644 results on '"Müller, Cristina"'
Search Results
252. A New 18F-Labeled Folic Acid Derivative with Improved Properties for the PET Imaging of Folate Receptor--Positive Tumors.
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Ross, Tobias L., Honer, Michael, Müller, Cristina, Groehn, Viola, Schibli, Roger, and Ametamey, Simon M.
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- 2010
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253. Pemetrexed Improves Tumor Selectivity of 111In-DTPA-Folate in Mice with Folate Receptor-Positive Ovarian Cancer.
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Müller, Cristina, Schibli, Roger, Krenning, Eric P., and de Jong, Marion
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- 2008
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254. SPECT Study of Folate Receptor-Positive Malignant and Normal Tissues in Mice Using a Novel 99mTc-Radiofolate.
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Müller, Cristina, Forrer, Flavio, Schibli, Roger, Krenning, Eric P., and de Jong, Marion
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- 2008
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255. Dose-dependent effects of (anti)folate preinjection on 99mTc-radiofolate uptake in tumors and kidneys
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Müller, Cristina, Schibli, Roger, Forrer, Flavio, Krenning, Eric P., and de Jong, Marion
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TUMORS , *KIDNEYS , *NUCLEAR medicine , *BIOLOGY - Abstract
Abstract: Introduction: The folate receptor (FR) is frequently overexpressed in tumors and can be targeted with folate-based (radio)pharmaceuticals. However, significant accumulation of radiofolates in FR-positive kidneys represents a drawback. We have shown that preadministration of the antifolate pemetrexed (PMX) significantly improved the tumor-to-kidney ratio of radiofolates in mice. The aim of this study was to investigate the dose dependence of these effects and whether the same results could be achieved with folic acid (FA) or 5-methyl-tetrahydrofolate (5-Me-THF). Methods: Biodistribution was assessed 4 h postinjection of the organometallic 99mTc-picolylamine monoacetic acid folate in nude mice bearing FR-positive KB tumor xenografts. PMX (50–400 μg/mouse) was injected 1 h previous to radioactivity. The effects of FA and 5-Me-THF (0.5–50 μg/mouse) were investigated likewise. Tissues and organs were collected and counted for radioactivity and the values tabulated as percentage of injected dose per gram tissue (% ID/g). Results: PMX administration reduced renal retention (<1.6% ID/g vs. control: >10% ID/g), while the tumor uptake (average 1.35%±0.40% ID/g vs. control: 1.79%±0.49% ID/g) was only slightly affected independent of the PMX dose. Replacement of PMX by FA or 5-Me-THF (50 μg/mouse) resulted in a significant renal blockade (<0.1% ID/g) but at the same time in an undesired reduction of tumor uptake (<0.2% ID/g). Conclusions: Selective reduction of radiofolate uptake in kidneys under retention of high tumor accumulation could be achieved in combination with PMX over a broad dose range but not with FA or 5-Me-THF. [Copyright &y& Elsevier]
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- 2007
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256. Isostructural folate conjugates radiolabeled with the matched pair 99mTc/188Re: a potential strategy for diagnosis and therapy of folate receptor-positive tumors
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Müller, Cristina, Schubiger, P. August, and Schibli, Roger
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FOLIC acid , *TUMORS , *NUCLEAR medicine , *BIOLOGY - Abstract
Abstract: 99mTc-technetium (99mTc) and 188Re-rhenium (188Re) represent an interesting pair of radionuclides for diagnosis and therapy. The aim of this study was to synthesize and characterize in vitro/in vivo the first 188Re-folate derivative [188Re(CO)3–picolylamine monoacetic acid 188Re-PAMA-folate (2)] for potential targeted radionuclide therapy of FR-positive tumors. The data were compared with those of the isostructural 99mTc-analog [99mTc–PAMA folate (1)] reported previously. Methods: In vitro stability of compound 2 was tested in phosphate-buffered saline and human plasma. Cell binding experiments were performed with FR-positive human KB cells. Biodistribution was assessed in female nude mice, bearing KB tumor xenografts. Results: Cell binding experiments showed high and FR-specific uptake. In vivo, compound 2 accumulated specifically in the FR-positive tumors with maximal values 4 h post injection (p.i.) [ 2 : 1.87±0.04 percent injected dose per gram of weight tissue (% ID/g) vs. 1 : 2.33±0.36% ID/g]. Unfavorably high retention of radioactivity was found in FR-positive kidneys (12.04±0.62% ID/g; 4 h p.i.). Tumor-to-blood ratio of radioactivity ( 2 : 14.5±1.32, 4 h p.i.) was lower than for compound 1 (58.0±12.2, 4 h p.i.), whereas tumor-to-kidney ratios were in the same range ( 2 : 0.15±0.01 vs. 1 : 0.13±0.02, 4 h p.i.). Preadministration of the antifolate pemetrexed significantly improved the tumor-to-kidney ratio ( 2 : 1.59±0.30, 4 h p.i.). Conclusions: The isostructural radiofolates 1 and 2 displayed almost identical pharmacokinetic profiles and accumulated both specifically in FR-positive tumors. However, only the coapplication of the antifolate pemetrexed improved the biodistribution of the radiotracers in such ways that a potential therapeutic application of compound 2 can be envisaged in the future. [Copyright &y& Elsevier]
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- 2007
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257. In vitro and in vivo targeting of different folate receptor-positive cancer cell lines with a novel 99mTc-radiofolate tracer.
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Müller, Cristina, Schubiger, P. August, and Schibli, Roger
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CANCER cells , *SARCOMA , *RODENTS , *CYTOLOGICAL techniques , *TUMORS , *MEDICAL radiology - Abstract
Purpose: For the assessment of folate-based radiopharmaceuticals, human nasopharyngeal KB carcinoma cells are traditionally used although nasopharyngeal cancer is rare. On the other hand, the folate receptor (FR) is frequently overexpressed on diverse cancer types, the highest frequency (>90%) being on ovarian carcinomas. The goal of our study was the in vitro and in vivo assessment of different FR-positive human carcinoma cells. In addition, a murine sarcoma cell line was assessed as a pre-clinical alternative to human xenograft models. Methods: FR-positive human nasopharyngeal, cervical, ovarian and colorectal cancer cell lines and the transgenic mouse sarcoma (24JK-FBP) cell line were targeted with a novel 99mTc-tricarbonyl folate derivative 2. Comparative in vitro cell binding studies were carried out under standardised folate-deficient conditions. In vivo studies were performed in nude mice and C6 black mice. Results: The in vitro cell experiments revealed only FR-specific binding (unspecific <0.02%), ranging from 3.5% to 52% of complex 2 owing to variable levels of FR expression of the cell lines. In vivo tumour uptake of radiotracer 2 varied less than in vitro. It ranged from 0.66± 0.17% ID/g (LoVo) through 1.16±0.64% ID/g (IGROV-1) and 1.55±0.43% ID/g (24JK-FBP) to 2.33±0.36% ID/g (KB) 4 h p.i. Conclusion: These pre-clinical studies indicate that in vitro data obtained in FR-positive cancer cells do not necessarily correspond with or predict in vivo radiofolate uptake in corresponding (xeno)grafts. In addition, the murine 24JK-FBP cell line proved to be a valuable preclinical alternative to human tumour models. [ABSTRACT FROM AUTHOR]
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- 2006
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258. Preclinical evaluation of novel organometallic 99mTc-folate and 99mTc-pteroate radiotracers for folate receptor-positive tumour targeting.
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Müller, Cristina, Hohn, Alexander, Schubiger, P., and Schibli, Roger
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TUMOR markers , *RADIOACTIVE tracers , *TUMORS , *FOLIC acid , *CANCER , *LABORATORY mice - Abstract
Purpose: The folate receptor (FR) is a valuable tumour marker, since it is frequently overexpressed on various cancer types. The purpose of the present study was to pre-clinically evaluate novel site-specifically modified 99mTc(CO)3 folate (γ-derivative 4, α-derivative 5) and pteroate (6) conjugates for FR targeting. Methods: The 99mTc(CO)3 radiotracers 4-6 were prepared by a kit-like procedure. In vitro characterisation (KD and Bmax) of the radiotracers was performed with FR-positive KB cells. Tissue distribution was studied in tumour-bearing mice. SPECT/CT experiments were performed with a dedicated small animal SPECT/CT scanner. Results: The complexes 4-6 were formed in high yields (>92%). Binding constants of the radiotracers (KD in nM: 4: 2.09; 5: 2.51; 6: 14.52) were similar to those of 3H-folic acid (KD in nM: 7.22). In vivo the folate derivatives showed significantly better tumour uptake (4: 2.3±0.4% ID/g and 5: 1.2±0.2% ID/g, 4 h p.i.) than the pteroate derivative (6: 0.4±0.2% ID/g, 4 h p.i.). Clearance of all radiotracers from the blood pool and from non-targeted tissues was efficient (tumour to blood ratio approx. 200-350, 24 h p.i.). FR-positive tissue and organs were successfully visualised via small animal SPECT/CT. Conclusion: Radiotracers 4-6 are the first 99mTc(CO)3 tracers prepared via a kit formulation which exhibit full biological activity in vitro and in vivo. Folate derivatives 4 and 5 revealed significantly better pharmacokinetic properties than the pteroate derivative 6. Promising preclinical SPECT results warrant further assessment of 99mTc (CO)3 radiofolates for detection of FR-positive tumours. [ABSTRACT FROM AUTHOR]
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- 2006
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259. Synthesis and Preclinical Evaluation of a Folic Acid Derivative Labeled with 18F for PET Imaging of Folate Receptor--Positive Tumors.
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Bettio, Andrea, Honer, Michael, Müller, Cristina, Brühlmeier, Matthias, Müller, Ursina, Schibli, Roger, Groehn, Viola, Schubiger, August P., and Ametamey, Simon M.
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- 2006
260. Organometallic 99mTc-technetium(I)- and Re-rhenium(I)-folate derivatives for potential use in nuclear medicine
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Müller, Cristina, Dumas, Cécile, Hoffmann, Ute, Schubiger, P. August, and Schibli, Roger
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RADIOACTIVE substances , *FOLIC acid , *VITAMIN B complex , *CANCER cells - Abstract
Abstract: The folate receptor (FR) is a high affinity membrane protein which is overexpressed on a wide variety of tumor cells, but highly restricted in normal tissues. Therefore folate derivatives labeled with short living isotopes such as 99mTc (γ, t1/2=6 h) or 188Re (β−, t1/2=17 h) could be used for tumor diagnosis and therapy. In this respect there is a great interest to develop organometallic technetium(I) and rhenium(I) modified folate radiopharmaceuticals. For this purpose folic acid was functionalized with a tridentate picolylamine monoacetic acid chelating system. The chelating system was selectively coupled via an aminohexane spacer to the γ- or α-carboxyl group of the glutamate moiety of folic acid to obtain the corresponding γ- or α-folate derivative or – if directly attached to pteroic acid – the pteroate derivative. The derivatives were reacted with the precursor [M(OH2)3(CO)3]+ (M=99mTc, Re) to form uniform organometallic folate complexes under mild reaction conditions. All compounds were chemically characterized by means of NMR, MS, IR and HPLC. The determination of the IC50-values for the PAMA-γ-folate derivative (100 nM) and the corresponding organometallic rhenium complex (110 nM) proved retained receptor binding properties. The radiolabeling with [99mTc(OH2)3(CO)3]+ was achieved in excellent yield (>95%) at low ligand concentration (10−4 M). The cell binding (>45% of total activity) and internalization (>15% of total activity) of all 99mTc-complexes was very high and specificity for the FR was proved by their complete displacement with excess folic acid. The 99mTc-complexes were positively tested for their plasma stability and for the absence of binding to plasma proteins. [Copyright &y& Elsevier]
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- 2004
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261. Dosimetric Analysis of the Short-Ranged Particle Emitter 161 Tb for Radionuclide Therapy of Metastatic Prostate Cancer.
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Bernhardt, Peter, Svensson, Johanna, Hemmingsson, Jens, van der Meulen, Nicholas P., Zeevaart, Jan Rijn, Konijnenberg, Mark W., Müller, Cristina, Kindblom, Jon, and Goffin, Karolien
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RADIOISOTOPE therapy ,METASTASIS ,PROTEOLYTIC enzymes ,IODINE radioisotopes ,RADIOACTIVE elements ,PROSTATE-specific membrane antigen ,RADIATION dosimetry ,PROSTATE tumors ,LIGANDS (Biochemistry) - Abstract
Simple Summary: A tremendous effort and rapid development of the prostate-specific membrane antigen (PSMA)-targeting radio ligands for radionuclide therapy has resulted in encouraging response rates for advanced prostate cancer. Different radionuclides have been utilized or suggested as suitable candidates. In this study, a dynamic model of metastatic progress was developed and utilized to estimate a radiopharmaceutical's potential of obtaining metastatic control of advanced prostate cancer. The simulations performed demonstrated the advantage of utilizing radionuclides with short-range particle emission, i.e., alpha-emitters and low-energy electrons. The recently-proposed beta-emitting radionuclide terbium-161 demonstrates great potential of being a future candidate towards targeted radionuclide therapy of advanced prostate cancer. This is in line with recent encouraging preclinical results and development of upscaling the product quality. Recently, the first in-human application with a [
161 Tb]Tb-DOTATOC also demonstrated good SPECT image quality, which can enable dosimetry calculations for new161 Tb-based radiopharmaceuticals. The aim of this study was to analyze the required absorbed doses to detectable metastases (Dreq ) when using radionuclides with prostate specific membrane antigen (PSMA)-targeting radioligands to achieve a high probability for metastatic control. The Monte Carlo based analysis was performed for the clinically-used radionuclides yttrium-90, iodine-131, lutetium-177, and actinium-225, and the newly-proposed low-energy electron emitter terbium-161. It was demonstrated that metastatic formation rate highly influenced the metastatic distribution. Lower values generated few large detectable metastases, as in the case with oligo metastases, while high values generated a distribution of multiple small detectable metastases, as observed in patients with diffused visualized metastases. With equal number of detectable metastases, the total metastatic volume burden was 4–6 times higher in the oligo metastatic scenario compared to the diffusely visualized scenario. The Dreq was around 30% higher for the situations with 20 detectable metastases compared to one detectable metastasis. The Dreq for iodine-131 and yttrium-90 was high (920–3300 Gy). The Dreq for lutetium-177 was between 560 and 780 Gy and considerably lower Dreq were obtained for actinium-225 and terbium-161, with 240–330 Gy and 210–280 Gy, respectively. In conclusion, the simulations demonstrated that terbium-161 has the potential for being a more effective targeted radionuclide therapy for metastases using PSMA ligands. [ABSTRACT FROM AUTHOR]- Published
- 2021
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262. 68 Ga-Labeling: Laying the Foundation for an Anti-Radiolytic Formulation for NOTA-sdAb PET Tracers.
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Baudhuin, Henri, Cousaert, Julie, Vanwolleghem, Philippe, Raes, Geert, Caveliers, Vicky, Keyaerts, Marleen, Lahoutte, Tony, Xavier, Catarina, and Müller, Cristina
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GEL permeation chromatography ,THIN layer chromatography ,RADIOCHEMICAL purification ,VITAMIN C ,RADIOLYSIS ,DRUG labeling ,LABELS - Abstract
During the preparation of [
68 Ga]Ga-NOTA-sdAb at high activity, degradation of the tracers was observed, impacting the radiochemical purity (RCP). Increasing starting activities in radiolabelings is often paired with increased degradation of the tracer due to the formation of free radical species, a process known as radiolysis. Radical scavengers and antioxidants can act as radioprotectant due to their fast interaction with formed radicals and can therefore reduce the degree of radiolysis. This study aims to optimize a formulation to prevent radiolysis during the labeling of NOTA derivatized single domain antibody (sdAbs) with68 Ga. Gentisic acid, ascorbic acid, ethanol and polyvinylpyrrolidone were tested individually or in combination to find an optimal mix able to prevent radiolysis without adversely influencing the radiochemical purity (RCP) or the functionality of the tracer. RCP and degree of radiolysis were assessed via thin layer chromatography and size exclusion chromatography for up to three hours after radiolabeling. Individually, the radioprotectants showed insufficient efficacy in reducing radiolysis when using high activities of68 Ga, while being limited in amount due to negative impact on radiolabeling of the tracer. A combination of 20% ethanol (VEtOH/VBuffer%) and 5 mg ascorbic acid proved successful in preventing radiolysis during labeling with starting activities up to 1–1.2 GBq of68 Ga, and is able to keep the tracer stable for up to at least 3 h after labeling at room temperature. The prevention of radiolysis by the combination of ethanol and ascorbic acid potentially allows radiolabeling compatibility of NOTA-sdAbs with all currently available68 Ge/68 Ga generators. Additionally, a design is proposed to allow the incorporation of the radioprotectant in an ongoing diagnostic kit development for68 Ga labeling of NOTA-sdAbs. [ABSTRACT FROM AUTHOR]- Published
- 2021
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263. Preclinical Investigations to Explore the Difference between the Diastereomers [177Lu]Lu-SibuDAB and [177Lu]Lu-RibuDAB toward Prostate Cancer Therapy
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Borgna, Francesca, Deberle, Luisa M., Busslinger, Sarah D., Tschan, Viviane J., Walde, Laura M., Becker, Anna E., Schibli, Roger, and Müller, Cristina
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[177Lu]Lu-Ibu-DAB-PSMA, a radioligand modified with ibuprofen as the albumin binder, showed higher accumulation in PSMA-positive tumors of mice than the clinically used [177Lu]Lu-PSMA-617 but lower retention in non-targeted tissues than previously developed albumin-binding PSMA radioligands. The aim of this study was to investigate whether the stereochemistry of the incorporated ibuprofen affects the radioligand’s in vitroand in vivoproperties and to select the more favorable radioligand for further development. For this purpose, SibuDAB and RibuDAB containing (S)- and (R)-ibuprofen, respectively, were synthesized and labeled with lutetium-177. In vitro, the two isomers had similar properties; however, [177Lu]Lu-SibuDAB showed increased binding to mouse and human plasma proteins (91 ± 1 and 88 ± 2%, respectively) compared to [177Lu]Lu-RibuDAB (75 ± 2 and 79 ± 2%, respectively). In vivo, [177Lu]Lu-SibuDAB was metabolically more stable than [177Lu]Lu-RibuDAB with ∼90 vs ∼67% intact radioligand detected in the blood at 4 h post injection (p.i.). In line with the lower albumin-binding affinity, the blood clearance of [177Lu]Lu-RibuDAB in mice was considerably faster [27% of injected activity (% IA), 1 h p.i.] than for [177Lu]Lu-SibuDAB (50% IA, 1 h p.i.). Time-dependent biodistribution studies performed in tumor-bearing athymic nude mice showed high PSMA-specific tumor uptake for both isomers. A twofold increased area under the curve (AUC0→8d) of the blood retention was determined for [177Lu]Lu-SibuDAB as compared to [177Lu]Lu-RibuDAB, whereas the kidney AUC0→8dvalue of [177Lu]Lu-SibuDAB was only half as high as for [177Lu]Lu-RibuDAB. As a result, a more favorable tumor-to-kidney AUC0→8dratio was obtained for [177Lu]Lu-SibuDAB, which was also visualized on SPECT/CT images. Based on its improved kidney clearance and higher metabolic stability, [177Lu]Lu-SibuDAB was selected as the more favorable radioligand. Therapy studies performed with [177Lu]Lu-SibuDAB (5 MBq/mouse) demonstrated the anticipated therapeutic superiority over the current gold-standard [177Lu]Lu-PSMA-617 (5 MBq/mouse). The significantly increased survival time of mice treated with [177Lu]Lu-SibuDAB as compared to those injected with [177Lu]Lu-PSMA-617 justifies further development of this novel radioligand toward clinical application.
- Published
- 2022
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264. Comparison of the dosimetry of scandium-43 and scandium-44 patient organ doses in relation to commonly used gallium-68 for imaging neuroendocrine tumours.
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Gomes, Carlos Vinícius, Mendes, Bruno Melo, Paixão, Lucas, Gnesin, Silvano, Müller, Cristina, van der Meulen, Nicholas P., Strobel, Klaus, Fonseca, Telma Cristina Ferreira, and Lima, Thiago Viana Miranda
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NEUROENDOCRINE tumors , *MEDICAL dosimetry , *CLINICAL chemistry , *HALF-life (Nuclear physics) , *ABSORBED dose , *THERMOLUMINESCENCE dosimetry , *DOSE-response relationship (Radiation) - Abstract
Background: Several research groups have explored the potential of scandium radionuclides for theragnostic applications due to their longer half-lives and equal or similar coordination chemistry between their diagnostic and therapeutic counterparts, as well as lutetium-177 and terbium-161, respectively. Unlike the gallium-68/lutetium-177 pair, which may show different in-vivo uptake patterns, the use of scandium radioisotopes promises consistent behaviour between diagnostic and therapeutic radiopeptides. An advantage of scandium's longer half-life over gallium-68 is the ability to study radiopeptide uptake over extended periods and its suitability for centralized production and distribution. However, concerns arise from scandium-44's decay characteristics and scandium-43's high production costs. This study aimed to evaluate the dosimetric implications of using scandium radioisotopes with somatostatin analogues against gallium-68 for PET imaging of neuroendocrine tumours. Methods: Absorbed dose per injected activity (AD/IA) from the generated time-integrated activity curve (TIAC) were estimated using the radiopeptides [43/44/44mSc]Sc- and [68Ga]Ga-DOTATATE. The kidneys, liver, spleen, and red bone marrow (RBM) were selected for dose estimation studies. The EGSnrc and MCNP6.1 Monte Carlo (MC) codes were used with female (AF) and male (AM) ICRP phantoms. The results were compared to Olinda/EXM software, and the effective dose concentrations assessed, varying composition between the scandium radioisotopes. Results: Our findings showed good agreement between the MC codes, with − 3 ± 8% mean difference. Kidneys, liver, and spleen showed differences between the MC codes (min and max) in a range of − 4% to 8%. This was observed for both phantoms for all radiopeptides used in the study. Compared to Olinda/EXM the largest observed difference was for the RBM, of 21% for the AF and 16% for the AM for scandium- and gallium-based radiopeptides. Despite the differences, our findings showed a higher absorbed dose on [43/44Sc]Sc-DOTATATE compared to its 68Ga-based counterpart. Conclusion: This study found that [43/44Sc]Sc-DOTATATE delivers a higher absorbed dose to organs at risk compared to [68Ga]Ga-DOTATATE, assuming equal distribution. This is due to the longer half-life of scandium radioisotopes compared to gallium-68. However, calculated doses are within acceptable ranges, making scandium radioisotopes a feasible replacement for gallium-68 in PET imaging, potentially offering enhanced diagnostic potential with later timepoint imaging. [ABSTRACT FROM AUTHOR]
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- 2024
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265. Simultaneous Visualization of 161 Tb- and 177 Lu-Labeled Somatostatin Analogues Using Dual-Isotope SPECT Imaging.
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Borgna, Francesca, Barritt, Patrick, Grundler, Pascal V., Talip, Zeynep, Cohrs, Susan, Zeevaart, Jan Rijn, Köster, Ulli, Schibli, Roger, van der Meulen, Nicholas P., Müller, Cristina, and Seimbille, Yann
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COMPUTED tomography ,SINGLE-photon emission computed tomography ,SOMATOSTATIN ,VISUALIZATION ,TERBIUM ,RADIOISOTOPES - Abstract
The decay of terbium-161 results in the emission of β¯-particles as well as conversion and Auger electrons, which makes terbium-161 interesting for therapeutic purposes. The aim of this study was to use dual-isotope SPECT imaging in order to demonstrate visually that terbium-161 and lutetium-177 are interchangeable without compromising the pharmacokinetic profile of the radiopharmaceutical. The
161 Tb- and177 Lu-labeled somatostatin (SST) analogues DOTATOC (agonist) and DOTA-LM3 (antagonist) were tested in vitro to demonstrate equal properties regarding distribution coefficients and cell uptake into SST receptor-positive AR42J tumor cells. The radiopeptides were further investigated in AR42J tumor-bearing nude mice using the method of dual-isotope (terbium-161/lutetium-177) SPECT/CT imaging to enable the visualization of their distribution profiles in the same animal. Equal pharmacokinetic profiles were demonstrated for either of the two peptides, irrespective of whether it was labeled with terbium-161 or lutetium-177. Moreover, the visualization of the sub-organ distribution confirmed similar behavior of161 Tb- and177 Lu-labeled SST analogues. The data were verified in quantitative biodistribution studies using either type of peptide labeled with terbium-161 or lutetium-177. While the radionuclide did not have an impact on the organ distribution, this study confirmed previous data of a considerably higher tumor uptake of radiolabeled DOTA-LM3 as compared to the radiolabeled DOTATOC. [ABSTRACT FROM AUTHOR]- Published
- 2021
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266. Developments toward the Implementation of 44 Sc Production at a Medical Cyclotron.
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van der Meulen, Nicholas P., Hasler, Roger, Talip, Zeynep, Grundler, Pascal V., Favaretto, Chiara, Umbricht, Christoph A., Müller, Cristina, Dellepiane, Gaia, Carzaniga, Tommaso S., Braccini, Saverio, Roivainen, Anne, and Li, Xiang-Guo
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CYCLOTRONS ,POSITRON emission tomography ,NUCLEAR reactions ,NUCLEAR medicine ,PROSTATE-specific membrane antigen ,ION exchange chromatography - Abstract
44 Sc has favorable properties for cancer diagnosis using Positron Emission Tomography (PET) making it a promising candidate for application in nuclear medicine. The implementation of its production with existing compact medical cyclotrons would mean the next essential milestone in the development of this radionuclide. While the production and application of44 Sc has been comprehensively investigated, the development of specific targetry and irradiation methods is of paramount importance. As a result, the target was optimized for the44 Ca(p,n)44 Sc nuclear reaction using CaO instead of CaCO3 , ensuring decrease in target radioactive degassing during irradiation and increased radionuclidic yield. Irradiations were performed at the research cyclotron at the Paul Scherrer Institute (~11 MeV, 50 µA, 90 min) and the medical cyclotron at the University of Bern (~13 MeV, 10 µA, 240 min), with yields varying from 200 MBq to 16 GBq. The development of targetry, chemical separation as well as the practical issues and implications of irradiations, are analyzed and discussed. As a proof-of-concept study, the44 Sc produced at the medical cyclotron was used for a preclinical study using a previously developed albumin-binding prostate-specific membrane antigen (PSMA) ligand. This work demonstrates the feasibility to produce44 Sc with high yields and radionuclidic purity using a medical cyclotron, equipped with a commercial solid target station. [ABSTRACT FROM AUTHOR]- Published
- 2020
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267. Can Nuclear Imaging of Activated Macrophages with Folic Acid-Based Radiotracers Serve as a Prognostic Means to Identify COVID-19 Patients at Risk?
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Müller, Cristina, Schibli, Roger, and Maurer, Britta
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RADIOACTIVE tracers , *COVID-19 , *ADULT respiratory distress syndrome , *MACROPHAGES , *INTERSTITIAL lung diseases - Abstract
Herein, we discuss the potential role of folic acid-based radiopharmaceuticals for macrophage imaging to support clinical decision-making in patients with COVID-19. Activated macrophages play an important role during coronavirus infections. Exuberant host responses, i.e., a cytokine storm with increase of macrophage-related cytokines, such as TNFα, IL-1β, and IL-6 can lead to life-threatening complications, such as acute respiratory distress syndrome (ARDS), which develops in approximately 20% of the patients. Diverse immune modulating therapies are currently being tested in clinical trials. In a preclinical proof-of-concept study in experimental interstitial lung disease, we showed the potential of 18F-AzaFol, an 18F-labeled folic acid-based radiotracer, as a specific novel imaging tool for the visualization and monitoring of macrophage-driven lung diseases. 18F-AzaFol binds to the folate receptor-beta (FRβ) that is expressed on activated macrophages involved in inflammatory conditions. In a recent multicenter cancer trial, 18F-AzaFol was successfully and safely applied (NCT03242993). It is supposed that the visualization of activated macrophage-related disease processes by folate radiotracer-based nuclear imaging can support clinical decision-making by identifying COVID-19 patients at risk of a severe disease progression with a potentially lethal outcome. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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268. Albumin-Binding PSMA Radioligands: Impact of Minimal Structural Changes on the Tissue Distribution Profile.
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Deberle, Luisa M., Tschan, Viviane J., Borgna, Francesca, Sozzi-Guo, Fan, Bernhardt, Peter, Schibli, Roger, Müller, Cristina, and Trabocchi, Andrea
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SOLID-phase synthesis ,ABSORBED dose ,TISSUES ,IN vivo studies ,PROSTATE cancer - Abstract
The concept of using ibuprofen as an albumin-binding entity was recently demonstrated by the development of [
177 Lu]Lu-Ibu-PSMA-01. In the present study, we designed a novel ibuprofen-containing radioligand (Ibu-PSMA-02) with subtle structural changes regarding the linker entity in order to investigate a potential impact on the in vitro and in vivo properties. Ibu-PSMA-02 was prepared using solid-phase synthesis techniques and labeled with lutetium-177. [177 Lu]Lu-Ibu-PSMA-02 was evaluated in vitro with regard to its plasma protein-binding properties, PSMA affinity and uptake into PSMA-expressing PC-3 PIP tumor cells. The tissue distribution profile of [177 Lu]Lu-Ibu-PSMA-02 was assessed in tumor-bearing mice and dose estimations were performed. The in vitro characteristics of [177 Lu]Lu-Ibu-PSMA-02 were similar to those previously obtained for [177 Lu]Lu-Ibu-PSMA-01 with respect to plasma protein-binding, PSMA affinity and tumor cell uptake. The in vivo studies revealed, however, an unprecedentedly high uptake of [177 Lu]Lu-Ibu-PSMA-02 in PC-3 PIP tumors, resulting in an increased absorbed tumor dose of 7.7 Gy/MBq as compared to 5.1 Gy/MBq calculated for [177 Lu]Lu-Ibu-PSMA-01. As a consequence of the high tumor accumulation, [177 Lu]Lu-Ibu-PSMA-02 showed higher tumor-to-background ratios than [177 Lu]Lu-Ibu-PSMA-01. This study exemplified that smallest structural changes in the linker entity of PSMA radioligands may have a significant impact on their pharmacokinetic profiles and, thus, may be applied as a means for ligand design optimization. [ABSTRACT FROM AUTHOR]- Published
- 2020
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269. New 55Co-labeled Albumin-Binding Folate Derivatives as Potential PET Agents for Folate Receptor Imaging.
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Radford, Lauren L., Fernandez, Solana, Beacham, Rebecca, El Sayed, Retta, Farkas, Renata, Benešová, Martina, Müller, Cristina, and Lapi, Suzanne E.
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POSITRON emission tomography ,DOPAMINE receptors - Abstract
Overexpression of folate receptors (FRs) on different tumor types (e.g., ovarian, lung) make FRs attractive in vivo targets for directed diagnostic/therapeutic agents. Currently, no diagnostic agent suitable for positron emission tomography (PET) has been adopted for clinical FR imaging. In this work, two
55 Co-labeled albumin-binding folate derivatives-[55 Co]Co-cm10 and [55 Co]Co-rf42-with characteristics suitable for PET imaging have been developed and evaluated. High radiochemical yields (≥95%) and in vitro stabilities (≥93%) were achieved for both compounds, and cell assays demonstrated FR-mediated uptake. Both55 Co-labeled folate conjugates demonstrated high tumor uptake of 17% injected activity per gram of tissue (IA/g) at 4 h in biodistribution studies performed in KB tumor-bearing mice. Renal uptake was similar to other albumin-binding folate derivatives, and liver uptake was lower than that of previously reported [64 Cu]Cu-rf42. Small animal PET/CT images confirmed the biodistribution results and showed the clear delineation of FR-expressing tumors. [ABSTRACT FROM AUTHOR]- Published
- 2019
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270. Combination of Proton Therapy and Radionuclide Therapy in Mice: Preclinical Pilot Study at the Paul Scherrer Institute.
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Müller, Cristina, De Prado Leal, Maria, Dominietto, Marco D., Umbricht, Christoph A., Safai, Sairos, Perrin, Rosalind L., Egloff, Martina, Bernhardt, Peter, van der Meulen, Nicholas P., Weber, Damien C., Schibli, Roger, and Lomax, Antony J.
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PROTON therapy , *RADIOISOTOPES , *POSITRON emission tomography , *RADIOACTIVE tracers , *PILOT projects , *PROSTATE-specific membrane antigen - Abstract
Proton therapy (PT) is a treatment with high dose conformality that delivers a highly-focused radiation dose to solid tumors. Targeted radionuclide therapy (TRT), on the other hand, is a systemic radiation therapy, which makes use of intravenously-applied radioconjugates. In this project, it was aimed to perform an initial dose-searching study for the combination of these treatment modalities in a preclinical setting. Therapy studies were performed with xenograft mouse models of folate receptor (FR)-positive KB and prostate-specific membrane antigen (PSMA)-positive PC-3 PIP tumors, respectively. PT and TRT using 177Lu-folate and 177Lu-PSMA-617, respectively, were applied either as single treatments or in combination. Monitoring of the mice over nine weeks revealed a similar tumor growth delay after PT and TRT, respectively, when equal tumor doses were delivered either by protons or by β¯-particles, respectively. Combining the methodologies to provide half-dose by either therapy approach resulted in equal (PC-3 PIP tumor model) or even slightly better therapy outcomes (KB tumor model). In separate experiments, preclinical positron emission tomography (PET) was performed to investigate tissue activation after proton irradiation of the tumor. The high-precision radiation delivery of PT was confirmed by the resulting PET images that accurately visualized the irradiated tumor tissue. In this study, the combination of PT and TRT resulted in an additive effect or a trend of synergistic effects, depending on the type of tumor xenograft. This study laid the foundation for future research regarding therapy options in the situation of metastasized solid tumors, where surgery or PT alone are not a solution but may profit from combination with systemic radiation therapy. [ABSTRACT FROM AUTHOR]
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- 2019
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271. Therapeutic Potential of 47Sc in Comparison to 177Lu and 90Y: Preclinical Investigations.
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Siwowska, Klaudia, Guzik, Patrycja, Domnanich, Katharina A., Monné Rodríguez, Josep M., Bernhardt, Peter, Ponsard, Bernard, Hasler, Roger, Borgna, Francesca, Schibli, Roger, Köster, Ulli, van der Meulen, Nicholas P., and Müller, Cristina
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PEPTIDE receptors ,ABSORBED dose ,OVARIAN tumors ,TUMOR growth ,RADIOISOTOPES ,DRUG side effects ,CELL survival - Abstract
Targeted radionuclide therapy with
177 Lu- and90 Y-labeled radioconjugates is a clinically-established treatment modality for metastasized cancer.47 Sc is a therapeutic radionuclide that decays with a half-life of 3.35 days and emits medium-energy β− -particles. In this study,47 Sc was investigated, in combination with a DOTA-folate conjugate, and compared to the therapeutic properties of177 Lu-folate and90 Y-folate, respectively. In vitro,47 Sc-folate demonstrated effective reduction of folate receptor-positive ovarian tumor cell viability similar to177 Lu-folate, but90 Y-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 with47 Sc-folate (12.5 MBq),177 Lu-folate (10 MBq), and90 Y-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,47 Sc is likely to be comparable to177 Lu when employed for targeted radionuclide therapy. It may, therefore, have potential for clinical translation and be of particular interest in tandem with44 Sc or43 Sc as a diagnostic match, enabling the realization of radiotheragnostics in future. [ABSTRACT FROM AUTHOR]- Published
- 2019
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272. Design and Preclinical Evaluation of a Novel Prostate-Specific Membrane Antigen Radioligand Modified with a Transthyretin Binder.
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Vaccarin, Christian, Mapanao, Ana Katrina, Deberle, Luisa M., Becker, Anna E., Borgna, Francesca, Marzaro, Giovanni, Schibli, Roger, and Müller, Cristina
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IN vitro studies , *BIOLOGICAL models , *PROSTATE-specific antigen , *LIGANDS (Biochemistry) , *RADIOPHARMACEUTICALS , *RESEARCH funding , *DESCRIPTIVE statistics , *MICE , *ANIMAL experimentation , *SERUM albumin - Abstract
Simple Summary: Prostate-specific membrane antigen (PSMA)-targeting radioligands have been used clinically to treat metastatic prostate cancer. To deliver a sufficient radiation dose to eliminate cancer cells, the accumulation of the radioligand in the tumor should be high. Therefore, small-molecular-weight molecules have been modified with albumin binders to enhance their blood circulation time and, hence, increase the tumor uptake. The goal of this study was to investigate the utility of a transthyretin binder (TB-01) to achieve high tumor uptake of the resultant PSMA radioligand. Indeed, the newly developed [177Lu]Lu-PSMA-TB-01 demonstrated enhanced blood circulation as compared to the clinically employed [177Lu]Lu-PSMA-617. Consequently, a significantly higher accumulation of activity was observed in the tumor tissue, while activity retention in off-target tissue was only higher in the kidneys, but otherwise in the same range as for [177Lu]Lu-PSMA-617. Transthyretin binders have previously been used to improve the pharmacokinetic properties of small-molecule drug conjugates and could, thus, be utilized for radiopharmaceuticals as an alternative to the widely explored "albumin binder concept". In this study, a novel PSMA ligand modified with a transthyretin-binding entity (TB-01) was synthesized and labeled with lutetium-177 to obtain [177Lu]Lu-PSMA-TB-01. A high and specific uptake of [177Lu]Lu-PSMA-TB-01 was found in PSMA-positive PC-3 PIP cells (69 ± 3% after 4 h incubation), while uptake in PSMA-negative PC-3 flu cells was negligible (<1%). In vitro binding studies showed a 174-fold stronger affinity of [177Lu]Lu-PSMA-TB-01 to transthyretin than to human serum albumin. Biodistribution studies in PC-3 PIP/flu tumor-bearing mice confirmed the enhanced blood retention of [177Lu]Lu-PSMA-TB-01 (16 ± 1% IA/g at 1 h p.i.), which translated to a high tumor uptake (69 ± 13% IA/g at 4 h p.i.) with only slow wash-out over time (31 ± 8% IA/g at 96 h p.i.), while accumulation in the PC-3 flu tumor and non-targeted normal tissue was reasonably low. Further optimization of the radioligand design would be necessary to fine-tune the biodistribution and enable its use for therapeutic purposes. This study was the first of this kind and could motivate the use of the "transthyretin binder concept" for the development of future radiopharmaceuticals. [ABSTRACT FROM AUTHOR]
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- 2024
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273. First-in-human administration of terbium-161-labelled somatostatin receptor subtype 2 antagonist ([161Tb]Tb-DOTA-LM3) in a patient with a metastatic neuroendocrine tumour of the ileum.
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Fricke, Julia, Westerbergh, Frida, McDougall, Lisa, Favaretto, Chiara, Christ, Emanuel, Nicolas, Guillaume P., Geistlich, Susanne, Borgna, Francesca, Fani, Melpomeni, Bernhardt, Peter, van der Meulen, Nicholas P., Müller, Cristina, Schibli, Roger, and Wild, Damian
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SOMATOSTATIN receptors , *NEUROENDOCRINE tumors , *LINEAR energy transfer , *ILEUM , *METASTASIS , *COMPUTED tomography - Abstract
This article reports on the first-in-human administration of terbium-161-labelled somatostatin receptor subtype 2 antagonist ([161Tb]Tb-DOTA-LM3) in a patient with a metastatic neuroendocrine tumor of the ileum. The patient had previously received long-acting octreotide and underwent a test infusion of [161Tb]Tb-DOTA-LM3. The study found that [161Tb]Tb-DOTA-LM3 showed promising potential as an alternative to the current standard peptide receptor radionuclide therapy for patients with metastatic gastroenteropancreatic neuroendocrine tumors. The research was funded by the Swiss National Science Foundation and supported by other organizations. The study was conducted in accordance with ethical guidelines and the patient provided informed consent. [Extracted from the article]
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- 2024
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274. Preclinical investigations and first-in-human application of 152Tb-PSMA-617 for PET/CT imaging of prostate cancer.
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Müller, Cristina, Singh, Aviral, Umbricht, Christoph A., Kulkarni, Harshad R., Johnston, Karl, Benešová, Martina, Senftleben, Stefan, Müller, Dirk, Vermeulen, Christiaan, Schibli, Roger, Köster, Ulli, van der Meulen, Nicholas P., and Baum, Richard P.
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POSITRON emission tomography computed tomography , *CASTRATION-resistant prostate cancer , *PROSTATE cancer , *IMAGING of cancer , *NUCLEAR medicine , *DIAGNOSTIC imaging - Abstract
Background: For almost a decade, terbium radioisotopes have been explored for their potential theragnostic application in nuclear medicine: 152Tb and 155Tb are the radioisotopes identified for PET or SPECT imaging, while 149Tb and 161Tb have suitable decay characteristics for α- and combined β−/Auger-e−-therapy, respectively. In the present study, the application of 152Tb, in combination with PSMA-617 for imaging of prostate-specific membrane antigen (PSMA)-positive prostate cancer, was demonstrated in a preclinical setting and in a patient with metastatic castration-resistant prostate cancer (mCRPC). Results: 152Tb was produced at the ISOLDE facility at CERN/Geneva, Switzerland, by spallation, followed by on-line mass separation. The chemical separation was performed at Paul Scherrer Institute using chromatographic methods, as previously reported. 152Tb was employed for labeling PSMA-617, and the radioligand was extensively investigated in vitro to demonstrate similar characteristics to its 177Lu-labeled counterpart. Preclinical PET/CT imaging studies performed with mice enabled visualization of PSMA-positive PC-3 PIP tumors, while uptake in PSMA-negative PC-3 flu tumors were absent. Based on these promising preclinical results, 152Tb was shipped to Zentralklinik Bad Berka, Germany, where it was used for labeling of PSMA-617, enabling PET imaging of a patient with mCRPC. PET/CT scans were performed over a period of 25 h post injection (p.i.) of the radioligand (140 MBq). The images were of diagnostic quality, particularly those acquired at later time points, and enabled the detection of the same metastatic lesions and of local recurrent tumor as previously detected by 68Ga-PSMA-11 PET/CT acquired 45 min p.i. Conclusions: The results of this study demonstrate the successful preparation and preclinical testing of 152Tb-PSMA-617 and its first application in a patient with mCRPC. This work could pave the way towards clinical application of other Tb radionuclides in the near future, most importantly 161Tb, which has promising decay characteristics for an effective treatment of mCRPC patients. [ABSTRACT FROM AUTHOR]
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- 2019
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275. Production and characterization of no-carrier-added 161Tb as an alternative to the clinically-applied 177Lu for radionuclide therapy.
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Gracheva, Nadezda, Müller, Cristina, Talip, Zeynep, Heinitz, Stephan, Köster, Ulli, Zeevaart, Jan Rijn, Vögele, Alexander, Schibli, Roger, and van der Meulen, Nicholas P.
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NUCLEAR research , *RADIOCHEMICAL purification , *NEUTRON irradiation , *RESEARCH reactors , *RADIOISOTOPES , *AUGER effect - Abstract
Background: 161Tb is an interesting radionuclide for cancer treatment, showing similar decay characteristics and chemical behavior to clinically-employed 177Lu. The therapeutic effect of 161Tb, however, may be enhanced due to the co-emission of a larger number of conversion and Auger electrons as compared to 177Lu. The aim of this study was to produce 161Tb from enriched 160Gd targets in quantity and quality sufficient for first application in patients. Methods: No-carrier-added 161Tb was produced by neutron irradiation of enriched 160Gd targets at nuclear research reactors. The 161Tb purification method was developed with the use of cation exchange (Sykam resin) and extraction chromatography (LN3 resin), respectively. The resultant product (161TbCl3) was characterized and the 161Tb purity compared with commercial 177LuCl3. The purity of the final product (161TbCl3) was analyzed by means of γ-ray spectrometry (radionuclidic purity) and radio TLC (radiochemical purity). The radiolabeling yield of 161Tb-DOTA was assessed over a two-week period post processing in order to observe the quality change of the obtained 161Tb towards future clinical application. To understand how the possible drug products (peptides radiolabeled with 161Tb) vary with time, stability of the clinically-applied somatostatin analogue DOTATOC, radiolabeled with 161Tb, was investigated over a 24-h period. The radiolytic stability experiments were compared to those performed with 177Lu-DOTATOC in order to investigate the possible influence of conversion and Auger electrons of 161Tb on peptide disintegration. Results: Irradiations of enriched 160Gd targets yielded 6–20 GBq 161Tb. The final product was obtained at an activity concentration of 11–21 MBq/μL with ≥99% radionuclidic and radiochemical purity. The DOTA chelator was radiolabeled with 161Tb or 177Lu at the molar activity deemed useful for clinical application, even at the two-week time point after end of chemical separation. DOTATOC, radiolabeled with either 161Tb or 177Lu, was stable over 24 h in the presence of a stabilizer. Conclusions: In this study, it was shown that 161Tb can be produced in high activities using different irradiation facilities. The developed method for 161Tb separation from the target material yielded 161TbCl3 in quality suitable for high-specific radiolabeling, relevant for future clinical application. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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276. Internal radiation dosimetry of a 152Tb-labeled antibody in tumor-bearing mice.
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Cicone, Francesco, Gnesin, Silvano, Denoël, Thibaut, Stora, Thierry, van der Meulen, Nicholas P., Müller, Cristina, Vermeulen, Christiaan, Benešová, Martina, Köster, Ulli, Johnston, Karl, Amato, Ernesto, Auditore, Lucrezia, Coukos, George, Stabin, Michael, Schaefer, Niklaus, Viertl, David, and Prior, John O.
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RADIATION dosimetry ,ORGANS (Anatomy) ,ABSORBED dose ,CHIMERIC proteins ,CAMERA calibration ,MICE - Abstract
Background: Biodistribution studies based on organ harvesting represent the gold standard pre-clinical technique for dose extrapolations. However, sequential imaging is becoming increasingly popular as it allows the extraction of longitudinal data from single animals, and a direct correlation with deterministic radiation effects. We assessed the feasibility of mouse-specific, microPET-based dosimetry of an antibody fragment labeled with the positron emitter
152 Tb [(T1/2 = 17.5 h, Eβ+ mean = 1140 keV (20.3%)]. Image-based absorbed dose estimates were compared with those obtained from the extrapolation to152 Tb of a classical biodistribution experiment using the same antibody fragment labeled with111 In.152 Tb was produced by proton-induced spallation in a tantalum target, followed by mass separation and cation exchange chromatography. The endosialin-targeting scFv78-Fc fusion protein was conjugated with the chelator p-SCN-Bn-CHX-A"-DTPA, followed by labeling with either152 Tb or111 In. Micro-PET images of four immunodeficient female mice bearing RD-ES tumor xenografts were acquired 4, 24, and 48 h after the i.v. injection of152 Tb-CHX-DTPA-scFv78-Fc. After count/activity camera calibration, time-integrated activity coefficients (TIACs) were obtained for the following compartments: heart, lungs, liver, kidneys, intestines, tumor, and whole body, manually segmented on CT. For comparison, radiation dose estimates of152 Tb-CHX-DTPA-scFv78-Fc were extrapolated from mice dissected 4, 24, 48, and 96 h after the injection of111 In-CHX-DTPA-scFv78-Fc (3–5 mice per group). Imaging-derived and biodistribution-derived organ TIACs were used as input in the 25 g mouse model of OLINDA/EXM® 2.0, after appropriate mass rescaling. Tumor absorbed doses were obtained using the OLINDA2 sphere model. Finally, the relative percent difference (RD%) between absorbed doses obtained from imaging and biodistribution were calculated. Results: RD% between microPET-based dosimetry and biodistribution-based dose extrapolations were + 12, − 14, and + 17 for the liver, the kidneys, and the tumors, respectively. Compared to biodistribution, the imaging method significantly overestimates the absorbed doses to the heart and the lungs (+ 89 and + 117% dose difference, respectively). Conclusions: MicroPET-based dosimetry of152 Tb is feasible, and the comparison with organ harvesting resulted in acceptable dose discrepancies for body districts that can be segmented on CT. These encouraging results warrant additional validation using radiolabeled biomolecules with a different biodistribution pattern. [ABSTRACT FROM AUTHOR]- Published
- 2019
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277. Scandium and terbium radionuclides for radiotheranostics: current state of development towards clinical application.
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Müller, Cristina, Umbricht, Christoph A, van der Meulen, Nicholas P, and Domnanich, Katharina A
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RADIOTHERAPY , *COMPANION diagnostics , *TERBIUM , *SCANDIUM , *NUCLEAR medicine - Abstract
Currently, different radiometals are in use for imaging and therapy in nuclear medicine: 68Ga and 111In are examples of nuclides for positron emission tomography (PET) and single photon emission computed tomography (SPECT), respectively, while 177Lu and 225Ac are used for β−- and α-radionuclide therapy. The application of diagnostic and therapeutic radionuclides of the same element (radioisotopes) would utilize chemically-identical radiopharmaceuticals for imaging and subsequent treatment, thereby enabling the radiotheranostic concept. There are two elements which are of particular interest in this regard: Scandium and Terbium. Scandium presents three radioisotopes for theranostic application. 43Sc (T1/2 = 3.9 h) and 44Sc (T1/2 = 4.0 h) can both be used for PET, while 47Sc (T1/2 = 3.35 d) is the therapeutic match—also suitable for SPECT. Currently, 44Sc is most advanced in terms of production, as well as with pre-clinical investigations, and has already been employed in proof-of-concept studies in patients. Even though the production of 43Sc may be more challenging, it would be advantageous due to the absence of high-energetic γ-ray emission. The development of 47Sc is still in its infancy, however, its therapeutic potential has been demonstrated preclinically. Terbium is unique in that it represents four medically-interesting radioisotopes. 155Tb (T1/2 = 5.32 d) and 152Tb (T1/2 = 17.5 h) can be used for SPECT and PET, respectively. Both radioisotopes were produced and tested preclinically. 152Tb has been the first Tb isotope that was tested (as 152Tb-DOTATOC) in a patient. Both radionuclides may be of interest for dosimetry purposes prior to the application of radiolanthanide therapy. The decay properties of 161Tb (T1/2 = 6.89 d) are similar to 177Lu, but the coemission of Auger electrons make it attractive for a combined β−/Auger electron therapy, which was shown to be effective in preclinical experiments. 149Tb (T1/2 = 4.1 h) has been proposed for targeted α-therapy with the possibility of PET imaging. In terms of production, 161Tb and 155Tb are most promising to be made available at the large quantities suitable for future clinical translation. This review article is dedicated to the production routes, the methods of separating the radioisotopes from the target material, preclinical investigations and clinical proof-of-concept studies of Sc and Tb radionuclides. The availability, challenges of production and first (pre)clinical application, as well as the potential of these novel radionuclides for future application in nuclear medicine, are discussed. [ABSTRACT FROM AUTHOR]
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- 2018
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278. Additional file 1: of Preclinical investigations and first-in-human application of 152Tb-PSMA-617 for PET/CT imaging of prostate cancer
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Müller, Cristina, Aviral Singh, Umbricht, Christoph, Harshad Kulkarni, Johnston, Karl, Benešová, Martina, Senftleben, Stefan, Müller, Dirk, Vermeulen, Christiaan, Schibli, Roger, Köster, Ulli, Meulen, Nicholas, and Baum, Richard
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3. Good health - Abstract
Figure S1. Representative chromatograms of (a) 152Tb-PSMA-617 and (b) 177Lu-PSMA-617 after successful radiolabeling. Table S1. Stability of 152Tb-PSMA-617. (DOCX 517 kb)
279. 44Sc-PSMA-617 for radiotheragnostics in tandem with 177Lu-PSMA-617—preclinical investigations in comparison with 68Ga-PSMA-11 and 68Ga-PSMA-617
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Umbricht, Christoph A., Benešová, Martina, Schmid, Raffaella M., Türler, Andreas, Schibli, Roger, van der Meulen, Nicholas P., and Müller, Cristina
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44Sc ,68Ga ,177Lu ,Prostate cancer ,PSMA ,PET imaging ,Theragnostics ,Cyclotron ,urologic and male genital diseases ,Original Research - Abstract
Background The targeting of the prostate-specific membrane antigen (PSMA) is of particular interest for radiotheragnostic purposes of prostate cancer. Radiolabeled PSMA-617, a 1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid (DOTA)-functionalized PSMA ligand, revealed favorable kinetics with high tumor uptake, enabling its successful application for PET imaging (68Ga) and radionuclide therapy (177Lu) in the clinics. In this study, PSMA-617 was labeled with cyclotron-produced 44Sc (T 1/2 = 4.04 h) and investigated preclinically for its use as a diagnostic match to 177Lu-PSMA-617. Results 44Sc was produced at the research cyclotron at PSI by irradiation of enriched 44Ca targets, followed by chromatographic separation. 44Sc-PSMA-617 was prepared under standard labeling conditions at elevated temperature resulting in a radiochemical purity of >97% at a specific activity of up to 10 MBq/nmol. 44Sc-PSMA-617 was evaluated in vitro and compared to the 177Lu- and 68Ga-labeled match, as well as 68Ga-PSMA-11 using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu prostate cancer cells. In these experiments it revealed similar in vitro properties to that of 177Lu- and 68Ga-labeled PSMA-617. Moreover, 44Sc-PSMA-617 bound specifically to PSMA-expressing PC-3 PIP tumor cells, while unspecific binding to PC-3 flu cells was not observed. The radioligands were investigated with regard to their in vivo properties in PC-3 PIP/flu tumor-bearing mice. 44Sc-PSMA-617 showed high tumor uptake and a fast renal excretion. The overall tissue distribution of 44Sc-PSMA-617 resembled that of 177Lu-PSMA-617 most closely, while the 68Ga-labeled ligands, in particular 68Ga-PSMA-11, showed different distribution kinetics. 44Sc-PSMA-617 enabled distinct visualization of PC-3 PIP tumor xenografts shortly after injection, with increasing tumor-to-background contrast over time while unspecific uptake in the PC-3 flu tumors was not observed. Conclusions The in vitro characteristics and in vivo kinetics of 44Sc-PSMA-617 were more similar to 177Lu-PSMA-617 than to 68Ga-PSMA-617 and 68Ga-PSMA-11. Due to the almost four-fold longer half-life of 44Sc as compared to 68Ga, a centralized production of 44Sc-PSMA-617 and transport to satellite PET centers would be feasible. These features make 44Sc-PSMA-617 particularly appealing for clinical application., EJNMMI Research, 7 (1), ISSN:2191-219X
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280. PEGylation, increasing specific activity and multiple dosing as strategies to improve the risk-benefit profile of targeted radionuclide therapy with 177Lu-DOTA-bombesin analogues
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Däpp, Simone, Müller, Cristina, García-Garayoa, Elisa, Bläuenstein, Peter, Maes, Veronique, Brans, Luc, Tourwé, Dirk A., and Schibli, Roger
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Gastrin-releasing peptide ,Prostate cancer ,Lu ,PEGylation ,Radionuclide therapy ,3. Good health - Abstract
Background Radiolabelled bombesin (BN) conjugates are promising radiotracers for imaging and therapy of breast and prostate tumours, in which BN2/gastrin-releasing peptide receptors are overexpressed. We describe the influence of the specific activity of a 177Lu-DOTA-PEG5k-Lys-B analogue on its therapeutic efficacy and compare it with its non-PEGylated counterpart. Methods Derivatisation of a stabilised DOTA-BN(7–14)[Cha13,Nle14] analogue with a linear PEG molecule of 5 kDa (PEG5k) was performed by PEGylation of the ϵ-amino group of a β3hLys-βAla-βAla spacer between the BN sequence and the DOTA chelator. The non-PEGylated and the PEGylated analogues were radiolabelled with 177Lu. In vitro evaluation was performed in human prostate carcinoma PC-3 cells, and in vivo studies were carried out in nude mice bearing PC-3 tumour xenografts. Different specific activities of the PEGylated BN analogue and various dose regimens were evaluated concerning their therapeutic efficacy. Results The specificity and the binding affinity of the BN analogue for BN2/GRP receptors were only slightly reduced by PEGylation. In vitro binding kinetics of the PEGylated analogue was slower since steady-state condition was reached after 4 h. PEGylation improved the stability of BN conjugate in vitro in human plasma by a factor of 5.6. The non-PEGylated BN analogue showed favourable pharmacokinetics already, i.e. fast blood clearance and renal excretion, but PEGylation improved the in vivo behaviour further. One hour after injection, the tumour uptake of the PEG5k-BN derivative was higher compared with that of the non-PEGylated analogue (3.43 ± 0.63% vs. 1.88 ± 0.4% ID/g). Moreover, the increased tumour retention resulted in a twofold higher tumour accumulation at 24 h p.i., and increased tumour-to-non-target ratios (tumour-to-kidney, 0.6 vs. 0.4; tumour-to-liver, 8.8 vs. 5.9, 24 h p.i.). In the therapy study, both 177Lu-labelled BN analogues significantly inhibited tumour growth. The therapeutic efficacy was highest for the PEGylated derivative of high specific activity administered in two fractions (2 × 20 MBq = 40 MBq) at day 0 and day 7 (73% tumour growth inhibition, 3 weeks after therapy). Conclusions PEGylation and increasing the specific activity enhance the pharmacokinetic properties of a 177Lu-labelled BN-based radiopharmaceutical and provide a protocol for targeted radionuclide therapy with a beneficial anti-tumour effectiveness and a favourable risk-profile at the same time., EJNMMI Research, 2 (1), ISSN:2191-219X
281. Clinical evaluation of the radiolanthanide terbium-152: first-in-human PET/CT with 152 Tb-DOTATOC
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Baum, Richard P., Singh, Aviral, Benešová, Martina, Vermeulen, Christiaan, Gnesin, Silvano, Köster, Ulli, Johnston, Karl, Müller, Dirk, Senftleben, Stefan, Kulkarni, Harshad R., Türler, Andreas, Schibli, Roger, Prior, John O., Van Der Meulen, Nicholas P., and Müller, Cristina
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540 Chemistry ,570 Life sciences ,biology ,3. Good health
282. Additional file 1: Figure S1a. of 47Sc as useful β–-emitter for the radiotheragnostic paradigm: a comparative study of feasible production routes
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Domnanich, Katharina, Müller, Cristina, Benešová, Martina, Rugard Dressler, Haller, Stephanie, Köster, Ulli, Ponsard, Bernard, Schibli, Roger, Türler, Andreas, and Meulen, Nicholas Van Der
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7. Clean energy - Abstract
Formula for the calculation of the 47Sc activity in Bq (s−1), accessible under the applied irradiation conditions. σ = nuclear cross section of the 46Ca(n,γ)47Ca reaction in cm−2, NT = number of 46Ca atoms, Φth = thermal neutron flux in n * cm−2 * s−1, λSc and λCa = decay constants of 47Sc and 47Ca in s−1, tirr = irradiation time and twait = post irradiation waiting time in s. b Formula for the calculation of the optimal post irradiation waiting time (topt) in s, accessible at the applied irradiation time (tirr in s). The decay constants of 47Sc (λSc) and 47Ca (λCa) are given in s−1. c Formula for the calculation of the optimal relative 47Sc activity (a(47Sc)opt) (dimensionless), accessible under the applied irradiation conditions. σ = nuclear cross section of the 46Ca(n,γ)47Ca reaction in cm−2, NT = number of 46Ca atoms, Φth = thermal neutron flux in n * cm−2 * s−1, λSc and λCa = decay constants of 47Sc and 47Ca in s−1. d Formula for the maximal obtainable 47Sc activity (dimensionless). The irradiation time (tirr) is given in s and the decay constants of 47Sc (λSc) and 47Ca (λCa) in s−1. Figure S2. γ-Ray spectra of 47Sc and 47Ca from the neutron-irradiated 46Ca ampoule, obtained 71 h after the end of irradiation (measurement time: 10 s) (a) and of the pure 47Sc eluate after separation (Method B), obtained 1 h after the end of separation (measurement time: 250 s) (b). Figure S3. γ-Ray spectrum of the neutron-irradiated 47Ti ampoule at SINQ, obtained 21 d after the end of irradiation (measurement time: 9600 s). Figure S4. Measured cross section values (squares, retrieved from the EXFOR-database) (Zerkin 2016) as well as the theoretical calculations from the TENDL-2015 library (straight line) (Koning, Rochman et al. 2015) for the 47Ti(n,p)47Sc (blue) and the 47Ti(n,p + n)46Sc (black) nuclear reactions. Table S5. Trace metal analysis of the reduced 46Ti metal by ICP-OES. Only the elements determined at a concentration higher than the detection limit are listed below. (DOCX 415 kb)
283. Impact of the mouse model and molar amount of injected ligand on the tissue distribution profile of PSMA radioligands
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Tschan, Viviane J., Borgna, Francesca, Schibli, Roger, and Müller, Cristina
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PC-3 PIP ,PSMA ligands ,LNCaP ,Albumin binder ,Molar amount ,urologic and male genital diseases ,3. Good health - Abstract
Purpose Various preclinical study designs are described in the literature for the evaluation of PSMA radioligands. In this study, [177Lu]Lu-Ibu-DAB-PSMA, an albumin-binding radioligand, and [177Lu]Lu-PSMA-617 were investigated and compared under variable experimental conditions. Methods In vitro cell uptake studies were performed with PC-3 PIP and LNCaP tumor cells using a range of molar concentrations (0.75–500 nM) of both radioligands. Biodistribution and SPECT/CT imaging studies were carried out with the respective tumor mouse models using 0.05 nmol and 1.0 nmol injected ligand per mouse. Results In both tumor cell lines, the uptake of the radioligands was increased when using low molar concentrations of the respective ligand. The observed saturation effect at high ligand concentrations was more pronounced for LNCaP cells that express PSMA at lower levels than for PC-3 PIP cells. At all investigated timepoints, the in vivo uptake of both radioligands was higher in PC-3 PIP tumors than in LNCaP tumors. A low molar amount of injected ligand increased the PC-3 PIP tumor uptake mainly for [177Lu]Lu-Ibu-DAB-PSMA; however, the molar amount of ligand was relevant for both radioligands when using LNCaP tumors. Renal retention of both radioligands was, however, up to fourfold higher during the first hours after application of a low ligand amount compared to the high ligand amount. Conclusion The results of this preclinical study underline the relevance of the tumor model and applied ligand amount for the characterization of PSMA radioligands. The application of equal preclinical study designs is crucial to allow the comparison of novel radioligands with existing ones and, thus, predict potential advantages of new radioligands in view of a clinical application., European Journal of Nuclear Medicine and Molecular Imaging, 49 (2), ISSN:1619-7070, ISSN:1619-7089
284. Therapeutic potential of 47Sc in comparison to 177Lu and 90Y: Preclinical investigations
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Siwowska, Klaudia, Guzik, Patrycja, Domnanich, Katharina A., Monné Rodríguez, Josep M., Bernhardt, Peter, Ponsard, Bernard, Hasler, Roger, Borgna, Francesca, Schibli, Roger, Köster, Ulli, van der Meulen, Nicholas P., and Müller, Cristina
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folate receptor ,SPECT ,47Sc ,radionuclide therapy ,177Lu ,IGROV-1 tumor xenografts ,90Y ,DOTA-folate ,3. Good health ,preclinical therapy - Abstract
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)
285. Additional file 1: of Preclinical investigations and first-in-human application of 152Tb-PSMA-617 for PET/CT imaging of prostate cancer
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Müller, Cristina, Aviral Singh, Umbricht, Christoph, Harshad Kulkarni, Johnston, Karl, Benešová, Martina, Senftleben, Stefan, Müller, Dirk, Vermeulen, Christiaan, Schibli, Roger, Köster, Ulli, Meulen, Nicholas, and Baum, Richard
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3. Good health - Abstract
Figure S1. Representative chromatograms of (a) 152Tb-PSMA-617 and (b) 177Lu-PSMA-617 after successful radiolabeling. Table S1. Stability of 152Tb-PSMA-617. (DOCX 517 kb)
286. A short-term biological indicator for long-term kidney damage after radionuclide therapy in mice
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Pellegrini, Giovanni, Siwowska, Klaudia, Haller, Stephanie, Antoine, Daniel J., Schibli, Roger, Kipar, Anja, and Müller, Cristina
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Radiofolate ,γ-H2AX ,DNA double-strand breaks ,177Lu ,Kidney ,Radiation nephropathy ,3. Good health - Abstract
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
287. New 55Co-labeled Albumin-Binding Folate Derivatives as Potential PET Agents for Folate Receptor Imaging
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Radford, Lauren L., Fernandez, Solana, Beacham, Rebecca, El Sayed, Retta, Farkas, Renáta, Benešová, Martina, Müller, Cristina, and Lapi, Suzanne E.
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folic acid ,albumin binder ,ovarian cancer ,folate receptors ,PET imaging ,cobalt-55 ,3. Good health - Abstract
Overexpression of folate receptors (FRs) on different tumor types (e.g., ovarian, lung) make FRs attractive in vivo targets for directed diagnostic/therapeutic agents. Currently, no diagnostic agent suitable for positron emission tomography (PET) has been adopted for clinical FR imaging. In this work, two 55Co-labeled albumin-binding folate derivatives-[55Co]Co-cm10 and [55Co]Co-rf42-with characteristics suitable for PET imaging have been developed and evaluated. High radiochemical yields (≥95%) and in vitro stabilities (≥93%) were achieved for both compounds, and cell assays demonstrated FR-mediated uptake. Both 55Co-labeled folate conjugates demonstrated high tumor uptake of 17% injected activity per gram of tissue (IA/g) at 4 h in biodistribution studies performed in KB tumor-bearing mice. Renal uptake was similar to other albumin-binding folate derivatives, and liver uptake was lower than that of previously reported [64Cu]Cu-rf42. Small animal PET/CT images confirmed the biodistribution results and showed the clear delineation of FR-expressing tumors., Pharmaceuticals, 12 (4), ISSN:1424-8247
288. Simultaneous Visualization of 161Tb- and 177Lu-Labeled Somatostatin Analogues Using Dual-Isotope SPECT Imaging
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Borgna, Francesca, Barritt, Patrick, Grundler, Pascal V., Talip, Zeynep, Cohrs, Susan, Zeevaart, Jan Rijn, Köster, Ulli, Schibli, Roger, van der Meulen, Nicholas P., and Müller, Cristina
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NET ,antagonists ,dualisotope SPECT ,lutetium-177 ,agonists ,radionuclide therapy ,terbium-161 ,3. Good health - Abstract
The decay of terbium-161 results in the emission of β¯-particles as well as conversion and Auger electrons, which makes terbium-161 interesting for therapeutic purposes. The aim of this study was to use dual-isotope SPECT imaging in order to demonstrate visually that terbium-161 and lutetium-177 are interchangeable without compromising the pharmacokinetic profile of the radiopharmaceutical. The 161Tb- and 177Lu-labeled somatostatin (SST) analogues DOTATOC (agonist) and DOTA-LM3 (antagonist) were tested in vitro to demonstrate equal properties regarding distribution coefficients and cell uptake into SST receptor-positive AR42J tumor cells. The radiopeptides were further investigated in AR42J tumor-bearing nude mice using the method of dual-isotope (terbium-161/lutetium-177) SPECT/CT imaging to enable the visualization of their distribution profiles in the same animal. Equal pharmacokinetic profiles were demonstrated for either of the two peptides, irrespective of whether it was labeled with terbium-161 or lutetium-177. Moreover, the visualization of the sub-organ distribution confirmed similar behavior of 161Tb- and 177Lu-labeled SST analogues. The data were verified in quantitative biodistribution studies using either type of peptide labeled with terbium-161 or lutetium-177. While the radionuclide did not have an impact on the organ distribution, this study confirmed previous data of a considerably higher tumor uptake of radiolabeled DOTA-LM3 as compared to the radiolabeled DOTATOC., Pharmaceutics, 13 (4)
289. Production and characterization of no-carrier-added 161Tb as an alternative to the clinically-applied 177Lu for radionuclide therapy
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Gracheva, Nadezda, Müller, Cristina, Talip, Zeynep, Heinitz, Stephan, Köster, Ulli, Zeevaart, Jan Rijn, Vögele, Alexander, Schibli, Roger, and van der Meulen, Nicholas P.
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DOTA ,161Tb ,Purification method ,Somatostatin analogues ,Auger/conversion electrons ,3. Good health - Abstract
Background 161Tb is an interesting radionuclide for cancer treatment, showing similar decay characteristics and chemical behavior to clinically-employed 177Lu. The therapeutic effect of 161Tb, however, may be enhanced due to the co-emission of a larger number of conversion and Auger electrons as compared to 177Lu. The aim of this study was to produce 161Tb from enriched 160Gd targets in quantity and quality sufficient for first application in patients. Methods No-carrier-added 161Tb was produced by neutron irradiation of enriched 160Gd targets at nuclear research reactors. The 161Tb purification method was developed with the use of cation exchange (Sykam resin) and extraction chromatography (LN3 resin), respectively. The resultant product (161TbCl3) was characterized and the 161Tb purity compared with commercial 177LuCl3. The purity of the final product (161TbCl3) was analyzed by means of γ-ray spectrometry (radionuclidic purity) and radio TLC (radiochemical purity). The radiolabeling yield of 161Tb-DOTA was assessed over a two-week period post processing in order to observe the quality change of the obtained 161Tb towards future clinical application. To understand how the possible drug products (peptides radiolabeled with 161Tb) vary with time, stability of the clinically-applied somatostatin analogue DOTATOC, radiolabeled with 161Tb, was investigated over a 24-h period. The radiolytic stability experiments were compared to those performed with 177Lu-DOTATOC in order to investigate the possible influence of conversion and Auger electrons of 161Tb on peptide disintegration. Results Irradiations of enriched 160Gd targets yielded 6–20 GBq 161Tb. The final product was obtained at an activity concentration of 11–21 MBq/μL with ≥99% radionuclidic and radiochemical purity. The DOTA chelator was radiolabeled with 161Tb or 177Lu at the molar activity deemed useful for clinical application, even at the two-week time point after end of chemical separation. DOTATOC, radiolabeled with either 161Tb or 177Lu, was stable over 24 h in the presence of a stabilizer. Conclusions In this study, it was shown that 161Tb can be produced in high activities using different irradiation facilities. The developed method for 161Tb separation from the target material yielded 161TbCl3 in quality suitable for high-specific radiolabeling, relevant for future clinical application., EJNMMI Radiopharmacy and Chemistry, 4 (1)
290. Preclinical investigations and first-in-human application of 152Tb-PSMA-617 for PET/CT imaging of prostate cancer
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Müller, Cristina, Singh, Aviral, Umbricht, Christoph A., Kulkarni, Harshad R., Johnston, Karl, Benešová, Martina, Senftleben, Stefan, Müller, Dirk, Vermeulen, Christiaan, Schibli, Roger, Köster, Ulli, van der Meulen, Nicholas P., and Baum, Richard P.
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Prostate cancer ,PET/CT imaging ,Theragnostics ,152Tb ,Terbium ,PSMA-617 ,3. Good health - Abstract
Background For almost a decade, terbium radioisotopes have been explored for their potential theragnostic application in nuclear medicine: 152Tb and 155Tb are the radioisotopes identified for PET or SPECT imaging, while 149Tb and 161Tb have suitable decay characteristics for α- and combined β−/Auger-e−-therapy, respectively. In the present study, the application of 152Tb, in combination with PSMA-617 for imaging of prostate-specific membrane antigen (PSMA)-positive prostate cancer, was demonstrated in a preclinical setting and in a patient with metastatic castration-resistant prostate cancer (mCRPC). Results 152Tb was produced at the ISOLDE facility at CERN/Geneva, Switzerland, by spallation, followed by on-line mass separation. The chemical separation was performed at Paul Scherrer Institute using chromatographic methods, as previously reported. 152Tb was employed for labeling PSMA-617, and the radioligand was extensively investigated in vitro to demonstrate similar characteristics to its 177Lu-labeled counterpart. Preclinical PET/CT imaging studies performed with mice enabled visualization of PSMA-positive PC-3 PIP tumors, while uptake in PSMA-negative PC-3 flu tumors were absent. Based on these promising preclinical results, 152Tb was shipped to Zentralklinik Bad Berka, Germany, where it was used for labeling of PSMA-617, enabling PET imaging of a patient with mCRPC. PET/CT scans were performed over a period of 25 h post injection (p.i.) of the radioligand (140 MBq). The images were of diagnostic quality, particularly those acquired at later time points, and enabled the detection of the same metastatic lesions and of local recurrent tumor as previously detected by 68Ga-PSMA-11 PET/CT acquired 45 min p.i. Conclusions The results of this study demonstrate the successful preparation and preclinical testing of 152Tb-PSMA-617 and its first application in a patient with mCRPC. This work could pave the way towards clinical application of other Tb radionuclides in the near future, most importantly 161Tb, which has promising decay characteristics for an effective treatment of mCRPC patients., EJNMMI Research, 9 (1), ISSN:2191-219X
291. Folate Receptor Targeted Alpha-Therapy Using Terbium-149
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Türler, Andreas, Zhernosekov, Konstantin, Johnston, Karl, Dorrer, Holger, Schibli, Roger, Reber, Josefine, Müller, Cristina, Köster, Ulli, and Haller, Stephanie
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540 Chemistry ,570 Life sciences ,biology ,3. Good health - Abstract
Terbium-149 is among the most interesting therapeutic nuclides for medical applications. It decays by emission of short-range α-particles (Eα = 3.967 MeV) with a half-life of 4.12 h. The goal of this study was to investigate the anticancer efficacy of a 149Tb-labeled DOTA-folate conjugate (cm09) using folate receptor (FR)-positive cancer cells in vitro and in tumor-bearing mice. 149Tb was produced at the ISOLDE facility at CERN. Radiolabeling of cm09 with purified 149Tb resulted in a specific activity of ~1.2 MBq/nmol. In vitro assays performed with 149Tb-cm09 revealed a reduced KB cell viability in a FR-specific and activity concentration-dependent manner. Tumor-bearing mice were injected with saline only (group A) or with 149Tb-cm09 (group B: 2.2 MBq; group C: 3.0 MBq). A significant tumor growth delay was found in treated animals resulting in an increased average survival time of mice which received 149Tb-cm09 (B: 30.5 d; C: 43 d) compared to untreated controls (A: 21 d). Analysis of blood parameters revealed no signs of acute toxicity to the kidneys or liver in treated mice over the time of investigation. These results demonstrated the potential of folate-based α-radionuclide therapy in tumor-bearing mice.
292. Terbium-161 for PSMA-targeted radionuclide therapy of prostate cancer
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Müller, Cristina, Umbricht, Christoph A., Gracheva, Nadezda, Tschan, Viviane J., Pellegrini, Giovanni, Bernhardt, Peter, Zeevaart, Jan Rijn, Köster, Ulli, Schibli, Roger, and van der Meulen, Nicholas P.
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Prostate cancer ,Radioligand therapy ,PSMA ligands ,161Tb ,Auger electrons ,urologic and male genital diseases ,3. Good health - Abstract
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 161Tb (T1/2 = 6.89 days; Eβ͞av = 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. Methods 161Tb was used for the radiolabeling of PSMA-617 at high specific activities up to 100 MBq/nmol. 161Tb-PSMA-617 was tested in vitro and in tumor-bearing mice to confirm equal properties, as previously determined for 177Lu-PSMA-617. The effects of 161Tb-PSMA-617 and 177Lu-PSMA-617 on cell viability (MTT assay) and survival (clonogenic assay) were compared in vitro using PSMA-positive PC-3 PIP tumor cells. 161Tb-PSMA-617 was further investigated in therapy studies using PC-3 PIP tumor-bearing mice. Results 161Tb-PSMA-617 and 177Lu-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 161Tb-PSMA-617 as compared to the effect obtained with the same activities of 177Lu-PSMA-617 over the whole investigated concentration range. Treatment of mice with 161Tb-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 161Tb-PSMA-617 and 177Lu-PSMA-617 indicated the anticipated superiority of 161Tb over 177Lu. Conclusion 161Tb-PSMA-617 showed superior in-vitro and in-vivo results as compared to 177Lu-PSMA-617, confirming theoretical dose calculations that indicate an additive therapeutic effect of conversion and Auger electrons in the case of 161Tb. These data warrant more preclinical research for in-depth investigations of the proposed concept, and present a basis for future clinical translation of 161Tb-PSMA-617 for the treatment of mCRPC., European Journal of Nuclear Medicine and Molecular Imaging, 46 (9), ISSN:1619-7070, ISSN:1619-7089
293. Folate receptor targeted alpha-therapy using terbium-149
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Müller, Cristina, Reber, Josefine, Haller, Stephanie, Dorrer, Holger, Köster, Ulli, Johnston, Karl, Zhernosekov, Konstantin, Türler, Andreas, and Schibli, Roger
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Terbium-149 ,Folate receptor ,149Tb-cm09 ,Alpha-therapy ,Albumin binder ,Radionuclide therapy ,DOTA-folate ,3. Good health ,KB tumors - Abstract
Terbium-149 is among the most interesting therapeutic nuclides for medical applications. It decays by emission of short-range α-particles (Eα = 3.967 MeV) with a half-life of 4.12 h. The goal of this study was to investigate the anticancer efficacy of a 149Tb-labeled DOTA-folate conjugate (cm09) using folate receptor (FR)-positive cancer cells in vitro and in tumor-bearing mice. 149Tb was produced at the ISOLDE facility at CERN. Radiolabeling of cm09 with purified 149Tb resulted in a specific activity of ~1.2 MBq/nmol. In vitro assays performed with 149Tb-cm09 revealed a reduced KB cell viability in a FR-specific and activity concentration-dependent manner. Tumor-bearing mice were injected with saline only (group A) or with 149Tb-cm09 (group B: 2.2 MBq; group C: 3.0 MBq). A significant tumor growth delay was found in treated animals resulting in an increased average survival time of mice which received 149Tb-cm09 (B: 30.5 d; C: 43 d) compared to untreated controls (A: 21 d). Analysis of blood parameters revealed no signs of acute toxicity to the kidneys or liver in treated mice over the time of investigation. These results demonstrated the potential of folate-based α-radionuclide therapy in tumor-bearing mice., Pharmaceuticals, 7 (3), ISSN:1424-8247
294. Combining Albumin-Binding Properties and Interaction with Pemetrexed to Improve the Tissue Distribution of Radiofolates
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Müller, Cristina, Guzik, Patrycja, Siwowska, Klaudia, Cohrs, Susan, Schmid, Raffaella M., and Schibli, Roger
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folic acid ,albumin-binder ,SPECT ,KB ,radiofolate ,177Lu ,pemetrexed ,3. Good health ,IGROV-1 - Abstract
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
295. Single photon emission computed tomography tracer
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Müller Cristina and Schibli Roger
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Single photon emission computed tomography (SPECT) is the state of the art imaging modality in nuclear medicine despite the fact that only a few new SPECT tracers have become available in the past 20 years. Critical for the future success of SPECT is the design of new and specific tracers for the detection localization and staging of a disease and for monitoring therapy. The utility of SPECT imaging to address oncologic questions is dependent on radiotracers that ideally exhibit excellent tissue penetration high affinity to the tumor associated target structure specific uptake and retention in the malignant lesions and rapid clearance from non targeted tissues and organs. In general a target specific SPECT radiopharmaceutical can be divided into two main parts: a targeting biomolecule (e.g. peptide antibody fragment) and a ? radiation emitting radionuclide (e.g. (99m)Tc (123)I). If radiometals are used as the radiation source a bifunctional chelator is needed to link the radioisotope to the targeting entity. In a rational SPECT tracer design these single components have to be critically evaluated in order to achieve a balance among the demands for adequate target binding and a rapid clearance of the radiotracer. The focus of this chapter is to depict recent developments of tumor targeted SPECT radiotracers for imaging of cancer diseases. Possibilities for optimization of tracer design and potential causes for design failure are discussed and highlighted with selected examples.
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296. Internal radiation dosimetry of a Tb-152-labeled antibody in tumor-bearing mice
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Cicone, Francesco, Gnesin, Silvano, Denoël, Thibaut, Stora, Thierry, van der Meulen, Nicholas P., Müller, Cristina, Vermeulen, Christiaan, Benešová, Martina, Köster, Ulli, Johnston, Karl, Amato, Ernesto, Auditore, Lucrezia, Coukos, George, Stabin, Michael, Schaefer, Niklaus, Viertl, David, and Prior, John O.
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Tb-152 ,OLINDA/EXM® 2.0 ,Spherical model ,Biodistribution ,Murine phantoms ,Radiolabeled monoclonal antibodies ,Organ harvesting ,TEM-1 ,Small animal dosimetry ,microPET ,3. Good health - Abstract
Background Biodistribution studies based on organ harvesting represent the gold standard pre-clinical technique for dose extrapolations. However, sequential imaging is becoming increasingly popular as it allows the extraction of longitudinal data from single animals, and a direct correlation with deterministic radiation effects. We assessed the feasibility of mouse-specific, microPET-based dosimetry of an antibody fragment labeled with the positron emitter 152Tb [(T1/2 = 17.5 h, Eβ+mean = 1140 keV (20.3%)]. Image-based absorbed dose estimates were compared with those obtained from the extrapolation to 152Tb of a classical biodistribution experiment using the same antibody fragment labeled with 111In. 152Tb was produced by proton-induced spallation in a tantalum target, followed by mass separation and cation exchange chromatography. The endosialin-targeting scFv78-Fc fusion protein was conjugated with the chelator p-SCN-Bn-CHX-A”-DTPA, followed by labeling with either 152Tb or 111In. Micro-PET images of four immunodeficient female mice bearing RD-ES tumor xenografts were acquired 4, 24, and 48 h after the i.v. injection of 152Tb-CHX-DTPA-scFv78-Fc. After count/activity camera calibration, time-integrated activity coefficients (TIACs) were obtained for the following compartments: heart, lungs, liver, kidneys, intestines, tumor, and whole body, manually segmented on CT. For comparison, radiation dose estimates of 152Tb-CHX-DTPA-scFv78-Fc were extrapolated from mice dissected 4, 24, 48, and 96 h after the injection of 111In-CHX-DTPA-scFv78-Fc (3–5 mice per group). Imaging-derived and biodistribution-derived organ TIACs were used as input in the 25 g mouse model of OLINDA/EXM® 2.0, after appropriate mass rescaling. Tumor absorbed doses were obtained using the OLINDA2 sphere model. Finally, the relative percent difference (RD%) between absorbed doses obtained from imaging and biodistribution were calculated. Results RD% between microPET-based dosimetry and biodistribution-based dose extrapolations were + 12, − 14, and + 17 for the liver, the kidneys, and the tumors, respectively. Compared to biodistribution, the imaging method significantly overestimates the absorbed doses to the heart and the lungs (+ 89 and + 117% dose difference, respectively). Conclusions MicroPET-based dosimetry of 152Tb is feasible, and the comparison with organ harvesting resulted in acceptable dose discrepancies for body districts that can be segmented on CT. These encouraging results warrant additional validation using radiolabeled biomolecules with a different biodistribution pattern., EJNMMI Research, 9, ISSN:2191-219X
297. Promising potential of [Lu-177]Lu-DOTA-folate to enhance tumor response to immunotherapy-a preclinical study using a syngeneic breast cancer model
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Guzik, Patrycja, Siwowska, Klaudia, Fang, Hsin-Yu, Cohrs, Susan, Bernhardt, Peter, Schibli, Roger, and Müller, Cristina
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Folate receptor ,[Lu-177]Lu-DOTA-folate ,CTLA-4 ,Immunotherapy ,3. Good health ,NF9006 breast tumor cells - 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., European Journal of Nuclear Medicine and Molecular Imaging, 48 (4), ISSN:1619-7070, ISSN:1619-7089
298. Contribution of Auger/conversion electrons to renal side effects after radionuclide therapy: preclinical comparison of 161Tb-folate and 177Lu-folate
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Haller, Stephanie, Pellegrini, Giovanni, Vermeulen, Christiaan, van der Meulen, Nicholas P., Köster, Ulli, Bernhardt, Peter, Schibli, Roger, and Müller, Cristina
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Radiofolate ,161Tb ,177Lu ,Radionuclide therapy ,Kidney ,Radionephropathy ,Auger/conversion electrons ,3. Good health - Abstract
Background The radiolanthanide 161Tb has, in recent years, attracted increasing interest due to its favorable characteristics for medical application. 161Tb exhibits similar properties to the widely-used therapeutic radionuclide 177Lu. In contrast to 177Lu, 161Tb yields a significant number of short-ranging Auger/conversion electrons (≤50 keV) during its decay process. 161Tb has been shown to be more effective for tumor therapy than 177Lu if applied using the same activity. The purpose of this study was to investigate long-term damage to the kidneys after application of 161Tb-folate and compare it to the renal effects caused by 177Lu-folate. Methods Renal side effects were investigated in nude mice after the application of different activities of 161Tb-folate (10, 20, and 30 MBq per mouse) over a period of 8 months. Renal function was monitored by the determination of 99mTc-DMSA uptake in the kidneys and by measuring blood urea nitrogen and creatinine levels in the plasma. Histopathological analysis was performed by scoring of the tissue damage observed in HE-stained kidney sections from euthanized mice. Results Due to the co-emitted Auger/conversion electrons, the mean absorbed renal dose of 161Tb-folate (3.0 Gy/MBq) was about 24 % higher than that of 177Lu-folate (2.3 Gy/MBq). After application of 161Tb-folate, kidney function was reduced in a dose- and time-dependent manner, as indicated by the decreased renal uptake of 99mTc-DMSA and the increased levels of blood urea nitrogen and creatinine. Similar results were obtained when 177Lu-folate was applied at the same activity. Histopathological investigations confirmed comparable renal cortical damage after application of the same activities of 161Tb-folate and 177Lu-folate. This was characterized by collapsed tubules and enlarged glomeruli with fibrin deposition in moderately injured kidneys and glomerulosclerosis in severely damaged kidneys. Conclusions Tb-folate induced dose-dependent radionephropathy over time, but did not result in more severe damage than 177Lu-folate when applied at the same activity. These data are an indication that Auger/conversion electrons do not exacerbate overall renal damage after application with 161Tb-folate as compared to 177Lu-folate, even though they result in an increased dose deposition in the renal tissue. Global toxicity affecting other tissues than kidneys remains to be investigated after 161Tb-based therapy, however., EJNMMI Research, 6 (1), ISSN:2191-219X
299. Preclinical evaluation of 5-methyltetrahydrofolate-based radioconjugates-new perspectives for folate receptor-targeted radionuclide therapy
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Guzik, Patrycja, Benešová, Martina, Ratz, Magdalena, Monné Rodríguez, Josep M., Deberle, Luisa M., Schibli, Roger, and Müller, Cristina
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5-Methyltetrahydrofolate ,Albumin-binding entity ,Folate receptor ,Lutetium-177 ,Radionuclide therapy ,3. Good health - Abstract
Purpose The folate receptor (FR) is frequently overexpressed in a variety of tumor types and, hence, an interesting target for radionuclide therapy. The aim of this study was to evaluate a new class of albumin-binding radioconjugates comprising 5-methyltetrahydrofolate (5-MTHF) as a targeting agent and to compare their properties with those of the previously established folic acid-based [Lu-177]Lu-OxFol-1. Methods [Lu-177]Lu-6R-RedFol-1 and [Lu-177]Lu-6S-RedFol-1 were investigated in vitro using FR-positive KB tumor cells. Biodistribution studies were performed in KB tumor-bearing mice, and the areas under the curve (AUC(0 -> 120h)) were determined for the uptake in tumors and kidneys. [Lu-177]Lu-6R-RedFol-1 was compared with [Lu-177]Lu-OxFol-1 in a therapy study over 8 weeks using KB tumor-bearing mice. Results Both radioconjugates demonstrated similar in vitro properties as [Lu-177]Lu-OxFol-1; however, the tumor uptake of [Lu-177]Lu-6R-RedFol-1 and [Lu-177]Lu-6S-RedFol-1 was significantly increased in comparison with [Lu-177]Lu-OxFol-1. In the case of [Lu-177]Lu-6S-RedFol-1, also the kidney uptake was increased; however, renal retention of [Lu-177]Lu-6R-RedFol-1 was similar to that of [Lu-177]Lu-OxFol-1. This led to an almost 4-fold increased tumor-to-kidney AUC(0 -> 120h)ratio of [Lu-177]Lu-6R-RedFol-1 as compared with [Lu-177]Lu-6S-RedFol-1 and [Lu-177]Lu-OxFol-1. At equal activity, the therapeutic effect of [Lu-177]Lu-6R-RedFol-1 was better than that of [Lu-177]Lu-OxFol-1, reflected by a slower tumor growth and, consequently, an increased median survival time (49 days vs. 34 days). Conclusion This study demonstrated the promising potential of 5-MTHF-based radioconjugates for FR-targeting. Application of [Lu-177]Lu-6R-RedFol-1 resulted in unprecedentedly high tumor-to-kidney ratios and, as a consequence, a superior therapeutic effect as compared with [Lu-177]Lu-OxFol-1. These findings, together with the absence of early side effects, make [Lu-177]Lu-6R-RedFol-1 attractive in view of a future clinical translation., European Journal of Nuclear Medicine and Molecular Imaging, 48 (4), ISSN:1619-7070, ISSN:1619-7089
300. Additional file 1: Figure S1a. of 47Sc as useful β–-emitter for the radiotheragnostic paradigm: a comparative study of feasible production routes
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Domnanich, Katharina, Müller, Cristina, Benešová, Martina, Rugard Dressler, Haller, Stephanie, Köster, Ulli, Ponsard, Bernard, Schibli, Roger, Türler, Andreas, and Meulen, Nicholas Van Der
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7. Clean energy - Abstract
Formula for the calculation of the 47Sc activity in Bq (s−1), accessible under the applied irradiation conditions. σ = nuclear cross section of the 46Ca(n,γ)47Ca reaction in cm−2, NT = number of 46Ca atoms, Φth = thermal neutron flux in n * cm−2 * s−1, λSc and λCa = decay constants of 47Sc and 47Ca in s−1, tirr = irradiation time and twait = post irradiation waiting time in s. b Formula for the calculation of the optimal post irradiation waiting time (topt) in s, accessible at the applied irradiation time (tirr in s). The decay constants of 47Sc (λSc) and 47Ca (λCa) are given in s−1. c Formula for the calculation of the optimal relative 47Sc activity (a(47Sc)opt) (dimensionless), accessible under the applied irradiation conditions. σ = nuclear cross section of the 46Ca(n,γ)47Ca reaction in cm−2, NT = number of 46Ca atoms, Φth = thermal neutron flux in n * cm−2 * s−1, λSc and λCa = decay constants of 47Sc and 47Ca in s−1. d Formula for the maximal obtainable 47Sc activity (dimensionless). The irradiation time (tirr) is given in s and the decay constants of 47Sc (λSc) and 47Ca (λCa) in s−1. Figure S2. γ-Ray spectra of 47Sc and 47Ca from the neutron-irradiated 46Ca ampoule, obtained 71 h after the end of irradiation (measurement time: 10 s) (a) and of the pure 47Sc eluate after separation (Method B), obtained 1 h after the end of separation (measurement time: 250 s) (b). Figure S3. γ-Ray spectrum of the neutron-irradiated 47Ti ampoule at SINQ, obtained 21 d after the end of irradiation (measurement time: 9600 s). Figure S4. Measured cross section values (squares, retrieved from the EXFOR-database) (Zerkin 2016) as well as the theoretical calculations from the TENDL-2015 library (straight line) (Koning, Rochman et al. 2015) for the 47Ti(n,p)47Sc (blue) and the 47Ti(n,p + n)46Sc (black) nuclear reactions. Table S5. Trace metal analysis of the reduced 46Ti metal by ICP-OES. Only the elements determined at a concentration higher than the detection limit are listed below. (DOCX 415 kb)
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