed with a long spacer consisting of a PEG-11 entity, and compound cm13 contained a short alkane chain between the albumin-binding moiety and folic acid. All of the derivatives were labeled with Lu-177 (t(1/2) = 6.65 days, E beta(-),(average) = 134 keV; E gamma = 113 keV, 208 keV), a clinically established radionuclide for therapeutic purposes. The evaluation revealed that all of the albumin-binding radiofolates exhibited increased in vitro stability compared with the reference compound (Lu-177-cm14) without albumin binder. Serum protein binding, determined with an ultrafiltration assay, was high (>88%) for the derivatives with albumin-binding entities. The FR-binding affinity was in the same range (K-D = 4.0-7.5 nM) for all of the radiofolates, independent of the albumin-binding entity and spacer length. FR-specific uptake was proven in vitro using FR-positive KB tumor cells. In vivo studies with KB-tumor-bearing mice were performed in order to assess the tissue distribution profile of the novel radiofolates. Lu-177-cm13 showed high tumor uptake at late time points (13.3 +/- 2.94% IA/g, 48 h p.i.) and tumor-to-kidney ratios (0.59 +/- 0.03, 48 h p.i.) in the same range as Lu-177-cm10 (0.55 +/- 0.07, 48 h p.i.). However, the tumor-to-kidney ratio of Lu-177-cm12 (0.28 +/- 0.07, 48 h p.i.) was reduced compared with Lu-177-cm10 and Lu-177-cm13. The results of this study indicate that the spacer entity between folic acid and the albumin binder is of critical importance with regard to the tissue distribution profile of the radiofolate. The PEG spacer compromised the beneficial effects of the lead compound, but the design with a short alkane spacer appeared to be promising. Future studies will focus on the design of radiofolates with lipophilic and more rigid spacer entities, which may allow a further improvement of their tissue distribution profiles.
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