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Pharmaceutics
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Radiopharmaceuticals for Cancer Imaging and Therapy
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Radiopharmaceuticals for Cancer Imaging and Therapy

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (20 June 2023) | Viewed by 34813

Special Issue Editors

Prof. Dr. Frederik Cleeren

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Guest Editor
Radiopharmaceutical Research, Department of Pharmacy and Pharmacology, University of Leuven, 3000 Leuven, Belgium
Interests: radiochemistry; targeted radionuclide therapy; theranostics
Prof. Dr. Guy Bormans

E-Mail Website
Guest Editor
Radiopharmaceutical Research, Department of Pharmacy and Pharmacology, University of Leuven, 3000 Leuven, Belgium
Interests: radiochemistry; targeted radionuclide therapy; theranostics

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to the Special Issue on “Radiopharmaceuticals for Cancer Imaging and Therapy” that will be published in Pharmaceutics.

Using dedicated radiopharmaceuticals, nuclear medicine significantly contributes to all stages of cancer patient care, including early detection, diagnosis, therapy monitoring, and treatment. Radiopharmaceuticals are distributed within the body by the vascular system and allow targeting of a primary tumor and its metastases. The specific decay characteristics of the radionuclide determine if the radiopharmaceutical can be used for diagnostic (e.g., PET, SPECT) or therapeutic (targeted radionuclide therapy) purposes (theranostic approach).  In this exciting research field, new, continuous developments are being made in identifying novel molecular targets, vector molecule design, radiochemistry with established and upcoming radionuclides, and quality control to achieve more specific imaging of cancer targets and to improve therapeutic efficacy. Moreover, as big pharma has stepped in the arena of radiopharmaceuticals for targeted radionuclide therapy and contributed toward the initial success and large investment in this area, a spectacular growth of these radiopharmaceuticals is expected in the near future.

This Special Issue aims to highlight the research field of radiopharmaceutical research for cancer imaging and therapy. In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

  • Improved radiolabeling strategies with diagnostic/therapeutic radionuclides;
  • Novel PET tracers for cancer imaging;
  • Targeted radionuclide therapy using β-, α or Auger electron emitters;
  • Quality control of diagnostic and therapeutic radiopharmaceuticals.

We look forward to receiving your contributions.

Prof. Dr. Frederik Cleeren
Prof. Dr. Guy Bormans
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • positron emission tomography
  • targeted radionuclide therapy
  • nuclear medicine
  • theranostics
  • cancer

Published Papers (18 papers)

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Editorial

Jump to: Research, Review

2 pages, 174 KiB  
Editorial
Radiopharmaceuticals for Cancer Imaging and Therapy
by Guy Bormans and Frederik Cleeren
Pharmaceutics 2023, 15(9), 2262; https://doi.org/10.3390/pharmaceutics15092262 - 31 Aug 2023
Viewed by 833
Abstract
Nuclear medicine has emerged as a pivotal player in cancer patient care, revolutionizing the way cancer is detected, diagnosed, monitored, and treated [...] Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)

Research

Jump to: Editorial, Review

16 pages, 848 KiB  
Article
Development of the 99mTc-Labelled SST2 Antagonist TECANT-1 for a First-in-Man Multicentre Clinical Study
by Doroteja Novak, Barbara Janota, Anton Amadeus Hörmann, Agnieszka Sawicka, Marko Kroselj, Alicja Hubalewska-Dydejczyk, Melpomeni Fani, Renata Mikolajczak, Petra Kolenc, Clemens Decristoforo and Piotr Garnuszek
Pharmaceutics 2023, 15(3), 885; https://doi.org/10.3390/pharmaceutics15030885 - 09 Mar 2023
Cited by 2 | Viewed by 1351
Abstract
Broad availability and cost-effectiveness of 99Mo/99mTc generators worldwide support the use, and thus the development, of novel 99mTc-labelled radiopharmaceuticals. In recent years, preclinical and clinical developments for neuroendocrine neoplasms patient management focused on somatostatin receptor subtype 2 (SST2 [...] Read more.
Broad availability and cost-effectiveness of 99Mo/99mTc generators worldwide support the use, and thus the development, of novel 99mTc-labelled radiopharmaceuticals. In recent years, preclinical and clinical developments for neuroendocrine neoplasms patient management focused on somatostatin receptor subtype 2 (SST2) antagonists, mainly due to their superiority in SST2-tumour targeting and improved diagnostic sensitivity over agonists. The goal of this work was to provide a reliable method for facile preparation of a 99mTc-labelled SST2 antagonist, [99mTc]Tc-TECANT-1, in a hospital radiopharmacy setting, suitable for a multi-centre clinical trial. To ensure successful and reproducible on-site preparation of the radiopharmaceutical for human use shortly before administration, a freeze-dried three-vial kit was developed. The final composition of the kit was established based on the radiolabelling results obtained during the optimisation process, in which variables such as precursor content, pH and buffer, as well as kit formulations, were tested. Finally, the prepared GMP-grade batches met all predefined specification parameters together with long-term kit stability and stability of the product [99mTc]Tc-TECANT-1. Furthermore, the selected precursor content complies with micro-dosing, based on an extended single-dose toxicity study, where histopathology NOEL was established at 0.5 mg/kg BW, being more than 1000 times higher than the planned human dose of 20 µg. In conclusion, [99mTc]Tc-TECANT-1 is suitable to be advanced into a first-in-human clinical trial. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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16 pages, 1913 KiB  
Article
Effect of N-Terminal Peptide Modifications on In Vitro and In Vivo Properties of 177Lu-Labeled Peptide Analogs Targeting CCK2R
by Anton Amadeus Hörmann, Maximilian Klingler, Christine Rangger, Christian Mair, Lieke Joosten, Gerben M. Franssen, Peter Laverman and Elisabeth von Guggenberg
Pharmaceutics 2023, 15(3), 796; https://doi.org/10.3390/pharmaceutics15030796 - 28 Feb 2023
Cited by 3 | Viewed by 1246
Abstract
The therapeutic potential of minigastrin (MG) analogs for the treatment of cholecystokinin-2 receptor (CCK2R)-expressing cancers is limited by poor in vivo stability or unfavorable accumulation in non-target tissues. Increased stability against metabolic degradation was achieved by modifying the C-terminal receptor-specific region. This modification [...] Read more.
The therapeutic potential of minigastrin (MG) analogs for the treatment of cholecystokinin-2 receptor (CCK2R)-expressing cancers is limited by poor in vivo stability or unfavorable accumulation in non-target tissues. Increased stability against metabolic degradation was achieved by modifying the C-terminal receptor-specific region. This modification led to significantly improved tumor targeting properties. In this study, further N-terminal peptide modifications were investigated. Two novel MG analogs were designed starting from the amino acid sequence of DOTA-MGS5 (DOTA-DGlu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1Nal-NH2). Introduction of a penta-DGlu moiety and replacement of the four N-terminal amino acids by a non-charged hydrophilic linker was investigated. Retained receptor binding was confirmed using two CCK2R-expressing cell lines. The effect on metabolic degradation of the new 177Lu-labeled peptides was studied in human serum in vitro, as well as in BALB/c mice in vivo. The tumor targeting properties of the radiolabeled peptides were assessed using BALB/c nude mice bearing receptor-positive and receptor-negative tumor xenografts. Both novel MG analogs were found to have strong receptor binding, enhanced stability, and high tumor uptake. Replacement of the four N-terminal amino acids by a non-charged hydrophilic linker lowered the absorption in the dose-limiting organs, whereas introduction of the penta-DGlu moiety increased uptake in renal tissue. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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15 pages, 2617 KiB  
Article
Imaging of Gαq Proteins in Mouse and Human Organs and Tissues
by Jan H. Voss, Haneen Al-Hroub, Robin Gedschold, Jennifer M. Dietrich, Evelyn Gaffal, Marieta Toma, Stefan Kehraus, Gabriele M. König, Peter Brust, Bernd K. Fleischmann, Daniela Wenzel, Winnie Deuther-Conrad and Christa E. Müller
Pharmaceutics 2023, 15(1), 57; https://doi.org/10.3390/pharmaceutics15010057 - 24 Dec 2022
Cited by 1 | Viewed by 1514
Abstract
G protein-coupled receptors (GPCRs) transfer extracellular signals across cell membranes by activating intracellular heterotrimeric G proteins. Several studies suggested G proteins as novel drug targets for the treatment of complex diseases, e.g., asthma and cancer. Recently, we developed specific radiotracers, [³H]PSB-15900-FR and [³H]PSB-16254-YM, [...] Read more.
G protein-coupled receptors (GPCRs) transfer extracellular signals across cell membranes by activating intracellular heterotrimeric G proteins. Several studies suggested G proteins as novel drug targets for the treatment of complex diseases, e.g., asthma and cancer. Recently, we developed specific radiotracers, [³H]PSB-15900-FR and [³H]PSB-16254-YM, for the Gαq family of G proteins by tritiation of the macrocyclic natural products FR900359 (FR) and YM-254890 (YM). In the present study, we utilized these potent radioligands to perform autoradiography studies in tissues of healthy mice, mouse models of disease, and human tissues. Specific binding was high, while non-specific binding was extraordinarily low, giving nearly identical results for both radioligands. High expression levels of Gαq proteins were detected in healthy mouse organs showing the following rank order of potency: kidney > liver > brain > pancreas > lung > spleen, while expression in the heart was low. Organ sub-structures, e.g., of mouse brain and lung, were clearly distinguishable. Whereas an acute asthma model in mice did not result in altered Gαq protein expressions as compared to control animals, a cutaneous melanoma model displayed significantly increased expression in comparison to healthy skin. These results suggest the future development of Gαq-protein-binding radio-tracers as novel diagnostics. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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12 pages, 3414 KiB  
Article
PET Imaging of the Neurotensin Targeting Peptide NOTA-NT-20.3 Using Cobalt-55, Copper-64 and Gallium-68
by Hailey A. Houson, Volkan Tekin, Wilson Lin, Eduardo Aluicio-Sarduy, Jonathan W. Engle and Suzanne E. Lapi
Pharmaceutics 2022, 14(12), 2724; https://doi.org/10.3390/pharmaceutics14122724 - 06 Dec 2022
Cited by 4 | Viewed by 1768
Abstract
Introduction: Neurotensin receptor 1 (NTSR1) is an emerging target for imaging and therapy of many types of cancer. Nuclear imaging of NTSR1 allows for noninvasive assessment of the receptor levels of NTSR1 on the primary tumor, as well as potential metastases. This work [...] Read more.
Introduction: Neurotensin receptor 1 (NTSR1) is an emerging target for imaging and therapy of many types of cancer. Nuclear imaging of NTSR1 allows for noninvasive assessment of the receptor levels of NTSR1 on the primary tumor, as well as potential metastases. This work focuses on a the neurotensin peptide analogue NT-20.3 conjugated to the chelator NOTA for radiolabeling for use in noninvasive positron emission tomography (PET). NOTA-NT-20.3 was radiolabeled with gallium-68, copper-64, and cobalt-55 to determine the effect that modification of the radiometal has on imaging and potential therapeutic properties of NOTA-NT-20.3. Methods: In vitro assays investigating cell uptake and subcellular localization of the radiolabeled peptides were performed using human colorectal adenocarcinoma HT29 cells. In vivo PET/CT imaging was used to determine the distribution and clearance of the peptide in mice bearing NTSR1 expressing HT29 tumors. Results: Cell uptake studies showed that the highest uptake was obtained with [55Co] Co-NOTA-NT-20.3 (18.70 ± 1.30%ID/mg), followed by [64Cu] Cu-NOTA-NT-20.3 (15.46 ± 0.91%ID/mg), and lastly [68Ga] Ga-NOTA-NT-20.3 (10.94 ± 0.46%ID/mg) (p < 0.001). Subcellular distribution was similar across the three constructs, with the membranous fraction containing the highest amount of radioactivity. In vivo PET/CT imaging of the three constructs revealed similar distribution and tumor uptake at the 1 h imaging timepoint. Tumor uptake was receptor-specific and blockable by co-injection of non-radiolabeled NOTA-NT-20.3. SUV ratios of tumor to heart at the 24 h imaging timepoint show that [55Co] Co-NOTA-NT-20.3 (20.28 ± 3.04) outperformed [64Cu] Cu-NOTA-NT-20.3 (6.52 ± 1.97). In conclusion, our studies show that enhanced cell uptake and increasing tumor to blood ratios over time displayed the superiority of [55Co] Co-NOTA-NT-20.3 over [68Ga] Ga-NOTA-NT-20.3 and [64Cu] Cu-NOTA-NT-20.3 for the targeting of NTSR1. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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15 pages, 2695 KiB  
Article
Exploring the Potential of High-Molar-Activity Samarium-153 for Targeted Radionuclide Therapy with [153Sm]Sm-DOTA-TATE
by Koen Vermeulen, Michiel Van de Voorde, Charlotte Segers, Amelie Coolkens, Sunay Rodriguez Pérez, Noami Daems, Charlotte Duchemin, Melissa Crabbé, Tomas Opsomer, Clarita Saldarriaga Vargas, Reinhard Heinke, Laura Lambert, Cyril Bernerd, Andrew R. Burgoyne, Thomas Elias Cocolios, Thierry Stora and Maarten Ooms
Pharmaceutics 2022, 14(12), 2566; https://doi.org/10.3390/pharmaceutics14122566 - 23 Nov 2022
Cited by 4 | Viewed by 1665
Abstract
Samarium-153 is a promising theranostic radionuclide, but low molar activities (Am) resulting from its current production route render it unsuitable for targeted radionuclide therapy (TRNT). Recent efforts combining neutron activation of 152Sm in the SCK CEN BR2 reactor with mass [...] Read more.
Samarium-153 is a promising theranostic radionuclide, but low molar activities (Am) resulting from its current production route render it unsuitable for targeted radionuclide therapy (TRNT). Recent efforts combining neutron activation of 152Sm in the SCK CEN BR2 reactor with mass separation at CERN/MEDICIS yielded high-Am 153Sm. In this proof-of-concept study, we further evaluated the potential of high-Am 153Sm for TRNT by radiolabeling to DOTA-TATE, a well-established carrier molecule binding the somatostatin receptor 2 (SSTR2) that is highly expressed in gastroenteropancreatic neuroendocrine tumors. DOTA-TATE was labeled with 153Sm and remained stable up to 7 days in relevant media. The binding specificity and high internalization rate were validated on SSTR2-expressing CA20948 cells. In vitro biological evaluation showed that [153Sm]Sm-DOTA-TATE was able to reduce CA20948 cell viability and clonogenic potential in an activity-dependent manner. Biodistribution studies in healthy and CA20948 xenografted mice revealed that [153Sm]Sm-DOTA-TATE was rapidly cleared and profound tumor uptake and retention was observed whilst these were limited in normal tissues. This proof-of-concept study showed the potential of mass-separated 153Sm for TRNT and could open doors towards wider applications of mass separation in medical isotope production. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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14 pages, 13234 KiB  
Article
Glucose Metabolism Modification Induced by Radioligand Therapy with [177Lu]Lu/[90Y]Y-DOTATOC in Advanced Neuroendocrine Neoplasms: A Prospective Pilot Study within FENET-2016 Trial
by Luca Urso, Stefano Panareo, Angelo Castello, Maria Rosaria Ambrosio, Maria Chiara Zatelli, Matteo Caracciolo, Eugenia Tonini, Giorgia Valpiani, Alessandra Boschi, Licia Uccelli, Corrado Cittanti and Mirco Bartolomei
Pharmaceutics 2022, 14(10), 2009; https://doi.org/10.3390/pharmaceutics14102009 - 22 Sep 2022
Cited by 8 | Viewed by 1559
Abstract
[18F]F-FDG (FDG) PET is emerging as a relevant diagnostic and prognostic tool in neuroendocrine neoplasms (NENs), as a simultaneous decrease in [68Ga]Ga-DOTA peptides and increase in FDG uptake (the “flip-flop” phenomenon) occurs during the natural history of these tumors. [...] Read more.
[18F]F-FDG (FDG) PET is emerging as a relevant diagnostic and prognostic tool in neuroendocrine neoplasms (NENs), as a simultaneous decrease in [68Ga]Ga-DOTA peptides and increase in FDG uptake (the “flip-flop” phenomenon) occurs during the natural history of these tumors. The aim of this study was to evaluate the variations on FDG PET in NEN patients treated with two different schemes of radioligand therapy (RLT) and to correlate them with clinical–pathologic variables. A prospective evaluation of 108 lesions in 56 patients (33 males and 23 females; median age, 64.5 years) affected by NENs of various primary origins (28 pancreatic, 13 gastrointestinal, 9 bronchial, 6 unknown primary (CUP-NENs) and 1 pheochromocytoma) and grades (median Ki-67 = 9%) was performed. The patients were treated with RLT within the phase II clinical trial FENET-2016 (CTID: NCT04790708). RLT was offered for 32 patients with the MONO scheme (five cycles of [177Lu]Lu-DOTATOC) and for 24 with the DUO scheme (three cycles of [177Lu]Lu-DOTATOC alternated with two cycles of [90Y]Y-DOTATOC). Variations in terms of the ΔSUVmax of a maximum of three target lesions per patient (58 for MONO and 50 for DUO RLT) were assessed between baseline and 3 months post-RLT FDG PET. In patients with negative baseline FDG PET, the three most relevant lesions on [68Ga]Ga-DOTA-peptide PET were assessed and matched on post-RLT FDG PET, to check for any possible changes in FDG avidity. Thirty-five patients (62.5%) had at least one pathological FDG uptake at the baseline scans, but the number was reduced to 29 (52%) after RLT. In the patients treated with DUO-scheme RLT, 20 out of 50 lesions were FDG positive before therapy, whereas only 14 were confirmed after RLT (p = 0.03). Moreover, none of the 30 FDG-negative lesions showed an increased FDG uptake after RLT. The lesions of patients with pancreatic and CUP-NENs treated with the DUO scheme demonstrated a significant reduction in ΔSUVmax in comparison to those treated with MONO RLT (p = 0.03 and p = 0.04, respectively). Moreover, we found a mild positive correlation between the grading and ΔSUVmax in patients treated with the MONO scheme (r = 0.39, p < 0.02), while no evidence was detected for patients treated with the DUO scheme. Our results suggest that RLT, mostly with the DUO scheme, could be effective in changing NEN lesions’ glycometabolism, in particular, in patients affected by pancreatic and CUP-NENs, regardless of their Ki-67 index. Probably, associating [90Y]Y-labelled peptides, which have high energy emission and a crossfire effect, and [177Lu]Lu ones, characterized by a longer half-life and a safer profile for organs at risk, might represent a valid option in FDG-positive NENs addressed to RLT. Further studies are needed to validate our preliminary findings. In our opinion, FDG PET/CT should represent a potent tool for fully assessing a patient’s disease characteristics, both before and after RLT. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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17 pages, 3358 KiB  
Article
Simultaneous Imaging and Therapy Using Epitope-Specific Anti-Epidermal Growth Factor Receptor (EGFR) Antibody Conjugates
by Anjong Florence Tikum, Anand Krishnan Nambisan, Jessica Pougoue Ketchemen, Hanan Babeker, Musharraf N. Khan, Emina E. Torlakovic and Humphrey Fonge
Pharmaceutics 2022, 14(9), 1917; https://doi.org/10.3390/pharmaceutics14091917 - 10 Sep 2022
Cited by 5 | Viewed by 2770
Abstract
Matuzumab and nimotuzumab are anti-EGFR monoclonal antibodies that bind to different epitopes of domain III of EGFR. We developed 89Zr-matuzumab as a PET probe for diagnosis/monitoring of response to treatment of a noncompeting anti-EGFR nimotuzumab antibody drug conjugate (ADC) using mouse colorectal [...] Read more.
Matuzumab and nimotuzumab are anti-EGFR monoclonal antibodies that bind to different epitopes of domain III of EGFR. We developed 89Zr-matuzumab as a PET probe for diagnosis/monitoring of response to treatment of a noncompeting anti-EGFR nimotuzumab antibody drug conjugate (ADC) using mouse colorectal cancer (CRC) xenografts. We developed 89Zr-matuzumab and performed quality control in EGFR-positive DLD-1 cells. The KD of matuzumab, DFO-matuzumab and 89Zr-matuzumab in DLD-1 cells was 5.9, 6.2 and 3 nM, respectively. A competitive radioligand binding assay showed that 89Zr-matuzumab and nimotuzumab bound to noncompeting epitopes of EGFR. MicroPET/CT imaging and biodistribution of 89Zr-matuzumab in mice bearing EGFR-positive xenografts (HT29, DLD-1 and MDA-MB-231) showed high uptake that was blocked with pre-dosing with matuzumab but not with the noncompeting binder nimotuzumab. We evaluated nimotuzumab-PEG6-DM1 ADC in CRC cells. IC50 of nimotuzumab-PEG6-DM1 in SNU-C2B, DLD-1 and SW620 cells was dependent on EGFR density and was up to five-fold lower than that of naked nimotuzumab. Mice bearing the SNU-C2B xenograft were treated using three 15 mg/kg doses of nimotuzumab-PEG6-DM1, and 89Zr-matuzumab microPET/CT was used to monitor the response to treatment. Treatment resulted in complete remission of the SNU-C2B tumor in 2/3 mice. Matuzumab and nimotuzumab are noncompeting and can be used simultaneously. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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16 pages, 3211 KiB  
Article
Evaluation of an Affibody-Based Binder for Imaging of Immune Check-Point Molecule B7-H3
by Maryam Oroujeni, Ekaterina A. Bezverkhniaia, Tianqi Xu, Yongsheng Liu, Evgenii V. Plotnikov, Ida Karlberg, Eva Ryer, Anna Orlova, Vladimir Tolmachev and Fredrik Y. Frejd
Pharmaceutics 2022, 14(9), 1780; https://doi.org/10.3390/pharmaceutics14091780 - 25 Aug 2022
Cited by 5 | Viewed by 2104
Abstract
Radionuclide molecular imaging could provide an accurate assessment of the expression of molecular targets in disseminated cancers enabling stratification of patients for specific therapies. B7-H3 (CD276) is a transmembrane protein belonging to the B7 superfamily. This protein is overexpressed in different types of [...] Read more.
Radionuclide molecular imaging could provide an accurate assessment of the expression of molecular targets in disseminated cancers enabling stratification of patients for specific therapies. B7-H3 (CD276) is a transmembrane protein belonging to the B7 superfamily. This protein is overexpressed in different types of human malignancies and such upregulation is generally associated with a poor clinical prognosis. In this study, targeting properties of an Affibody-based probe, AC12, containing a -GGGC amino acid sequence as a chelator (designated as AC12-GGGC) labelled with technetium-99m (99mTc) were evaluated for imaging of B7-H3-expressing tumours. AC12-GGGC was efficiently labelled with 99mTc. [99mTc]Tc-AC12-GGGC bound specifically to B7-H3 expressing cells in vitro with affinities in nanomolar range. In mice bearing B7-H3-expressing xenografts, [99mTc]Tc-AC12-GGGC showed tumour uptake of 2.1 ± 0.5 %ID/g at 2 h after injection. Its clearance from blood, normal organs and tissues was very rapid. This new targeting agent, [99mTc]Tc-AC12-GGGC, provided high tumour-to-blood ratio already at 2 h (8.2 ± 1.9), which increased to 11.0 ± 0.5 at 4 h after injection. Significantly (p < 0.05) higher tumour-to-liver and higher tumour-to-bone ratios at 2 h in comparison with 4 h after injection were observed. Thus, [99mTc]Tc-AC12-GGGC could be a promising candidate for further development. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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18 pages, 2637 KiB  
Article
Preclinical Evaluation of a New Format of 68Ga- and 111In-Labeled Affibody Molecule ZIGF-1R:4551 for the Visualization of IGF-1R Expression in Malignant Tumors Using PET and SPECT
by Yongsheng Liu, Shengze Yu, Tianqi Xu, Vitalina Bodenko, Anna Orlova, Maryam Oroujeni, Sara S. Rinne, Vladimir Tolmachev, Anzhelika Vorobyeva and Torbjörn Gräslund
Pharmaceutics 2022, 14(7), 1475; https://doi.org/10.3390/pharmaceutics14071475 - 15 Jul 2022
Cited by 4 | Viewed by 1921
Abstract
The Insulin-like growth factor-1 receptor (IGF-1R) is a molecular target for several monoclonal antibodies undergoing clinical evaluation as anticancer therapeutics. The non-invasive detection of IGF-1R expression in tumors might enable stratification of patients for specific treatment and improve the outcome of both clinical [...] Read more.
The Insulin-like growth factor-1 receptor (IGF-1R) is a molecular target for several monoclonal antibodies undergoing clinical evaluation as anticancer therapeutics. The non-invasive detection of IGF-1R expression in tumors might enable stratification of patients for specific treatment and improve the outcome of both clinical trials and routine treatment. The affibody molecule ZIGF-1R:4551 binds specifically to IGF-1R with subnanomolar affinity. The goal of this study was to evaluate the 68Ga and 111In-labeled affibody construct NODAGA-(HE)3-ZIGF-1R:4551 for the imaging of IGF-1R expression, using PET and SPECT. The labeling was efficient and provided stable coupling of both radionuclides. The two imaging probes, [68Ga]Ga-NODAGA-(HE)3-ZIGF-1R:4551 and [111In]In-NODAGA-(HE)3-ZIGF-1R:4551, demonstrated specific binding to IGF-1R-expressing human cancer cell lines in vitro and to IGF-1R-expressing xenografts in mice. Preclinical PET and SPECT/CT imaging demonstrated visualization of IGF-1R-expressing xenografts already one hour after injection. The tumor-to-blood ratios at 3 h after injection were 7.8 ± 0.2 and 8.0 ± 0.6 for [68Ga]Ga-NODAGA-(HE)3-ZIGF-1R:4551 and [111In]In-NODAGA-(HE)3-ZIGF-1R:4551, respectively. In conclusion, a molecular design of the ZIGF-1R:4551 affibody molecule, including placement of a (HE)3-tag on the N-terminus and site-specific coupling of a NODAGA chelator on the C-terminus, provides a tracer with improved imaging properties for visualization of IGF-1R in malignant tumors, using PET and SPECT. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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19 pages, 3898 KiB  
Article
Therapeutic Response Monitoring with 89Zr-DFO-Pertuzumab in HER2-Positive and Trastuzumab-Resistant Breast Cancer Models
by Minwoo Kang, Jong Il Shin, Sangjin Han, Jung Young Kim, Jeonghoon Park, Kwang Il Kim, Joo Hyun Kang and Tae Sup Lee
Pharmaceutics 2022, 14(7), 1338; https://doi.org/10.3390/pharmaceutics14071338 - 24 Jun 2022
Cited by 3 | Viewed by 2159
Abstract
Immuno-positron emission tomography (PET) has great potential to evaluate the target expression level and therapeutic response for targeted cancer therapy. Immuno-PET imaging with pertuzumab, due to specific recognition in different binding sites of HER2, could be useful for the determination of the therapeutic [...] Read more.
Immuno-positron emission tomography (PET) has great potential to evaluate the target expression level and therapeutic response for targeted cancer therapy. Immuno-PET imaging with pertuzumab, due to specific recognition in different binding sites of HER2, could be useful for the determination of the therapeutic efficacy of HER2-targeted therapy, trastuzumab, and heat shock protein 90 (HSP90) inhibitor, in HER2-expressing breast cancer. The aim of this study is to evaluate the feasibility of monitoring therapeutic response with 89Zr-DFO-pertuzumab for the treatment of HER2-targeted therapeutics, trastuzumab, or the HSP90 inhibitor 17-DMAG, in trastuzumab-resistant JIMT-1 breast cancer models. We prepared an immuno-PET imaging agent using desferoxamine (DFO)-pertuzumab labeled with 89Zr and performed the biodistribution and PET imaging in breast cancer xenograft models for monitoring therapeutic response to HER2-targeted therapy. 89Zr-DFO-pertuzumab was successfully prepared and showed specific binding to HER2 in vitro and clearly visualized HER2 expressing JIMT-1 tumors. 89Zr-DFO-pertuzumab had prominent tumor uptake in HER2 expressing JIMT-1 tumors. JIMT-1 tumors showed trastuzumab-resistant and HSP90 inhibitor sensitive characterization. In immuno-PET imaging, isotype antibody-treated JIMT-1 tumors had similar uptake in trastuzumab-treated JIMT-1 tumors, but 17-DMAG-treated JIMT-1 tumors showed greatly reduced uptake compared to vehicle-treated tumors. Additionally, HER2 downregulation evaluated by immuno-PET imaging was verified by western blot analysis and immunofluorescence staining which resulted in a significant reduction in the tumor’s HER2 level in 17-DMAG-treated JIMT-1 tumors. 89Zr-DFO-pertuzumab immuno-PET may be clinically translated to select pertinent patients for HER2-targeted therapy and to monitor the therapeutic response in HER2-positive cancer patients under various HER2-targeted therapeutics treatments. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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12 pages, 4155 KiB  
Article
Phase I Clinical Trial Using [99mTc]Tc-1-thio-D-glucose for Diagnosis of Lymphoma Patients
by Vladimir Chernov, Ekaterina Dudnikova, Roman Zelchan, Anna Medvedeva, Anstasiya Rybina, Olga Bragina, Viktor Goldberg, Albina Muravleva, Jens Sörensen and Vladimir Tolmachev
Pharmaceutics 2022, 14(6), 1274; https://doi.org/10.3390/pharmaceutics14061274 - 15 Jun 2022
Cited by 2 | Viewed by 2044
Abstract
Similar to [18F]-FDG, [99mTc]Tc-1-thio-D-glucose ([99mTc]Tc-TG) also binds to GLUT receptors. The aim of this Phase I study was to evaluate the safety, biodistribution and dosimetry of [99mTc]Tc-TG. Twelve lymphoma patients were injected with 729 ± [...] Read more.
Similar to [18F]-FDG, [99mTc]Tc-1-thio-D-glucose ([99mTc]Tc-TG) also binds to GLUT receptors. The aim of this Phase I study was to evaluate the safety, biodistribution and dosimetry of [99mTc]Tc-TG. Twelve lymphoma patients were injected with 729 ± 102 MBq [99mTc]Tc-TG. Whole-body planar imaging was performed in 10 patients at 2, 4, 6 and 24 h after injection. In all 12 patients, SPECT/CT (at 2 h) and SPECT (at 4 and 6 h) imaging was performed. Vital signs and possible side effects were monitored during imaging and up to 7 days after injection. [99mTc]Tc-TG injections were well-tolerated and no side effects or alterations in blood and urine analyses data were observed. The highest absorbed dose was in the kidneys and urinary bladder wall, followed by the adrenals, prostate, bone marrow, lungs, myocardium, ovaries, uterus, liver and gall bladder wall. [99mTc]Tc-TG SPECT/CT revealed foci of high activity uptake in the lymph nodes of all nine patients with known nodal lesions. Extranodal lesions were detected in all nine cases. In one patient, a lesion in the humerus head, which was not detected by CT, was visualized using [99mTc]Tc-TG. Potentially, [99mTc]Tc-TG can be considered as an additional diagnostic method for imaging GLUT receptors in lymphoma patients. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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19 pages, 4617 KiB  
Article
Experimental Therapy of HER2-Expressing Xenografts Using the Second-Generation HER2-Targeting Affibody Molecule 188Re-ZHER2:41071
by Yongsheng Liu, Anzhelika Vorobyeva, Anna Orlova, Mark W. Konijnenberg, Tianqi Xu, Olga Bragina, Annika Loftenius, Erica Rosander, Fredrik Y. Frejd and Vladimir Tolmachev
Pharmaceutics 2022, 14(5), 1092; https://doi.org/10.3390/pharmaceutics14051092 - 20 May 2022
Cited by 6 | Viewed by 2312
Abstract
HER2-targeted radionuclide therapy might be helpful for the treatment of breast, gastric, and ovarian cancers which have developed resistance to antibody and antibody-drug conjugate-based therapies despite preserved high HER2-expression. Affibody molecules are small targeting proteins based on a non-immunoglobulin scaffold. The goal of [...] Read more.
HER2-targeted radionuclide therapy might be helpful for the treatment of breast, gastric, and ovarian cancers which have developed resistance to antibody and antibody-drug conjugate-based therapies despite preserved high HER2-expression. Affibody molecules are small targeting proteins based on a non-immunoglobulin scaffold. The goal of this study was to test in an animal model a hypothesis that the second-generation HER2-targeting Affibody molecule 188Re-ZHER2:41071 might be useful for treatment of HER2-expressing malignant tumors. ZHER2:41071 was efficiently labeled with a beta-emitting radionuclide rhenium-188 (188Re). 188Re-ZHER2:41071 demonstrated preserved specificity and high affinity (KD = 5 ± 3 pM) of binding to HER2-expressing cells. In vivo studies demonstrated rapid washout of 188Re from kidneys. The uptake in HER2-expressing SKOV-3 xenografts was HER2-specific and significantly exceeded the renal uptake 4 h after injection and later. The median survival of mice, which were treated by three injections of 16 MBq 188Re-ZHER2:41071 was 68 days, which was significantly longer (<0.0001 in the log-rank Mantel-Cox test) than survival of mice in the control groups treated with vehicle (29 days) or unlabeled ZHER2:41071 (27.5 days). In conclusion, the experimental radionuclide therapy using 188Re-ZHER2:41071 enabled enhancement of survival of mice with human tumors without toxicity to the kidneys, which is the critical organ. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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Graphical abstract

16 pages, 1808 KiB  
Article
Improved Characteristics of RANKL Immuno-PET Imaging Using Radiolabeled Antibody Fab Fragments
by Jonatan Dewulf, Ivanna Hrynchak, Sarah Geudens, Isabel Pintelon, Christel Vangestel, José Sereno, Peter A. van Dam, Antero J. Abrunhosa, Filipe Elvas and Tim Van den Wyngaert
Pharmaceutics 2022, 14(5), 939; https://doi.org/10.3390/pharmaceutics14050939 - 26 Apr 2022
Cited by 4 | Viewed by 2311
Abstract
Purpose: RANKL expression in the tumor microenvironment has been identified as a biomarker of immune suppression, negating the effect of some cancer immunotherapies. Previously we had developed a radiotracer based on the FDA-approved RANKL-specific antibody denosumab, [89Zr]Zr-DFO-denosumab, enabling successful immuno-PET imaging. [...] Read more.
Purpose: RANKL expression in the tumor microenvironment has been identified as a biomarker of immune suppression, negating the effect of some cancer immunotherapies. Previously we had developed a radiotracer based on the FDA-approved RANKL-specific antibody denosumab, [89Zr]Zr-DFO-denosumab, enabling successful immuno-PET imaging. Radiolabeled denosumab, however, showed long blood circulation and delayed tumor uptake, potentially limiting its applications. Here we aimed to develop a smaller radiolabeled denosumab fragment, [64Cu]Cu-NOTA-denos-Fab, that would ideally show faster tumor accumulation and better diffusion into the tumor for the visualization of RANKL. Experimental design: Fab fragments were prepared from denosumab using papain and conjugated to a NOTA chelator for radiolabeling with 64Cu. The bioconjugates were characterized in vitro using SDS-PAGE analysis, and the binding affinity was assessed using a radiotracer cell binding assay. Small animal PET imaging evaluated tumor targeting and biodistribution in transduced RANKL-ME-180 xenografts. Results: The radiolabeling yield of [64Cu]Cu-NOTA-denos-Fab was 58 ± 9.2%, with a specific activity of 0.79 ± 0.11 MBq/µg (n = 3). A radiotracer binding assay proved specific targeting of RANKL in vitro. PET imaging showed fast blood clearance and high tumor accumulation as early as 1 h p.i. (2.14 ± 0.21% ID/mL), which peaked at 5 h p.i. (2.72 ± 0.61% ID/mL). In contrast, [64Cu]Cu-NOTA-denosumab reached its highest tumor uptake at 24 h p.i. (6.88 ± 1.12% ID/mL). [64Cu]Cu-NOTA-denos-Fab specifically targeted human RANKL in transduced ME-180 xenografts compared with the blocking group and negative ME-180 xenograft model. Histological analysis confirmed RANKL expression in RANKL-ME-180 xenografts. Conclusions: Here, we report on a novel RANKL PET imaging agent, [64Cu]Cu-NOTA-denos-Fab, that allows for fast tumor imaging with improved imaging contrast when compared with its antibody counterpart, showing promise as a potential PET RANKL imaging tool for future clinical applications. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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Review

Jump to: Editorial, Research

14 pages, 1626 KiB  
Review
Recent Innovations and Nano-Delivery of Actinium-225: A Narrative Review
by Sipho Mdanda, Lindokuhle M. Ngema, Amanda Mdlophane, Mike M. Sathekge and Jan Rijn Zeevaart
Pharmaceutics 2023, 15(6), 1719; https://doi.org/10.3390/pharmaceutics15061719 - 13 Jun 2023
Cited by 2 | Viewed by 2119
Abstract
The actinium-225 (225Ac) radioisotope exhibits highly attractive nuclear properties for application in radionuclide therapy. However, the 225Ac radionuclide presents multiple daughter nuclides in its decay chain, which can escape the targeted site, circulate in plasma, and cause toxicity in areas [...] Read more.
The actinium-225 (225Ac) radioisotope exhibits highly attractive nuclear properties for application in radionuclide therapy. However, the 225Ac radionuclide presents multiple daughter nuclides in its decay chain, which can escape the targeted site, circulate in plasma, and cause toxicity in areas such as kidneys and renal tissues. Several ameliorative strategies have been devised to circumvent this issue, including nano-delivery. Alpha-emitting radionuclides and nanotechnology applications in nuclear medicine have culminated in major advancements that offer promising therapeutic possibilities for treating several cancers. Accordingly, the importance of nanomaterials in retaining the 225Ac daughters from recoiling into unintended organs has been established. This review expounds on the advancements of targeted radionuclide therapy (TRT) as an alternative anticancer treatment. It discusses the recent developments in the preclinical and clinical investigations on 225Ac as a prospective anticancer agent. Moreover, the rationale for using nanomaterials in improving the therapeutic efficacy of α-particles in targeted alpha therapy (TAT) with an emphasis on 225Ac is discussed. Quality control measures in the preparation of 225Ac-conjugates are also highlighted. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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23 pages, 11365 KiB  
Review
Recent Advances in 18F-Labeled Amino Acids Synthesis and Application
by Chao Wang, Rong Lin and Shaobo Yao
Pharmaceutics 2022, 14(10), 2207; https://doi.org/10.3390/pharmaceutics14102207 - 17 Oct 2022
Cited by 2 | Viewed by 1964
Abstract
Radiolabeled amino acids are an important class of agents for positron emission tomography imaging that target amino acid transporters in many tumor types. Traditional 18F-labeled amino acid synthesis strategies are always based on nucleophilic aromatic substitution reactions with multistep radiosynthesis and low [...] Read more.
Radiolabeled amino acids are an important class of agents for positron emission tomography imaging that target amino acid transporters in many tumor types. Traditional 18F-labeled amino acid synthesis strategies are always based on nucleophilic aromatic substitution reactions with multistep radiosynthesis and low radiochemical yields. In recent years, new 18F-labeling methodologies such as metal-catalyzed radiofluorination and heteroatom (B, P, S, Si, etc.)-18F bond formation are being effectively used to synthesize radiopharmaceuticals. This review focuses on recent advances in the synthesis, radiolabeling, and application of a series of 18F-labeled amino acid analogs using new 18F-labeling strategies. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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20 pages, 876 KiB  
Review
Nanoparticles and Radioisotopes: A Long Story in a Nutshell
by Giulia Poletto, Laura Evangelista, Francesca Venturini, Fabiana Gramegna, Flavio Seno, Stefano Moro, Roberto Vettor, Nicola Realdon and Diego Cecchin
Pharmaceutics 2022, 14(10), 2024; https://doi.org/10.3390/pharmaceutics14102024 - 23 Sep 2022
Cited by 5 | Viewed by 1465
Abstract
The purpose of this narrative review was to assess the use of nanoparticles (NPs) to deliver radionuclides to targets, focusing on systems that have been tested in pre-clinical and, when available, clinical settings. A literature search was conducted in PubMed and Web of [...] Read more.
The purpose of this narrative review was to assess the use of nanoparticles (NPs) to deliver radionuclides to targets, focusing on systems that have been tested in pre-clinical and, when available, clinical settings. A literature search was conducted in PubMed and Web of Science databases using the following terms: “radionuclides” AND “liposomes” or “PLGA nanoparticles” or “gold nanoparticles” or “iron oxide nanoparticles” or “silica nanoparticles” or “micelles” or “dendrimers”. No filters were applied, apart from a minimum limit of 10 patients enrolled for clinical studies. Data from some significant studies from pre-clinical and clinical settings were retrieved, and we briefly describe the information available. All the selected seven classes of nanoparticles were highly tested in clinical trials, but they all present many drawbacks. Liposomes are the only ones that have been tested for clinical applications, though they have never been commercialized. In conclusion, the application of NPs for imaging has been the object of much interest over the years, albeit mainly in pre-clinical settings. Thus, we think that, based on the current state, radiolabeled NPs must be investigated longer before finding their place in nuclear medicine. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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19 pages, 1016 KiB  
Review
A Review on Tumor Control Probability (TCP) and Preclinical Dosimetry in Targeted Radionuclide Therapy (TRT)
by Kaat Spoormans, Melissa Crabbé, Lara Struelens, Marijke De Saint-Hubert and Michel Koole
Pharmaceutics 2022, 14(10), 2007; https://doi.org/10.3390/pharmaceutics14102007 - 22 Sep 2022
Cited by 5 | Viewed by 1822
Abstract
Targeted radionuclide therapy (TRT) uses radiopharmaceuticals to specifically irradiate tumor cells while sparing healthy tissue. Response to this treatment highly depends on the absorbed dose. Tumor control probability (TCP) models aim to predict the tumor response based on the absorbed dose by taking [...] Read more.
Targeted radionuclide therapy (TRT) uses radiopharmaceuticals to specifically irradiate tumor cells while sparing healthy tissue. Response to this treatment highly depends on the absorbed dose. Tumor control probability (TCP) models aim to predict the tumor response based on the absorbed dose by taking into account the different characteristics of TRT. For instance, TRT employs radiation with a high linear energy transfer (LET), which results in an increased effectiveness. Furthermore, a heterogeneous radiopharmaceutical distribution could result in a heterogeneous dose distribution at a tissue, cellular as well as subcellular level, which will generally reduce the tumor response. Finally, the dose rate in TRT is protracted, relatively low, and variable over time. This allows cells to repair more DNA damage, which may reduce the effectiveness of TRT. Within this review, an overview is given on how these characteristics can be included in TCP models, while some experimental findings are also discussed. Many parameters in TCP models are preclinically determined and TCP models also play a role in the preclinical stage of radiopharmaceutical development; however, this all depends critically on the calculated absorbed dose. Accordingly, an overview of the existing preclinical dosimetry methods is given, together with their limitation and applications. It can be concluded that although the theoretical extension of TCP models from external beam radiotherapy towards TRT has been established quite well, the experimental confirmation is lacking. Thus, requiring additional comprehensive studies at the sub-cellular, cellular, and organ level, which should be provided with accurate preclinical dosimetry. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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