Pub Date : 2024-11-22DOI: 10.1016/j.nucmedbio.2024.108976
Kyeara N. Mack , David Bauer , Lukas M. Carter , Sebastian E. Carrasco , Mohamed I. Atmane , Tara D. Viray , Cory L. Brooks , Michael A. Hollingsworth , Prakash Radhakrishnan , Jason S. Lewis
Background
Peritoneal metastasis with micrometastatic cell clusters is a common feature of advanced ovarian cancer. Targeted alpha therapy (TAT) is an attractive approach for treating micrometastatic diseases as alpha particles release enormous amounts of energy within a short distance. A pretargeting approach — leveraging the inverse-electron-demand Diels-Alder reaction between tetrazines (Tz) and trans-cyclooctene (TCO) — can minimize off-target toxicity related to TAT, often associated with full-length antibodies. We hypothesized that a pretargeting strategy could effectively treat high-grade serous (HGS) ovarian tumors while minimizing toxicity.
Methods
We utilized the humanized antibody, AR9.6, labeled with actinium-225 (225Ac). AR9.6 targets fully glycosylated and hypoglycosylated isoforms of MUC16. For biodistribution and radioimmunotherapy studies, AR9.6-TCO was injected into OVCAR3-bearing mice 72 h before administering [225Ac]Ac-mcp-PEG8-Tz, e.g. using a 1,2,4,5-tetrazine conjugated to the macropa chelator via a polyethylene glycol (PEG) linker.
Results
Biodistribution data revealed that the pretargeting approach achieved substantial tumor uptake. Cerenkov luminescence imaging confirmed successful in vivo pretargeting during TAT studies. Compared to the control groups, TAT with AR9.6-TCO and [225Ac]Ac-mcp-PEG8-Tz significantly suppressed tumor growth and improved overall survival in OVCAR3 tumor-bearing mice. Renal and ovarian pathology compatible with toxicity was observed in mice in addition to transient hematologic toxicity.
Conclusion
We confirmed that pretargeting with AR9.6-TCO and [225Ac]Ac-mcp-PEG8-Tz has durable antitumor effects in high MUC16-expressing tumors. These findings demonstrate great potential for using pretargeting in combination with TAT for the treatment of ovarian cancer.
{"title":"Pretargeted alpha therapy in MUC16-positive high-grade serous ovarian cancer","authors":"Kyeara N. Mack , David Bauer , Lukas M. Carter , Sebastian E. Carrasco , Mohamed I. Atmane , Tara D. Viray , Cory L. Brooks , Michael A. Hollingsworth , Prakash Radhakrishnan , Jason S. Lewis","doi":"10.1016/j.nucmedbio.2024.108976","DOIUrl":"10.1016/j.nucmedbio.2024.108976","url":null,"abstract":"<div><h3>Background</h3><div>Peritoneal metastasis with micrometastatic cell clusters is a common feature of advanced ovarian cancer. Targeted alpha therapy (TAT) is an attractive approach for treating micrometastatic diseases as alpha particles release enormous amounts of energy within a short distance. A pretargeting approach — leveraging the inverse-electron-demand Diels-Alder reaction between tetrazines (Tz) and trans-cyclooctene (TCO) — can minimize off-target toxicity related to TAT, often associated with full-length antibodies. We hypothesized that a pretargeting strategy could effectively treat high-grade serous (HGS) ovarian tumors while minimizing toxicity.</div></div><div><h3>Methods</h3><div>We utilized the humanized antibody, AR9.6, labeled with actinium-225 (<sup>225</sup>Ac). AR9.6 targets fully glycosylated and hypoglycosylated isoforms of MUC16. For biodistribution and radioimmunotherapy studies, AR9.6-TCO was injected into OVCAR3-bearing mice 72 h before administering [<sup>225</sup>Ac]Ac-mcp-PEG<sub>8</sub>-Tz, e.g. using a 1,2,4,5-tetrazine conjugated to the macropa chelator via a polyethylene glycol (PEG) linker.</div></div><div><h3>Results</h3><div>Biodistribution data revealed that the pretargeting approach achieved substantial tumor uptake. Cerenkov luminescence imaging confirmed successful in vivo pretargeting during TAT studies. Compared to the control groups, TAT with AR9.6-TCO and [<sup>225</sup>Ac]Ac-mcp-PEG<sub>8</sub>-Tz significantly suppressed tumor growth and improved overall survival in OVCAR3 tumor-bearing mice. Renal and ovarian pathology compatible with toxicity was observed in mice in addition to transient hematologic toxicity.</div></div><div><h3>Conclusion</h3><div>We confirmed that pretargeting with AR9.6-TCO and [<sup>225</sup>Ac]Ac-mcp-PEG<sub>8</sub>-Tz has durable antitumor effects in high MUC16-expressing tumors. These findings demonstrate great potential for using pretargeting in combination with TAT for the treatment of ovarian cancer.</div></div><div><h3>Classification</h3><div>Biological Sciences; Applied Biological Sciences.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"140 ","pages":"Article 108976"},"PeriodicalIF":3.6,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142748091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.nucmedbio.2024.108973
Michal Sakmár , Ján Kozempel , Jan Kučka , Tereza Janská , Matěj Štíbr , Lukáš Ondrák , Kateřina Ondrák Fialová , Martin Vlk , Luděk Šefc , Frank Bruchertseifer , Alfred Morgenstern
Background
Targeted alpha therapy (TAT) is an effective option for cancer treatment. To maximize its efficacy and minimize side effects, carriers must deliver radionuclides to target tissues. Most of the nuclides used in TAT decay via the alpha cascade, producing several radioactive daughter nuclei with sufficient energy to escape from the original carrier. Therefore, studying these daughter atoms is crucial in the search for new carriers. Nanoparticles have potential as carriers due to their structure, which can prevent the escape of daughter atoms and reduce radiation exposure to non-target tissues. This work focuses on determining the released activity of 221Fr and 213Bi resulting from the decay of 225Ac labelled TiO2 nanoparticles.
Results
Labelling of TiO2 nanoparticles has shown high sorption rates of 225Ac and its progeny, 221Fr and 213Bi, with over 92 % of activities sorbed on the nanoparticle surface for all measured radionuclides. However, in the quasi-dynamic in vitro system, the released activity of 221Fr and 213Bi is strongly dependent on the nanoparticles concentration, ranging from 15 % for a concentration of 1 mg/mL to approximately 50 % for a nanoparticle concentration of 10 μg/mL in saline solution. The released activities of 213Bi were lower, with a maximum value of around 20 % for concentrations of 0.05, 0.025, and 0.01 mg/mL. The leakage of 225Ac and its progeny was tested in various biological matrices. Minimal released activity was measured in saline at around 10 % after 48 h, while the maximum activity was measured in blood serum and plasma at 20 %. The amount of 225Ac released into the media was minimal (<3 %). The in vitro results were confirmed in a healthy mouse model. The difference in %ID/g was clearly visible immediately after dissection and again after 6 h when 213Bi reached equilibrium with 225Ac.
Conclusion
The study verified the potential release of 225Ac progeny from the labelled TiO2 nanoparticles. Experiments were performed to determine the dependence of released activity on nanoparticle concentration and the biological environment. The results demonstrated the high stability of the prepared 225Ac@TiO2 NPs and the potential release of progeny over time. In vivo studies confirmed our hypothesis. The data obtained suggest that the daughter atoms can escape from the original carrier and follow their own biological pathways in the organism.
{"title":"In vitro and in vivo study of 221Fr and 213Bi progeny release from the 225Ac-labelled TiO2 nanoparticles","authors":"Michal Sakmár , Ján Kozempel , Jan Kučka , Tereza Janská , Matěj Štíbr , Lukáš Ondrák , Kateřina Ondrák Fialová , Martin Vlk , Luděk Šefc , Frank Bruchertseifer , Alfred Morgenstern","doi":"10.1016/j.nucmedbio.2024.108973","DOIUrl":"10.1016/j.nucmedbio.2024.108973","url":null,"abstract":"<div><h3>Background</h3><div>Targeted alpha therapy (TAT) is an effective option for cancer treatment. To maximize its efficacy and minimize side effects, carriers must deliver radionuclides to target tissues. Most of the nuclides used in TAT decay <em>via</em> the alpha cascade, producing several radioactive daughter nuclei with sufficient energy to escape from the original carrier. Therefore, studying these daughter atoms is crucial in the search for new carriers. Nanoparticles have potential as carriers due to their structure, which can prevent the escape of daughter atoms and reduce radiation exposure to non-target tissues. This work focuses on determining the released activity of <sup>221</sup>Fr and <sup>213</sup>Bi resulting from the decay of <sup>225</sup>Ac labelled TiO<sub>2</sub> nanoparticles.</div></div><div><h3>Results</h3><div>Labelling of TiO<sub>2</sub> nanoparticles has shown high sorption rates of <sup>225</sup>Ac and its progeny, <sup>221</sup>Fr and <sup>213</sup>Bi, with over 92 % of activities sorbed on the nanoparticle surface for all measured radionuclides. However, in the quasi-dynamic <em>in vitro</em> system, the released activity of <sup>221</sup>Fr and <sup>213</sup>Bi is strongly dependent on the nanoparticles concentration, ranging from 15 % for a concentration of 1 mg/mL to approximately 50 % for a nanoparticle concentration of 10 μg/mL in saline solution. The released activities of <sup>213</sup>Bi were lower, with a maximum value of around 20 % for concentrations of 0.05, 0.025, and 0.01 mg/mL. The leakage of <sup>225</sup>Ac and its progeny was tested in various biological matrices. Minimal released activity was measured in saline at around 10 % after 48 h, while the maximum activity was measured in blood serum and plasma at 20 %. The amount of <sup>225</sup>Ac released into the media was minimal (<3 %). The <em>in vitro</em> results were confirmed in a healthy mouse model. The difference in %ID/g was clearly visible immediately after dissection and again after 6 h when <sup>213</sup>Bi reached equilibrium with <sup>225</sup>Ac.</div></div><div><h3>Conclusion</h3><div>The study verified the potential release of <sup>225</sup>Ac progeny from the labelled TiO<sub>2</sub> nanoparticles. Experiments were performed to determine the dependence of released activity on nanoparticle concentration and the biological environment. The results demonstrated the high stability of the prepared <sup>225</sup>Ac@TiO<sub>2</sub> NPs and the potential release of progeny over time. <em>In vivo</em> studies confirmed our hypothesis. The data obtained suggest that the daughter atoms can escape from the original carrier and follow their own biological pathways in the organism.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"140 ","pages":"Article 108973"},"PeriodicalIF":3.6,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.nucmedbio.2024.108971
S.T.M. Wenker , S.A.M. van Lith , G. Tamborino , M.W. Konijnenberg , J. Bussink , S. Heskamp
Tumor hypoxia contributes to cancer progression and therapy resistance. Several strategies have been investigated to relieve tumor hypoxia, of which some were successful. However, their clinical application remains challenging and therefore they are not used in daily clinical practice. Here, we review the potential of targeted radionuclide therapy (TRT) to eradicate hypoxic cancer cells. We present an overview of the published TRT strategies using β‐-particles, α-particles, and Auger electrons. Altogether, we conclude that α-particle emitting radionuclides are most promising since they can cause DNA double strand breaks independent of oxygen levels. Future directions for research are addressed, including more adequate in vitro and in vivo models to proof the potential of TRT to eliminate hypoxic cancer cells. Furthermore, dosimetry and radiobiology are identified as key to better understand the mechanism of action and dose-response relationships in hypoxic tumor areas. Finally, we can conclude that in order to achieve long-term anti-tumor efficacy, TRT combination treatment strategies may be necessary.
肿瘤缺氧会导致癌症进展和耐药性。目前已研究出多种缓解肿瘤缺氧的策略，其中一些获得了成功。然而，它们的临床应用仍然具有挑战性，因此并未用于日常临床实践。在此，我们回顾了放射性核素靶向治疗（TRT）根除缺氧癌细胞的潜力。我们概述了已发表的使用β粒子、α粒子和奥杰电子的TRT策略。总之，我们得出的结论是，发射α粒子的放射性核素最有前途，因为它们可以导致DNA双股断裂，而不受氧气水平的影响。我们还讨论了未来的研究方向，包括建立更充分的体外和体内模型，以证明 TRT 消除缺氧癌细胞的潜力。此外，剂量测定和放射生物学被认为是更好地了解缺氧肿瘤区域的作用机制和剂量-反应关系的关键。最后，我们可以得出结论，为了实现长期的抗肿瘤疗效，TRT 联合治疗策略可能是必要的。
{"title":"The potential of targeted radionuclide therapy to treat hypoxic tumor cells","authors":"S.T.M. Wenker , S.A.M. van Lith , G. Tamborino , M.W. Konijnenberg , J. Bussink , S. Heskamp","doi":"10.1016/j.nucmedbio.2024.108971","DOIUrl":"10.1016/j.nucmedbio.2024.108971","url":null,"abstract":"<div><div>Tumor hypoxia contributes to cancer progression and therapy resistance. Several strategies have been investigated to relieve tumor hypoxia, of which some were successful. However, their clinical application remains challenging and therefore they are not used in daily clinical practice. Here, we review the potential of targeted radionuclide therapy (TRT) to eradicate hypoxic cancer cells. We present an overview of the published TRT strategies using β<sup>‐</sup>-particles, α-particles, and Auger electrons. Altogether, we conclude that α-particle emitting radionuclides are most promising since they can cause DNA double strand breaks independent of oxygen levels. Future directions for research are addressed, including more adequate <em>in vitro</em> and <em>in vivo</em> models to proof the potential of TRT to eliminate hypoxic cancer cells. Furthermore, dosimetry and radiobiology are identified as key to better understand the mechanism of action and dose-response relationships in hypoxic tumor areas. Finally, we can conclude that in order to achieve long-term anti-tumor efficacy, TRT combination treatment strategies may be necessary.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"140 ","pages":"Article 108971"},"PeriodicalIF":3.6,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.nucmedbio.2024.108972
Anna A. Shchukina , Anastasia D. Zubenko , Oksana V. Tarasenko , Anton A. Larenkov , Viktor B. Bubenshchikov , Ekaterina Y. Chernikova , Yury V. Fedorov , Olga A. Fedorova
In this article, we present the synthesis and characterization of three macrocyclic chelators, H4PATA, PATAM, and H4PATPA, based on a pyridine-azacrown compound. Their complexation with 68Ga and 177Lu has been thoroughly investigated using MALDI TOF MS, 1H NMR spectroscopy, radiolabeling studies, and experiments in vitro with fetal bovine serum and a 1000-fold molar excess of H4EDTA. Our studies have shown that the chelators H4PATA and H4PATPA form complexes at room temperature with both radionuclides (RCY > 80 % and > 90 % for complexes with H4PATA and H4PATPA after 30 min, respectively). The chelator PATAM requires high temperature (95 °C) for complexation. In vitro stability assays in fetal bovine serum as well as H4EDTA-challenge revealed that transchelation occurs for all complexes with 68Ga. However, complexes of the ligands H4PATA and PATAM with 177Lu were found stable. Thus, taking into account the radiolabeling at room temperature and in vitro stability of the complex [177Lu]Lu·PATA, our investigations revealed the chelator H4PATA is a candidate for radiopharmaceutical use with 177Lu.
{"title":"Evaluation of chelating agents based on pyridine-azacrown compounds H4PATA, PATAM, and H4PATPA for 68Ga and 177Lu","authors":"Anna A. Shchukina , Anastasia D. Zubenko , Oksana V. Tarasenko , Anton A. Larenkov , Viktor B. Bubenshchikov , Ekaterina Y. Chernikova , Yury V. Fedorov , Olga A. Fedorova","doi":"10.1016/j.nucmedbio.2024.108972","DOIUrl":"10.1016/j.nucmedbio.2024.108972","url":null,"abstract":"<div><div>In this article, we present the synthesis and characterization of three macrocyclic chelators, <strong>H</strong><sub><strong>4</strong></sub><strong>PATA</strong>, <strong>PATAM</strong>, and <strong>H</strong><sub><strong>4</strong></sub><strong>PATPA</strong>, based on a pyridine-azacrown compound. Their complexation with <sup>68</sup>Ga and <sup>177</sup>Lu has been thoroughly investigated using MALDI TOF MS, <sup>1</sup>H NMR spectroscopy, radiolabeling studies, and experiments <em>in vitro</em> with fetal bovine serum and a 1000-fold molar excess of <strong>H</strong><sub><strong>4</strong></sub><strong>EDTA</strong>. Our studies have shown that the chelators <strong>H</strong><sub><strong>4</strong></sub><strong>PATA</strong> and <strong>H</strong><sub><strong>4</strong></sub><strong>PATPA</strong> form complexes at room temperature with both radionuclides (RCY > 80 % and > 90 % for complexes with <strong>H</strong><sub><strong>4</strong></sub><strong>PATA</strong> and <strong>H</strong><sub><strong>4</strong></sub><strong>PATPA</strong> after 30 min, respectively). The chelator <strong>PATAM</strong> requires high temperature (95 °C) for complexation. <em>In vitro</em> stability assays in fetal bovine serum as well as <strong>H</strong><sub><strong>4</strong></sub><strong>EDTA</strong>-challenge revealed that transchelation occurs for all complexes with <sup>68</sup>Ga. However, complexes of the ligands <strong>H</strong><sub><strong>4</strong></sub><strong>PATA</strong> and <strong>PATAM</strong> with <sup>177</sup>Lu were found stable. Thus, taking into account the radiolabeling at room temperature and <em>in vitro</em> stability of the complex [<sup>177</sup>Lu]Lu·<strong>PATA</strong>, our investigations revealed the chelator <strong>H</strong><sub><strong>4</strong></sub><strong>PATA</strong> is a candidate for radiopharmaceutical use with <sup>177</sup>Lu.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"140 ","pages":"Article 108972"},"PeriodicalIF":3.6,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-12DOI: 10.1016/j.nucmedbio.2024.108969
Thomas E. Wuensche , Pedro M. Pereira , Albert D. Windhorst , Kaare Bjerregaard-Andersen , Florence Sotty , Pekka Kallunki , Allan Jensen , Benny Bang-Andersen , Guus A.M.S. van Dongen , Wissam Beaino , Danielle J. Vugts
<div><h3>Background</h3><div>Recently, <sup>89</sup>Zr-immuno-PET imaging of therapeutic antibodies, actively transported over the blood-brain-barrier <em>via</em> transferrin-mediated transcytosis, was demonstrated using the chelator DFO*. In these studies, aducanumab targeting amyloid-beta was fused with a transferrin binding unit: a single-chain Fab fragment derived from 8D3 (scFab8D3). Alpha-synuclein is a hallmark protein of several neurodegenerative diseases such as Parkinson's Disease, Lewy-Body-Dementia, and Multiple System Atrophy. <sup>89</sup>Zr-immuno-PET imaging of alpha-synuclein can be a valuable tool for image-guided drug development and assessment of target engagement. The goal of this study was to compare two currently used constructs of 8D3 for targeting potential, namely a single moiety of scFab8D3 fused to the alpha-synuclein antibody HLu-3 (HLu-3-scFab8D3) <em>versus</em> HLu-3 fused with two 8D3 single-chain variable fragments (HLu-3-(scFv8D3)<sub>2</sub>), by <sup>89</sup>Zr-immuno-PET in an alpha-synuclein pre-formed fibril (PFF) deposition model. HLu-3 and the HIV-targeting B12-scFab8D3 were used as controls. The best-performing compound was further investigated in an animal model with predominantly intraneural target aggregation.</div></div><div><h3>Methods</h3><div>Antibodies were conjugated with DFO* using DFO*-NCS and subsequently radiolabeled with <sup>89</sup>Zr. Assessment of binding affinity was done by alpha-synuclein ELISA and with FACS analysis using mTfR1 expressing CHO-S cells. Radioimmunoconjugates were first evaluated in an extracellular alpha-synuclein deposition model established by intracranial injection of non-sonicated PFFs into the left striatum of C57Bl/6 WT mice, whereas saline was injected into the contralateral site as control. PET imaging was performed 1, 3, and 7 days post-injection, followed by <em>ex vivo</em> biodistribution, autoradiography and immunofluorescence analysis. Based on the results from these studies, the better-performing antibody candidate was tested similarly in an alpha-synuclein seeding model. The seeding model has intraneural alpha-synuclein aggregation and was established by intracranial injection of sonicated PFFs into both striata of F28tg mice, which overexpress human wild-type alpha-synuclein. Untreated F28tg and C57Bl/6 WT mice served as controls.</div></div><div><h3>Results</h3><div>The radioimmunoconjugate was produced in sufficient radiochemical yields and purity. There was no impairment of binding affinity towards alpha-synuclein, and acceptable binding with negligible losses to mTfR1. PET imaging with [<sup>89</sup>Zr]Zr-HLu-3-scFab8D3 and [<sup>89</sup>Zr]Zr-HLu-3-(scFv8D3)<sub>2</sub> in the deposition model showed uptake at the site of alpha-synuclein deposits. However, uptake was variable between mice. Reliable PET quantification was hampered due to the small deposition volume (~2 μL). Immunofluorescence revealed specific alpha-synuclein target engagement of
{"title":"New prospects for 89Zr-immuno-PET in brain applications – Alpha-synucleinopathies","authors":"Thomas E. Wuensche , Pedro M. Pereira , Albert D. Windhorst , Kaare Bjerregaard-Andersen , Florence Sotty , Pekka Kallunki , Allan Jensen , Benny Bang-Andersen , Guus A.M.S. van Dongen , Wissam Beaino , Danielle J. Vugts","doi":"10.1016/j.nucmedbio.2024.108969","DOIUrl":"10.1016/j.nucmedbio.2024.108969","url":null,"abstract":"<div><h3>Background</h3><div>Recently, <sup>89</sup>Zr-immuno-PET imaging of therapeutic antibodies, actively transported over the blood-brain-barrier <em>via</em> transferrin-mediated transcytosis, was demonstrated using the chelator DFO*. In these studies, aducanumab targeting amyloid-beta was fused with a transferrin binding unit: a single-chain Fab fragment derived from 8D3 (scFab8D3). Alpha-synuclein is a hallmark protein of several neurodegenerative diseases such as Parkinson's Disease, Lewy-Body-Dementia, and Multiple System Atrophy. <sup>89</sup>Zr-immuno-PET imaging of alpha-synuclein can be a valuable tool for image-guided drug development and assessment of target engagement. The goal of this study was to compare two currently used constructs of 8D3 for targeting potential, namely a single moiety of scFab8D3 fused to the alpha-synuclein antibody HLu-3 (HLu-3-scFab8D3) <em>versus</em> HLu-3 fused with two 8D3 single-chain variable fragments (HLu-3-(scFv8D3)<sub>2</sub>), by <sup>89</sup>Zr-immuno-PET in an alpha-synuclein pre-formed fibril (PFF) deposition model. HLu-3 and the HIV-targeting B12-scFab8D3 were used as controls. The best-performing compound was further investigated in an animal model with predominantly intraneural target aggregation.</div></div><div><h3>Methods</h3><div>Antibodies were conjugated with DFO* using DFO*-NCS and subsequently radiolabeled with <sup>89</sup>Zr. Assessment of binding affinity was done by alpha-synuclein ELISA and with FACS analysis using mTfR1 expressing CHO-S cells. Radioimmunoconjugates were first evaluated in an extracellular alpha-synuclein deposition model established by intracranial injection of non-sonicated PFFs into the left striatum of C57Bl/6 WT mice, whereas saline was injected into the contralateral site as control. PET imaging was performed 1, 3, and 7 days post-injection, followed by <em>ex vivo</em> biodistribution, autoradiography and immunofluorescence analysis. Based on the results from these studies, the better-performing antibody candidate was tested similarly in an alpha-synuclein seeding model. The seeding model has intraneural alpha-synuclein aggregation and was established by intracranial injection of sonicated PFFs into both striata of F28tg mice, which overexpress human wild-type alpha-synuclein. Untreated F28tg and C57Bl/6 WT mice served as controls.</div></div><div><h3>Results</h3><div>The radioimmunoconjugate was produced in sufficient radiochemical yields and purity. There was no impairment of binding affinity towards alpha-synuclein, and acceptable binding with negligible losses to mTfR1. PET imaging with [<sup>89</sup>Zr]Zr-HLu-3-scFab8D3 and [<sup>89</sup>Zr]Zr-HLu-3-(scFv8D3)<sub>2</sub> in the deposition model showed uptake at the site of alpha-synuclein deposits. However, uptake was variable between mice. Reliable PET quantification was hampered due to the small deposition volume (~2 μL). Immunofluorescence revealed specific alpha-synuclein target engagement of","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"140 ","pages":"Article 108969"},"PeriodicalIF":3.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-09DOI: 10.1016/j.nucmedbio.2024.108970
Constantine J. Georgiou , Madeline K. Brown , Zhongli Cai , Laila Alshafai , Andrew Gao , James T. Rutka , Mitchell A. Winnik , Raymond M. Reilly
<div><h3>Introduction</h3><div>Our objective was to study convection enhanced delivery (CED) of <sup>177</sup>Lu-labeled metal chelating polymer (MCP) conjugated to gold nanoparticles ([<sup>177</sup>Lu]Lu-MCP-AuNP) alone or combined with anti-PD1 immune checkpoint inhibition (ICI) for improving the survival of immunocompetent C57BL/6J mice with orthotopic GL261 murine glioma tumors.</div></div><div><h3>Methods</h3><div>C57BL/6J mice with GL261 tumors were treated with [<sup>177</sup>Lu]Lu-MCP-AuNP (0.8 or 2.7 MBq; 4 × 10<sup>11</sup> AuNP) alone or combined with anti-PD1 antibodies (200 μg i.p. every 2 d × 3 doses). Control mice received normal saline, non-radioactive MCP-AuNP or anti-PD1 antibodies. Kaplan-Meier median survival was estimated. T-cell infiltration into the brain was probed by flow cytometry. Toxicity was assessed by monitoring body weight and cognitive function tests [Object Location Test (OLT) and Novel Object Recognition Test (NORT)] and T2-weighted MRI of the brain, overall health and ex vivo histopathological examination of the brain.</div></div><div><h3>Results</h3><div>Treatment with [<sup>177</sup>Lu]Lu-MCP-AuNP (0.8 MBq) significantly increased median survival compared to MCP-AuNP (29 vs. 25 d; <em>P</em> = 0.007) or normal saline-treated mice (24 d; <em>P</em> < 0.001). Combining [<sup>177</sup>Lu]Lu-MCP-AuNP (0.8 MBq) with anti-PD1 antibodies increased median survival to 32 d (<em>P</em> < 0.0001 vs. normal saline). Increasing the mean amount of [<sup>177</sup>Lu]Lu-MCP-AuNP to 2.7 MBq and combining with anti-PD1 antibodies extended survival to at least 218 d in 5/9 mice. Increased CD8<sup>+</sup> cytotoxic T-cells and decreased CD4<sup>+</sup> helper T-cells were found in the brain vs. normal saline-treated mice. No weight loss (>20 %) was observed for treated or control mice. There was no change in cognitive function in mice treated with [<sup>177</sup>Lu]Lu-MCP-AuNP (0.8 MBq) alone or combined with anti-PD1 antibodies assessed by the OLT or NORT. T2-weighted MRI in mice treated with 2.7 MBq [<sup>177</sup>Lu]Lu-MCP-AuNP combined with anti-PD1 antibodies revealed edema, gliosis and <em>ex vacuo</em> dilatation of the ventricle proximal to the site of infusion. Histopathological examination of the brain revealed dilatation of the ventricle and gliosis proximal to the site of infusion but no radiation necrosis. MRI and histological analysis did not reveal tumor in the brain of these mice. Mice treated with 2.7 MBq [<sup>177</sup>Lu]Lu-MCP-AuNP combined with anti-PD1 antibodies did not demonstrate overall deleterious health effects.</div></div><div><h3>Conclusions</h3><div>We conclude that CED of [<sup>177</sup>Lu]Lu-MCP-AuNP combined with anti-PD1 checkpoint immunotherapy improved the survival of immunocompetent C67BL/6J mice with GL261 glioma tumors in the brain. Higher administered amounts of [<sup>177</sup>Lu]Lu-MCP-AuNP (2.7 MBq vs. 0.8 MBq) were most effective and yielded long-term survival.</div></div><di
{"title":"Convection-enhanced delivery of [177Lu]Lu-labeled gold nanoparticles combined with anti-PD1 checkpoint immunotherapy improves the survival of immunocompetent C57BL/6J mice with orthotopic GL261 murine glioma tumors","authors":"Constantine J. Georgiou , Madeline K. Brown , Zhongli Cai , Laila Alshafai , Andrew Gao , James T. Rutka , Mitchell A. Winnik , Raymond M. Reilly","doi":"10.1016/j.nucmedbio.2024.108970","DOIUrl":"10.1016/j.nucmedbio.2024.108970","url":null,"abstract":"<div><h3>Introduction</h3><div>Our objective was to study convection enhanced delivery (CED) of <sup>177</sup>Lu-labeled metal chelating polymer (MCP) conjugated to gold nanoparticles ([<sup>177</sup>Lu]Lu-MCP-AuNP) alone or combined with anti-PD1 immune checkpoint inhibition (ICI) for improving the survival of immunocompetent C57BL/6J mice with orthotopic GL261 murine glioma tumors.</div></div><div><h3>Methods</h3><div>C57BL/6J mice with GL261 tumors were treated with [<sup>177</sup>Lu]Lu-MCP-AuNP (0.8 or 2.7 MBq; 4 × 10<sup>11</sup> AuNP) alone or combined with anti-PD1 antibodies (200 μg i.p. every 2 d × 3 doses). Control mice received normal saline, non-radioactive MCP-AuNP or anti-PD1 antibodies. Kaplan-Meier median survival was estimated. T-cell infiltration into the brain was probed by flow cytometry. Toxicity was assessed by monitoring body weight and cognitive function tests [Object Location Test (OLT) and Novel Object Recognition Test (NORT)] and T2-weighted MRI of the brain, overall health and ex vivo histopathological examination of the brain.</div></div><div><h3>Results</h3><div>Treatment with [<sup>177</sup>Lu]Lu-MCP-AuNP (0.8 MBq) significantly increased median survival compared to MCP-AuNP (29 vs. 25 d; <em>P</em> = 0.007) or normal saline-treated mice (24 d; <em>P</em> < 0.001). Combining [<sup>177</sup>Lu]Lu-MCP-AuNP (0.8 MBq) with anti-PD1 antibodies increased median survival to 32 d (<em>P</em> < 0.0001 vs. normal saline). Increasing the mean amount of [<sup>177</sup>Lu]Lu-MCP-AuNP to 2.7 MBq and combining with anti-PD1 antibodies extended survival to at least 218 d in 5/9 mice. Increased CD8<sup>+</sup> cytotoxic T-cells and decreased CD4<sup>+</sup> helper T-cells were found in the brain vs. normal saline-treated mice. No weight loss (>20 %) was observed for treated or control mice. There was no change in cognitive function in mice treated with [<sup>177</sup>Lu]Lu-MCP-AuNP (0.8 MBq) alone or combined with anti-PD1 antibodies assessed by the OLT or NORT. T2-weighted MRI in mice treated with 2.7 MBq [<sup>177</sup>Lu]Lu-MCP-AuNP combined with anti-PD1 antibodies revealed edema, gliosis and <em>ex vacuo</em> dilatation of the ventricle proximal to the site of infusion. Histopathological examination of the brain revealed dilatation of the ventricle and gliosis proximal to the site of infusion but no radiation necrosis. MRI and histological analysis did not reveal tumor in the brain of these mice. Mice treated with 2.7 MBq [<sup>177</sup>Lu]Lu-MCP-AuNP combined with anti-PD1 antibodies did not demonstrate overall deleterious health effects.</div></div><div><h3>Conclusions</h3><div>We conclude that CED of [<sup>177</sup>Lu]Lu-MCP-AuNP combined with anti-PD1 checkpoint immunotherapy improved the survival of immunocompetent C67BL/6J mice with GL261 glioma tumors in the brain. Higher administered amounts of [<sup>177</sup>Lu]Lu-MCP-AuNP (2.7 MBq vs. 0.8 MBq) were most effective and yielded long-term survival.</div></div><di","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"140 ","pages":"Article 108970"},"PeriodicalIF":3.6,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.nucmedbio.2024.108965
Jonathan R. Dilworth , Jason S. Lewis , Sofia I. Pascu
{"title":"NMB Innovators Series Professor Jon Dilworth: Shining a Light on the Chemistry of Metals Used in Biology, Medicine and Radiochemistry","authors":"Jonathan R. Dilworth , Jason S. Lewis , Sofia I. Pascu","doi":"10.1016/j.nucmedbio.2024.108965","DOIUrl":"10.1016/j.nucmedbio.2024.108965","url":null,"abstract":"","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"138 ","pages":"Article 108965"},"PeriodicalIF":3.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142723436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.nucmedbio.2024.108967
Mette Louise Gram Kjærulff , Thien Vinh Luong , Gabriel Richard , Valérie St-Pierre , Esben Søndergaard , Niels Møller , Lars Christian Gormsen , Sébastien Tremblay , Etienne Croteau , Stephen C. Cunnane
Background
Ketone metabolism has been studied using positron emission tomography (PET) with the radiotracers [11C]acetoacetate and [11C]β-hydroxybutyrate. However, whether these two radiotracers actually yield equivalent estimates of cerebral and myocardial ketone metabolism has not yet been investigated. This study aimed to investigate and compare the kinetics of both tracers in the brain and heart of healthy rats under varying levels of circulating ketones at baseline and after a single-dose exogenous ketone ester (KE) supplement.
Methods
Six healthy Sprague-Dawley rats each underwent two scans with each tracer: one following oral KE administration and one with a placebo. Cerebral kinetic parameters (Ki, VT, and cerebral metabolic rate (CMR)) were obtained using the Patlak method, whereas myocardial kinetic parameters (K1, k2, and VT) were derived using a 1-tissue compartment model. Parameters were compared through mixed-effects, correlation, and Bland-Altman analyses.
Results
Global CMR increased 3–4-fold in the KE group versus placebo, with strong positive correlations between CMR and plasma ketone levels for both tracers. Correlations between [11C]acetoacetate and [11C]β-hydroxybutyrate were moderate and non-significant for relative cerebral uptake expressed as Ki (ρ = 0.40) and for VT (ρ = 0.38) but strongly positive for absolute uptake, CMR (r = 0.84), with a non-significant mean bias of −0.03. In contrast, myocardial kinetics showed only non-significant weak to moderate correlations between the radiotracers (K1 (r = 0.04), k2 (r = −0.27), and VT (ρ = 0.43)), with no systematic biases.
Conclusion
[11C]acetoacetate and [11C]β-hydroxybutyrate can be used interchangeably for measuring global CMR in healthy rats but differ in certain cerebral and myocardial kinetics. Whether these findings are generalizable to pathological conditions warrants further studies to explore the kinetics of these tracers in disease models.
{"title":"Cerebral and myocardial kinetics of [11C]acetoacetate and [11C]β-hydroxybutyrate: A comparative crossover study in healthy rats","authors":"Mette Louise Gram Kjærulff , Thien Vinh Luong , Gabriel Richard , Valérie St-Pierre , Esben Søndergaard , Niels Møller , Lars Christian Gormsen , Sébastien Tremblay , Etienne Croteau , Stephen C. Cunnane","doi":"10.1016/j.nucmedbio.2024.108967","DOIUrl":"10.1016/j.nucmedbio.2024.108967","url":null,"abstract":"<div><h3>Background</h3><div>Ketone metabolism has been studied using positron emission tomography (PET) with the radiotracers [<sup>11</sup>C]acetoacetate and [<sup>11</sup>C]β-hydroxybutyrate. However, whether these two radiotracers actually yield equivalent estimates of cerebral and myocardial ketone metabolism has not yet been investigated. This study aimed to investigate and compare the kinetics of both tracers in the brain and heart of healthy rats under varying levels of circulating ketones at baseline and after a single-dose exogenous ketone ester (KE) supplement.</div></div><div><h3>Methods</h3><div>Six healthy Sprague-Dawley rats each underwent two scans with each tracer: one following oral KE administration and one with a placebo. Cerebral kinetic parameters (<em>K</em><sub>i</sub>, <em>V</em><sub>T</sub>, and cerebral metabolic rate (CMR)) were obtained using the Patlak method, whereas myocardial kinetic parameters (<em>K</em><sub>1</sub>, <em>k</em><sub>2</sub>, and <em>V</em><sub>T</sub>) were derived using a 1-tissue compartment model. Parameters were compared through mixed-effects, correlation, and Bland-Altman analyses.</div></div><div><h3>Results</h3><div>Global CMR increased 3–4-fold in the KE group versus placebo, with strong positive correlations between CMR and plasma ketone levels for both tracers. Correlations between [<sup>11</sup>C]acetoacetate and [<sup>11</sup>C]β-hydroxybutyrate were moderate and non-significant for relative cerebral uptake expressed as <em>K</em><sub>i</sub> (ρ = 0.40) and for <em>V</em><sub>T</sub> (ρ = 0.38) but strongly positive for absolute uptake, CMR (<em>r</em> = 0.84), with a non-significant mean bias of −0.03. In contrast, myocardial kinetics showed only non-significant weak to moderate correlations between the radiotracers (<em>K</em><sub>1</sub> (<em>r</em> = 0.04), <em>k</em><sub>2</sub> (<em>r</em> = −0.27), and <em>V</em><sub>T</sub> (ρ = 0.43)), with no systematic biases.</div></div><div><h3>Conclusion</h3><div>[<sup>11</sup>C]acetoacetate and [<sup>11</sup>C]β-hydroxybutyrate can be used interchangeably for measuring global CMR in healthy rats but differ in certain cerebral and myocardial kinetics. Whether these findings are generalizable to pathological conditions warrants further studies to explore the kinetics of these tracers in disease models.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"138 ","pages":"Article 108967"},"PeriodicalIF":3.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Intranasal (IN) administration, often referred to as nose-to-brain (N2B) drug delivery, is an attractive approach for delivering drugs to the central nervous system. However, the efficacy of this method is limited because of the small size of the nasal olfactory region, which limits the drug dosage. Using permeation enhancers could improve drug delivery from this region to the brain, though their effects are not fully understood. We therefore investigated the effects of co-administration of permeation enhancers on N2B drug delivery of a model drug domperidone, a peripherally acting dopamine D2 receptor (D2R) blocker.
Methods
We conducted in vitro permeability assays to evaluate the effects of sodium lauryl sulfate (SLS), a classical permeation enhancer, and lauroylcholine chloride (LCC) on domperidone permeation in human nasal mucosa-derived cells. We also used the D2R ligand [11C]raclopride to assess the in vivo effects of LCC on domperidone delivery in the rat brain using a positron emission tomography (PET) competition paradigm. In comparative PET experiments, we tested the effects of intravenously administered domperidone without LCC co-administration.
Results
LCC effectively improved nasal mucosal permeation of domperidone in vitro compared to SLS. In rat IN administration experiments, striatal [11C]raclopride uptake was significantly decreased by the addition of LCC to domperidone. On the other hand, intravenously administered domperidone with or without intranasally administered LCC did not decrease [11C]raclopride brain uptake, suggesting a lesser influence of peripheral domperidone on [11C]raclopride brain uptake. PET studies showed that striatal D2R occupancy of domperidone was increased 2.4-fold by co-administration of LCC.
Conclusion
LCC effectively enhances the domperidone delivery from the rat olfactory region to the brain, probably not via a circulating blood. The combination of permeation enhancers and olfactory region-selective drug administration could be effective for N2B drug delivery.
{"title":"Brain drug delivery from the nasal olfactory region is enhanced using lauroylcholine chloride: An estimation using in vivo PET imaging","authors":"Shota Fukakusa , Chie Suzuki , Keita Sasaki , Yoh Sonoda , Yoshiya Hatano , Shunji Haruta , Yasuhiro Magata","doi":"10.1016/j.nucmedbio.2024.108968","DOIUrl":"10.1016/j.nucmedbio.2024.108968","url":null,"abstract":"<div><h3>Introduction</h3><div>Intranasal (IN) administration, often referred to as nose-to-brain (N2B) drug delivery, is an attractive approach for delivering drugs to the central nervous system. However, the efficacy of this method is limited because of the small size of the nasal olfactory region, which limits the drug dosage. Using permeation enhancers could improve drug delivery from this region to the brain, though their effects are not fully understood. We therefore investigated the effects of co-administration of permeation enhancers on N2B drug delivery of a model drug domperidone, a peripherally acting dopamine D2 receptor (D2R) blocker.</div></div><div><h3>Methods</h3><div>We conducted <em>in vitro</em> permeability assays to evaluate the effects of sodium lauryl sulfate (SLS), a classical permeation enhancer, and lauroylcholine chloride (LCC) on domperidone permeation in human nasal mucosa-derived cells. We also used the D2R ligand [<sup>11</sup>C]raclopride to assess the <em>in vivo</em> effects of LCC on domperidone delivery in the rat brain using a positron emission tomography (PET) competition paradigm. In comparative PET experiments, we tested the effects of intravenously administered domperidone without LCC co-administration.</div></div><div><h3>Results</h3><div>LCC effectively improved nasal mucosal permeation of domperidone <em>in vitro</em> compared to SLS. In rat IN administration experiments, striatal [<sup>11</sup>C]raclopride uptake was significantly decreased by the addition of LCC to domperidone. On the other hand, intravenously administered domperidone with or without intranasally administered LCC did not decrease [<sup>11</sup>C]raclopride brain uptake, suggesting a lesser influence of peripheral domperidone on [<sup>11</sup>C]raclopride brain uptake. PET studies showed that striatal D2R occupancy of domperidone was increased 2.4-fold by co-administration of LCC.</div></div><div><h3>Conclusion</h3><div>LCC effectively enhances the domperidone delivery from the rat olfactory region to the brain, probably not <em>via</em> a circulating blood. The combination of permeation enhancers and olfactory region-selective drug administration could be effective for N2B drug delivery.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"138 ","pages":"Article 108968"},"PeriodicalIF":3.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/S0969-8051(24)00110-0
{"title":"Outside Back Cover - Graphical abstract TOC/TOC in double column/Cover image legend if applicable, Bar code, Abstracting and Indexing information","authors":"","doi":"10.1016/S0969-8051(24)00110-0","DOIUrl":"10.1016/S0969-8051(24)00110-0","url":null,"abstract":"","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"138 ","pages":"Article 108984"},"PeriodicalIF":3.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143094501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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