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Pharmaceuticals
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Targeted Radionuclide Therapy (TRNT) in Modern Cancer Management
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Targeted Radionuclide Therapy (TRNT) in Modern Cancer Management

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Radiopharmaceutical Sciences".

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 27727

Special Issue Editors

Dr. Martina Benešová-Schäfer

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Guest Editor
Research Group Molecular Biology of Systemic Radiotherapy, Research Program Imaging and Radiooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 223, 69120 Heidelberg, Germany
Interests: theranostic radioligands; targeted radionuclide therapies; targeted alpha therapies; combination therapies; molecular imaging; pharmaceutical radiochemistry; coordination and bioinorganic chemistry; radionuclide production and separation methods
Special Issues, Collections and Topics in MDPI journals
Dr. Gábor Bakos

E-Mail Website
Guest Editor
Research Group Molecular Biology of Systemic Radiotherapy, Research Program Imaging and Radiooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 223, D-69120 Heidelberg, Germany
Interests: molecular and cell biology; biochemistry; cancer biology; targeted alpha therapies

Special Issue Information

Dear Colleagues,

Targeted radionuclide therapy (TRNT) allows us to deliver various radionuclides to cancer cells in a specific manner. The TRNT approach has been proven clinically highly promising given its experience in the treatment of neuroendocrine tumors or disseminated prostate cancer. The crucial aspect of TRNT is the evaluation of new targets, radionuclides and pharmaceuticals. The mechanisms of resistance and radiation-induced adverse effects limiting patients‘ survival or quality of life must also be addressed.

The purpose of this Special Issue is to host research and review papers on the development and evaluation of TRNT representing this rapidly evolving and highly promising modality of cancer treatment. Areas of interest include, but are not limited to:

  • Evaluation of novel targets for cancer treatment and theranostics;
  • Design and evaluation of novel radiopharmaceuticals for treatment and theranostics;
  • Evaluation of non-standard/exotic radionuclides potentially suitable for TRNT;
  • Established and experimental TRNT strategies;
  • Targeted alpha therapies;
  • Auger-electron radionuclide therapies;
  • Radiommunotherapies;
  • Prospective combination therapies involving TRNT;
  • Biological effects of TRNT;
  • Challenges of radiobiology in TRNT;

 We look forward to reading your research and breakthroughs in this exciting field and to cover them in this Special Issue.

Dr. Martina Benešová
Dr. Gábor Bakos
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. Pharmaceuticals 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

  • Novel and established cancer targets
  • therapeutic and theranostic radiopharmaceuticals
  • targeted radionuclide therapy
  • targeted alpha therapy
  • Auger-electron radionuclide therapy
  • radiommunotherapy
  • combination therapy
  • radiobiology
  • treatment resistance
  • dosimetry
  • personalized and precision medicine

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Published Papers (7 papers)

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Research

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22 pages, 2273 KiB  
Article
Albumin-Mediated Size Exclusion Chromatography: The Apparent Molecular Weight of PSMA Radioligands as Novel Parameter to Estimate Their Blood Clearance Kinetics
by Jan-Philip Kunert, Sebastian Fischer, Alexander Wurzer and Hans-Jürgen Wester
Pharmaceuticals 2022, 15(9), 1161; https://doi.org/10.3390/ph15091161 - 19 Sep 2022
Cited by 5 | Viewed by 2893
Abstract
A meticulously adjusted pharmacokinetic profile and especially fine-tuned blood clearance kinetics are key characteristics of therapeutic radiopharmaceuticals. We, therefore, aimed to develop a method that allowed the estimation of blood clearance kinetics in vitro. For this purpose, 177Lu-labeled PSMA radioligands were subjected [...] Read more.
A meticulously adjusted pharmacokinetic profile and especially fine-tuned blood clearance kinetics are key characteristics of therapeutic radiopharmaceuticals. We, therefore, aimed to develop a method that allowed the estimation of blood clearance kinetics in vitro. For this purpose, 177Lu-labeled PSMA radioligands were subjected to a SEC column with human serum albumin (HSA) dissolved in a mobile phase. The HSA-mediated retention time of each PSMA ligand generated by this novel ‘albumin-mediated size exclusion chromatography’ (AMSEC) was converted to a ligand-specific apparent molecular weight (MWapp), and a normalization accounting for unspecific interactions between individual radioligands and the SEC column matrix was applied. The resulting normalized MWapp,norm. could serve to estimate the blood clearance of renally excreted radioligands by means of their influence on the highly size-selective process of glomerular filtration (GF). Based on the correlation between MW and the glomerular sieving coefficients (GSCs) of a set of plasma proteins, GSCcalc values were calculated to assess the relative differences in the expected GF/blood clearance kinetics in vivo and to select lead candidates among the evaluated radioligands. Significant differences in the MWapp,norm. and GSCcalc values, even for stereoisomers, were found, indicating that AMSEC might be a valuable and high-resolution tool for the preclinical selection of therapeutic lead compounds for clinical translation. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy (TRNT) in Modern Cancer Management)
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12 pages, 1617 KiB  
Article
64Cu-SAR-Bombesin PET-CT Imaging in the Staging of Estrogen/Progesterone Receptor Positive, HER2 Negative Metastatic Breast Cancer Patients: Safety, Dosimetry and Feasibility in a Phase I Trial
by Keith Wong, Gemma Sheehan-Dare, Andrew Nguyen, Bao Ho, Victor Liu, Jonathan Lee, Lauren Brown, Rachel Dear, Lyn Chan, Shikha Sharma, Alessandra Malaroda, Isabelle Smith, Elgene Lim and Louise Emmett
Pharmaceuticals 2022, 15(7), 772; https://doi.org/10.3390/ph15070772 - 22 Jun 2022
Cited by 12 | Viewed by 3435
Abstract
Breast cancers are most frequently oestrogen receptor (ER) and progesterone receptor (PR) positive and [18F]Fluorodeoxyglucose PET-CT (FDG) has lower sensitivity for these subtypes. The gastrin-releasing peptide receptor (GRPR) is overexpressed in ER+/PR+ breast cancers. This study assessed the safety and potential [...] Read more.
Breast cancers are most frequently oestrogen receptor (ER) and progesterone receptor (PR) positive and [18F]Fluorodeoxyglucose PET-CT (FDG) has lower sensitivity for these subtypes. The gastrin-releasing peptide receptor (GRPR) is overexpressed in ER+/PR+ breast cancers. This study assessed the safety and potential of [64Cu]Cu-Sarcophagine (SAR)-Bombesin PET/CT (BBN) in re-staging metastatic ER+/PR+/human epidermal growth-factor-2-negative (HER2-) breast cancer. Seven patients with metastatic ER+/PR+/HER2- breast cancer undergoing staging underwent [64Cu]Cu-SAR-BBN PET-CT. Bloods, vital signs and electrocardiogram, blood tracer-clearance and dosimetry were undertaken. GRPR status was assessed in available metastatic biopsy samples. Staging with conventional imaging ([18F]FDG, bone scan and diagnostic CT) was within 3 weeks of [64Cu]Cu-SAR-BBN PET/CT. PET scans were assessed visually and quantitatively. Seven patients underwent imaging. One of the seven had de-novo metastatic breast cancer and six of the seven recurrent metastatic disease. Two of the seven had lobular subtype. No adverse events were reported. All seven patients were positive on conventional imaging (six of seven on FDG). [64Cu]Cu-SAR-BBN imaging was positive in five of the seven. Both [64Cu]Cu-SAR-BBN-negative patients had disease identified on [18F]FDG. One patient was [64Cu]Cu-SAR-BBN positive/[18F]FDG negative. Four of seven patients were [64Cu]Cu-SAR-BBN positive/[18F]FDG positive. In these four, mean SUVmax was higher for [64Cu]Cu-SAR-BBN than [18F]FDG (SUVmax 15 vs. 12). In the classical lobular subtype (two of seven), [64Cu]Cu-SAR-BBN was more avid compared to [18F]FDG (SUVmax 20 vs. 11, and 20 vs. <3). Dosimetry calculations estimated whole-body effective dose for 200 MBq of [64Cu]Cu-SAR-BBN to be 1.9 mSv. [64Cu]Cu-SAR-BBN PET/CT appears safe and may have diagnostic value in metastatic ER+/PR+/HER2- breast cancer, particularly the lobular subtype. Further evaluation is warranted. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy (TRNT) in Modern Cancer Management)
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11 pages, 1938 KiB  
Article
Copper-67-Labeled Bombesin Peptide for Targeted Radionuclide Therapy of Prostate Cancer
by Truc T. Huynh, Ellen M. van Dam, Sreeja Sreekumar, Cedric Mpoy, Benjamin J. Blyth, Fenella Muntz, Matthew J. Harris and Buck E. Rogers
Pharmaceuticals 2022, 15(6), 728; https://doi.org/10.3390/ph15060728 - 8 Jun 2022
Cited by 20 | Viewed by 3455
Abstract
The gastrin-releasing peptide receptor (GRPR) is a promising molecular target for imaging and therapy of prostate cancer using bombesin peptides that bind to the receptor with high affinity. Targeted copper theranostics (TCTs) using copper radionuclides, 64Cu for imaging and 67Cu for [...] Read more.
The gastrin-releasing peptide receptor (GRPR) is a promising molecular target for imaging and therapy of prostate cancer using bombesin peptides that bind to the receptor with high affinity. Targeted copper theranostics (TCTs) using copper radionuclides, 64Cu for imaging and 67Cu for therapy, offer significant advantages in the development of next-generation theranostics. [64Cu]Cu-SAR-BBN is in clinical development for PET imaging of GRPR-expressing cancers. This study explores the therapeutic efficacy of [67Cu]Cu-SAR-BBN in a pre-clinical mouse model. The peptide was radiolabeled with 67Cu, and specific binding of the radiolabeled peptide towards GRPR-positive PC-3 prostate cancer cells was confirmed with 52.2 ± 1.4% total bound compared to 5.8 ± 0.1% with blocking. A therapy study with [67Cu]Cu-SAR-BBN was conducted in mice bearing PC-3 tumors by injecting 24 MBq doses a total of six times. Tumor growth was inhibited by 93.3% compared to the control group on day 19, and median survival increased from 34.5 days for the control group to greater than 54 days for the treatment group. The ease and stability of the radiochemistry, favorable biodistribution, and the positive tumor inhibition demonstrate the suitability of this copper-based theranostic agent for clinical assessment in the treatment of cancers expressing GRPR. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy (TRNT) in Modern Cancer Management)
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13 pages, 6881 KiB  
Article
Carbonic Anhydrase IX-Targeted α-Radionuclide Therapy with 225Ac Inhibits Tumor Growth in a Renal Cell Carcinoma Model
by Robin I. J. Merkx, Mark Rijpkema, Gerben M. Franssen, Annemarie Kip, Bart Smeets, Alfred Morgenstern, Frank Bruchertseifer, Eddie Yan, Michael P. Wheatcroft, Egbert Oosterwijk, Peter F. A. Mulders and Sandra Heskamp
Pharmaceuticals 2022, 15(5), 570; https://doi.org/10.3390/ph15050570 - 2 May 2022
Cited by 10 | Viewed by 3751
Abstract
In this study, we compared the tumor-targeting properties, therapeutic efficacy, and tolerability of the humanized anti-CAIX antibody (hG250) labeled with either the α-emitter actinium-225 (225Ac) or the β--emitter lutetium-177 (177Lu) in mice. BALB/c nude mice were grafted [...] Read more.
In this study, we compared the tumor-targeting properties, therapeutic efficacy, and tolerability of the humanized anti-CAIX antibody (hG250) labeled with either the α-emitter actinium-225 (225Ac) or the β--emitter lutetium-177 (177Lu) in mice. BALB/c nude mice were grafted with human renal cell carcinoma SK-RC-52 cells and intravenously injected with 30 µg [225Ac] Ac-DOTA-hG250 (225Ac-hG250) or 30 µg [177Lu] Lu-DOTA-hG250 (177Lu-hG250), followed by ex vivo biodistribution studies. Therapeutic efficacy was evaluated in mice receiving 5, 15, and 25 kBq of 225Ac-hG250; 13 MBq of 177Lu-hG250; or no treatment. Tolerability was evaluated in non-tumor-bearing animals. High tumor uptake of both radioimmunoconjugates was observed and increased up to day 7 (212.8 ± 50.2 %IA/g vs. 101.0 ± 18.4 %IA/g for 225Ac-hG250 and 177Lu-hG250, respectively). Survival was significantly prolonged in mice treated with 15 kBq 225Ac-hG250, 25 kBq 225Ac-hG250, and 13 MBq 177Lu-hG250 compared to untreated control (p < 0.05). Non-tumor-bearing mice that received single-dose treatment with 15 or 25 kBq 225Ac-hG250 showed weight loss at the end of the experiment (day 126), and immunohistochemical analysis suggested radiation-induced nephrotoxicity. These results demonstrate the therapeutic potential of CAIX-targeted α-therapy in renal cell carcinoma. Future studies are required to find an optimal balance between therapeutic efficacy and toxicity. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy (TRNT) in Modern Cancer Management)
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18 pages, 1980 KiB  
Article
First-In-Human Results on the Biodistribution, Pharmacokinetics, and Dosimetry of [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2
by Sanjana Ballal, Madhav Prasad Yadav, Euy Sung Moon, Vasko S Kramer, Frank Roesch, Samta Kumari and Chandrasekhar Bal
Pharmaceuticals 2021, 14(12), 1212; https://doi.org/10.3390/ph14121212 - 24 Nov 2021
Cited by 66 | Viewed by 6686
Abstract
Recently, great interest has been gained regarding fibroblast activation protein (FAP) as an excellent target for theranostics. Several FAP inhibitor molecules such as [68Ga]Ga-labelled FAPI-02, 04, 46, and DOTA.SA.FAPi have been introduced and are highly promising molecular targets from the imaging [...] Read more.
Recently, great interest has been gained regarding fibroblast activation protein (FAP) as an excellent target for theranostics. Several FAP inhibitor molecules such as [68Ga]Ga-labelled FAPI-02, 04, 46, and DOTA.SA.FAPi have been introduced and are highly promising molecular targets from the imaging point of view. FAP inhibitors introduced via bifunctional DOTA and DOTAGA chelators offer the possibility to complex Lutetium-177 due to an additional coordination site, and are suitable for theranostic applications owing to the increased tumor accumulation and prolonged tumor retention time. However, for therapeutic applications, very little has been accomplished, mainly due to residence times of the compounds. In an attempt to develop a promising therapeutic radiopharmaceutical, the present study aimed to evaluate and compare the biodistribution, pharmacokinetics, and dosimetry of [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 in patients with various cancers. The FAPi agents, [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2, were administered in two different groups of patients. Three patients (mean age—50 years) were treated with a median cumulative activity of 2.96 GBq (IQR: 2.2–3 GBq) [177Lu]Lu-DOTA.SA.FAPi and seven (mean age—51 years) were treated with 1.48 GBq (IQR: 0.6–1.5) of [177Lu]Lu-DOTAGA.(SA.FAPi)2. Patients in both the groups underwent serial imaging whole-body planar and SPECT/CT scans that were acquired between 1 h and 168 h post-injection (p.i.). The residence time and absorbed dose estimate in the source organs and tumor were calculated using OLINDA/EXM 2.2 software. Time versus activity graphs were plotted to determine the effective half-life (Te) in the whole body and lesions for both the radiotracers. Physiological uptake of [177Lu]Lu-DOTA.SA.FAPi was observed in the kidneys, colon, pancreas, liver, gall bladder, oral mucosa, lacrimal glands, and urinary bladder contents. Physiological biodistribution of [177Lu]Lu-DOTAGA.(SA.FAPi)2 involved liver, gall bladder, colon, pancreas, kidneys, and urinary bladder contents, lacrimal glands, oral mucosa, and salivary glands. In the [177Lu]Lu-DOTA.SA.FAPi group, the highest absorbed doses were noted in the kidneys (0.618 ± 0.015 Gy/GBq), followed by the colon (right colon: 0.472 Gy/GBq and left colon: 0.430 Gy/GBq). In the [177Lu]Lu-DOTAGA.(SA.FAPi)2 group, the colon received the highest absorbed dose (right colon: 1.160 Gy/GBq and left colon: 2.870 Gy/GBq), and demonstrated a significantly higher mean absorbed dose than [177Lu]Lu-DOTA.SA.FAPi (p < 0.011). [177Lu]Lu-DOTAGA.(SA.FAPi)2 had significantly longer median whole-body Te compared to that of [177Lu]Lu-DOTA.SA.FAPi [46.2 h (IQR: 38.5–70.1) vs. 23.1 h (IQR: 17.8–31.5); p-0.0167]. The Te of tumor lesions was significantly higher for [177Lu]Lu-DOTAGA.(SA.FAPi)2 compared to [177Lu]Lu-DOTA.SA.FAPi [86.6 h (IQR: 34.3–94.6) vs. 14 h (IQR: 12.8–15.5); p-0.0004]. The median absorbed doses to the lesions were 0.603 (IQR: 0.230–1.810) Gy/GBq and 6.70 (IQR: 3.40–49) Gy/GBq dose per cycle in the [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 groups, respectively. The first clinical dosimetry study demonstrated significantly higher tumor absorbed doses with [177Lu]Lu-DOTAGA.(SA.FAPi)2 compared to [177Lu]Lu-DOTA.SA.FAPi. [177Lu]Lu-DOTAGA.(SA.FAPi)2 is safe and unveiled new frontiers to treat various end-stage cancer patients with a theranostic approach. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy (TRNT) in Modern Cancer Management)
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Review

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14 pages, 1280 KiB  
Review
Novel Theranostic Approaches Targeting CCR4-Receptor, Current Status and Translational Prospectives: A Systematic Review
by Joana Gorica, Maria Silvia De Feo, Ferdinando Corica, Marko Magdi Abdou Sidrak, Miriam Conte, Luca Filippi, Orazio Schillaci, Giuseppe De Vincentis and Viviana Frantellizzi
Pharmaceuticals 2023, 16(2), 313; https://doi.org/10.3390/ph16020313 - 17 Feb 2023
Cited by 3 | Viewed by 2283
Abstract
Background: With the high mortality rate of malignant tumors, there is a need to find novel theranostic approaches to provide an early diagnosis and targeted therapy. The chemokine receptor 4 (CCR4) is highly expressed in various tumors and plays an important role in [...] Read more.
Background: With the high mortality rate of malignant tumors, there is a need to find novel theranostic approaches to provide an early diagnosis and targeted therapy. The chemokine receptor 4 (CCR4) is highly expressed in various tumors and plays an important role in tumor pathogenesis. This systematic review aims to provide a complete overview on clinical and preclinical applications of the CCR4 receptor as a target for theranostics, using a systematic approach to classify and assemble published studies performed on humans and animals, sorted by field of application and specific tumor. Methods: A systematic literature search of articles suiting the inclusion criteria was conducted on Pubmed, Scopus, Central, and Web of Science databases, including papers published from January 2006 to November 2022. Eligible studies had to be performed on humans and/or in vivo/in vitro studying CCR4 expression in tumors. The methodological quality was assessed through the Critical Appraisal Skills Programme (CASP) assessing only the studies performed on humans. Results: A total of 17 articles were screened. The articles were assessed for eligibility with the exclusion of 4 articles. Ultimately, 13 articles were selected for the qualitative analysis, and six articles were selected for the critical appraisal skills program. Conclusions: The development of new radionuclides and radiopharmaceuticals targeting CCR4 show promising results in the theranostics of CCR4 sensible tumors. Although to widen its use in clinical practice, further translation of preclinical to clinical data is needed. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy (TRNT) in Modern Cancer Management)
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21 pages, 1640 KiB  
Review
Introducing HDAC-Targeting Radiopharmaceuticals for Glioblastoma Imaging and Therapy
by Liesbeth Everix, Elsie Neo Seane, Thomas Ebenhan, Ingeborg Goethals and Julie Bolcaen
Pharmaceuticals 2023, 16(2), 227; https://doi.org/10.3390/ph16020227 - 1 Feb 2023
Cited by 11 | Viewed by 3504
Abstract
Despite recent advances in multimodality therapy for glioblastoma (GB) incorporating surgery, radiotherapy, chemotherapy and targeted therapy, the overall prognosis remains poor. One of the interesting targets for GB therapy is the histone deacetylase family (HDAC). Due to their pleiotropic effects on, e.g., DNA [...] Read more.
Despite recent advances in multimodality therapy for glioblastoma (GB) incorporating surgery, radiotherapy, chemotherapy and targeted therapy, the overall prognosis remains poor. One of the interesting targets for GB therapy is the histone deacetylase family (HDAC). Due to their pleiotropic effects on, e.g., DNA repair, cell proliferation, differentiation, apoptosis and cell cycle, HDAC inhibitors have gained a lot of attention in the last decade as anti-cancer agents. Despite their known underlying mechanism, their therapeutic activity is not well-defined. In this review, an extensive overview is given of the current status of HDAC inhibitors for GB therapy, followed by an overview of current HDAC-targeting radiopharmaceuticals. Imaging HDAC expression or activity could provide key insights regarding the role of HDAC enzymes in gliomagenesis, thus identifying patients likely to benefit from HDACi-targeted therapy. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy (TRNT) in Modern Cancer Management)
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