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Pharmaceuticals
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The Future Direction of Radiopharmaceutical Development for Cancer Theranostics
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The Future Direction of Radiopharmaceutical Development for Cancer Theranostics

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

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 57411

Special Issue Editor

Dr. Martina Benešová-Schäfer

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, 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

Special Issue Information

Dear Colleagues,

The journal Pharmaceuticals is planning to publish a Special Issue covering the topic “The Future Direction of Radiopharmaceutical Development for Cancer Theranostics”, and I am cordially inviting you to contribute an article to this volume.

With rapid population growth and aging, cancer is expected to rank as the leading cause of death in every country of the world in the 21st century. The development of improved diagnostic and therapeutic strategies for the management of cancer is, therefore, of utmost importance. The term “theranostics” is used for combined diagnosis and therapy, among others, in the field of radiooncology. The application of the same vector molecule with either a diagnostic or therapeutic radionuclide has the potential to overcome undesirable differences in selectivity and biodistribution that usually exist for distinct agents.

In recent years, the field of cancer radiotheranostics has evolved considerably due to the definition of suitable biological targets and targeting strategies (e.g., SSTR- and PSMA-based concepts), development of various pharmaceuticals (e.g., small low- and high-molecular-weight molecules, various antibody-like structures and nanoparticles), and increased availability of prospective diagnostic and therapeutic radionuclides (e.g., α-, β+-, β–-, and Auger electron-emitters), as well as improvement of imaging techniques. In addition to optimal treatment choice, an improved staging of primary and recurrent disease, prognostic stratification, therapy follow-up, and guidance of clinical trial enrollment may maximize the likelihood of successful theranostic outcomes.

Targeted radionuclide therapy (TRNT) is an attractive treatment option in the field of cancer radiotheranostics, focusing on particular biological targets and their environments. Currently, targeted alpha therapy (TAT) represents the most rapidly developing field in nuclear medicine. Despite its great potential for cancer treatment, translation of TAT into the clinical setting is rather slow, mainly due to the lack of pre-clinical research directly linked to limited radionuclide availability. For many years, large-field radiation has been used for its immunosuppressive ability. On the contrary, the application of radioimmunotherapy demonstrates a more complex relationship with the immune system while inducing substantial changes in the tumor microenvironment beyond cellular cytotoxicity. Based on the critical role of the immune system in cancer development and dissemination, TRNT may potentially be combined with various strategies triggering immune response in order to achieve enhanced anti-tumor effect.

The purpose of this Special Issue is to host research and review papers on the development of novel radiopharmaceuticals and therapy strategies for cancer theranostics, which hold a great promise for improved patients’ outcomes in the future. Areas of interest include, but are not limited to: 

  • Identification of new targets for cancer theranostics;
  • Design of novel radiopharmaceuticals for cancer theranostics;
  • Evaluation of non-standard radionuclides potentially suitable for cancer theranostics;
  • Experimental targeted radionuclide therapy strategies;
  • Prospective combination therapy with targeted radionuclide therapy involved.

Dr. Martina Benešová
Guest Editor

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 cancer targets
  • non-standard radionuclides
  • molecular imaging
  • targeted radionuclide therapy
  • theranostic radiopharmaceuticals
  • radioimmunotherapy
  • nuclear medicine
  • personalized medicine
  • precision medicine

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Related Special Issues

Published Papers (9 papers)

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13 pages, 1287 KiB  
Article
Current Status of PSMA-Radiotracers for Prostate Cancer: Data Analysis of Prospective Trials Listed on ClinicalTrials.gov
by Claus Zippel, Sarah C. Ronski, Sabine Bohnet-Joschko, Frederik L. Giesel and Klaus Kopka
Pharmaceuticals 2020, 13(1), 12; https://doi.org/10.3390/ph13010012 - 13 Jan 2020
Cited by 35 | Viewed by 9088
Abstract
The recent development of dedicated prostate-specific membrane antigen (PSMA) targeted radioligands shows the potential to change and improve the diagnosis and therapy of prostate cancer. There is an increasing number of prospective trials to further establish these tracers in the clinical setting. We [...] Read more.
The recent development of dedicated prostate-specific membrane antigen (PSMA) targeted radioligands shows the potential to change and improve the diagnosis and therapy of prostate cancer. There is an increasing number of prospective trials to further establish these tracers in the clinical setting. We analyzed data from the ClinicalTrials.gov registry including all listed prospective trials with PSMA-ligands for prostate cancer as of October 2019 concerning the different tracers and study characteristics. We found n = 104 eligible studies with a total of n = 25 different tracers in use: most frequently [68Ga]Ga-PSMA-11 (32%), followed by [18F]DCFPyL (24%) and [177Lu]Lu-PSMA-617 (10%). 85% are single-center, 15% multi-center studies. 95% national and 5% international studies. 34% are phase-II, 24% phase-I, 13% phase-I/-II, 12% phase-II/-III and phase-III and 7% early-phase-I. The primary purpose was classified as diagnostic in 72% of cases and therapeutic in 23% of cases. Most studies were executed in the USA (70%), followed by Canada (13%) and France (6%). This quantitative descriptive registry analysis indicates the rapid and global clinical developments and current status of PSMA-radioligands with emphasis on radiopharmaceutical and organizational aspects. It will be very interesting to see which tracers will prevail in the clinical setting. Full article
(This article belongs to the Special Issue The Future Direction of Radiopharmaceutical Development for Cancer Theranostics)
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26 pages, 3042 KiB  
Article
A Robust Method for Assaying the Immunoreactive Fraction in Nonequilibrium Systems
by Thibaut Denoël, Luca Pedrelli, Giuseppe Pantaleo and John O. Prior
Pharmaceuticals 2019, 12(4), 177; https://doi.org/10.3390/ph12040177 - 3 Dec 2019
Cited by 9 | Viewed by 4389
Abstract
The immunoreactive fraction r provides important information on the functional purity of radiolabeled proteins. It is traditionally determined by saturating the radioimmunoconjugate with an increasing excess of antigen, followed by linear extrapolation to infinite antigen excess in a double inverse “Lindmo plot”. Although [...] Read more.
The immunoreactive fraction r provides important information on the functional purity of radiolabeled proteins. It is traditionally determined by saturating the radioimmunoconjugate with an increasing excess of antigen, followed by linear extrapolation to infinite antigen excess in a double inverse “Lindmo plot”. Although several reports have described shortcomings in the Lindmo plot, a systematic examination is lacking. Using an experimental and simulation-based approach, we compared—for accuracy, precision and robustness—the Lindmo plot with the “rectangular hyperbola” extrapolation method based on the Langmuir model. The differences between the theoretical and extrapolated r values demonstrate that nonequilibrium and antigen depletion are important sources of error. The mathematical distortions resulting from the linearization of the data in the Lindmo plot induce fragility towards stochastic errors and make it necessary to exclude low bound fractions. The rectangular hyperbola provides robust and precise r estimates from raw binding data, even for slow kinetics. Full article
(This article belongs to the Special Issue The Future Direction of Radiopharmaceutical Development for Cancer Theranostics)
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12 pages, 1402 KiB  
Article
New 55Co-labeled Albumin-Binding Folate Derivatives as Potential PET Agents for Folate Receptor Imaging
by Lauren L. Radford, Solana Fernandez, Rebecca Beacham, Retta El Sayed, Renata Farkas, Martina Benešová, Cristina Müller and Suzanne E. Lapi
Pharmaceuticals 2019, 12(4), 166; https://doi.org/10.3390/ph12040166 - 8 Nov 2019
Cited by 18 | Viewed by 5146
Abstract
Overexpression of folate receptors (FRs) on different tumor types (e.g., ovarian, lung) make FRs attractive in vivo targets for directed diagnostic/therapeutic agents. Currently, no diagnostic agent suitable for positron emission tomography (PET) has been adopted for clinical FR imaging. In this work, two [...] Read more.
Overexpression of folate receptors (FRs) on different tumor types (e.g., ovarian, lung) make FRs attractive in vivo targets for directed diagnostic/therapeutic agents. Currently, no diagnostic agent suitable for positron emission tomography (PET) has been adopted for clinical FR imaging. In this work, two 55Co-labeled albumin-binding folate derivatives-[55Co]Co-cm10 and [55Co]Co-rf42-with characteristics suitable for PET imaging have been developed and evaluated. High radiochemical yields (≥95%) and in vitro stabilities (≥93%) were achieved for both compounds, and cell assays demonstrated FR-mediated uptake. Both 55Co-labeled folate conjugates demonstrated high tumor uptake of 17% injected activity per gram of tissue (IA/g) at 4 h in biodistribution studies performed in KB tumor-bearing mice. Renal uptake was similar to other albumin-binding folate derivatives, and liver uptake was lower than that of previously reported [64Cu]Cu-rf42. Small animal PET/CT images confirmed the biodistribution results and showed the clear delineation of FR-expressing tumors. Full article
(This article belongs to the Special Issue The Future Direction of Radiopharmaceutical Development for Cancer Theranostics)
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16 pages, 2360 KiB  
Article
Synergistic Effect of a HER2 Targeted Thorium-227 Conjugate in Combination with Olaparib in a BRCA2 Deficient Xenograft Model
by Katrine Wickstroem, Jenny Karlsson, Christine Ellingsen, Véronique Cruciani, Alexander Kristian, Urs B. Hagemann, Roger M. Bjerke, Olav B. Ryan, Lars Linden, Dominik Mumberg, Michael Brands and Alan Cuthbertson
Pharmaceuticals 2019, 12(4), 155; https://doi.org/10.3390/ph12040155 - 15 Oct 2019
Cited by 28 | Viewed by 6156
Abstract
Targeted thorium-227 conjugates (TTCs) represent a novel class of therapeutic radiopharmaceuticals for the treatment of cancer. TTCs consist of the alpha particle emitter thorium-227 complexed to a 3,2-hydroxypyridinone chelator conjugated to a tumor-targeting monoclonal antibody. The high energy and short range of the [...] Read more.
Targeted thorium-227 conjugates (TTCs) represent a novel class of therapeutic radiopharmaceuticals for the treatment of cancer. TTCs consist of the alpha particle emitter thorium-227 complexed to a 3,2-hydroxypyridinone chelator conjugated to a tumor-targeting monoclonal antibody. The high energy and short range of the alpha particles induce potent and selective anti-tumor activity driven by the induction of DNA damage in the target cell. Methods: The efficacy of human epidermal growth factor receptor 2 (HER2)-TTC was tested in combination in vitro and in vivo with the poly ADP ribose polymerase (PARP) inhibitor (PARPi), olaparib, in the human colorectal adenocarcinoma isogenic cell line pair DLD-1 and the knockout variant DLD-1 BRCA2 -/- Results: The in vitro combination effects were determined to be synergistic in DLD-1 BRCA2 -/- and additive in DLD-1 parental cell lines. Similarly, the in vivo efficacy of the combination was determined to be synergistic only in the DLD-1 BRCA2 -/- xenograft model, with statistically significant tumor growth inhibition at a single TTC dose of 120 kBq/kg body weight (bw) and 50 mg/kg bw olaparib (daily, i.p. for 4 weeks), demonstrating comparable tumor growth inhibition to a single TTC dose of 600 kBq/kg bw. Conclusions: This study supports the further investigation of DNA damage response inhibitors in combination with TTCs as a new strategy for the effective treatment of mutation-associated cancers. Full article
(This article belongs to the Special Issue The Future Direction of Radiopharmaceutical Development for Cancer Theranostics)
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13 pages, 1077 KiB  
Article
Radioimmunotherapy in Non-Hodgkin’s Lymphoma: Retrospective Adverse Event Profiling of Zevalin and Bexxar
by Christos Sachpekidis, David B. Jackson and Theodoros G. Soldatos
Pharmaceuticals 2019, 12(4), 141; https://doi.org/10.3390/ph12040141 - 20 Sep 2019
Cited by 30 | Viewed by 6040
Abstract
The development of monoclonal antibodies has dramatically changed the outcome of patients with non-Hodgkin’s lymphoma (NHL), the most common hematological malignancy. However, despite the satisfying results of monoclonal antibody treatment, only few NHL patients are permanently cured with single-agent therapies. In this context, [...] Read more.
The development of monoclonal antibodies has dramatically changed the outcome of patients with non-Hodgkin’s lymphoma (NHL), the most common hematological malignancy. However, despite the satisfying results of monoclonal antibody treatment, only few NHL patients are permanently cured with single-agent therapies. In this context, radioimmunotherapy, the administration of radionuclides conjugated to monoclonal antibodies, is aimed to augment the single-agent efficacy of immunotherapy in order to deliver targeted radiation to tumors, particularly CD20+ B-cell lymphomas. Based on evidence from several trials in NHL, the radiolabeled antibodies 90Y-ibritumomab tiuxetan (Zevalin, Spectrum Pharmaceuticals) and 131I-tositumomab (Bexxar, GlaxoSmithKline) received FDA approval in 2002 and 2003, respectively. However, none of the two radioimmunotherapeutic agents has been broadly applied in clinical practice. The main reason for the under-utilization of radioimmunotherapy includes economic and logistic considerations. However, concerns about potential side effects have also been raised. Driven by these developments, we performed retrospective analysis of adverse events reporting Zevalin or Bexxar, extracted from the FDA’s Adverse Event Reporting System (FAERS) and the World Health Organization’s VigiBase repository. Our results indicate that the two radioimmunotherapeutic agents have both related and distinct side effect profiles and confirm their known toxicological considerations. Our work also suggests that computational analysis of real-world post-marketing data can provide informative clinical insights. While more prospective studies are necessary to fully characterize the efficacy and safety of radioimmunotherapy, we expect that it has not yet reached its full therapeutic potential in modern hematological oncology. Full article
(This article belongs to the Special Issue The Future Direction of Radiopharmaceutical Development for Cancer Theranostics)
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Review

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21 pages, 2749 KiB  
Review
Atomic Nanogenerators in Targeted Alpha Therapies: Curie’s Legacy in Modern Cancer Management
by Mareike Roscher, Gábor Bakos and Martina Benešová
Pharmaceuticals 2020, 13(4), 76; https://doi.org/10.3390/ph13040076 - 23 Apr 2020
Cited by 30 | Viewed by 5848
Abstract
Atomic in vivo nanogenerators such as actinium-225, thorium-227, and radium-223 are of increasing interest and importance in the treatment of patients with metastatic cancer diseases. This is due to their peculiar physical, chemical, and biological characteristics, leading to astonishing responses in otherwise resistant [...] Read more.
Atomic in vivo nanogenerators such as actinium-225, thorium-227, and radium-223 are of increasing interest and importance in the treatment of patients with metastatic cancer diseases. This is due to their peculiar physical, chemical, and biological characteristics, leading to astonishing responses in otherwise resistant patients. Nevertheless, there are still a few obstacles and hurdles to be overcome that hamper the broader utilization in the clinical setting. Next to the limited supply and relatively high costs, the in vivo complex stability and the fate of the recoiling daughter radionuclides are substantial problems that need to be solved. In radiobiology, the mechanisms underlying treatment efficiency, possible resistance mechanisms, and late side effect occurrence are still far from being understood and need to be unraveled. In this review, the current knowledge on the scientific and clinical background of targeted alpha therapies is summarized. Furthermore, open issues and novel approaches with a focus on the future perspective are discussed. Once these are unraveled, targeted alpha therapies with atomic in vivo nanogenerators can be tailored to suit the needs of each patient when applying careful risk stratification and combination therapies. They have the potential to become one of the major treatment pillars in modern cancer management. Full article
(This article belongs to the Special Issue The Future Direction of Radiopharmaceutical Development for Cancer Theranostics)
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25 pages, 8973 KiB  
Review
(Radio)Theranostic Patient Management in Oncology Exemplified by Neuroendocrine Neoplasms, Prostate Cancer, and Breast Cancer
by Irina Velikyan
Pharmaceuticals 2020, 13(3), 39; https://doi.org/10.3390/ph13030039 - 5 Mar 2020
Cited by 12 | Viewed by 5849
Abstract
The role of nuclear medicine in the management of oncological patients has expanded during last two decades. The number of radiopharmaceuticals contributing to the realization of theranostics/radiotheranostics in the context of personalized medicine is increasing. This review is focused on the examples of [...] Read more.
The role of nuclear medicine in the management of oncological patients has expanded during last two decades. The number of radiopharmaceuticals contributing to the realization of theranostics/radiotheranostics in the context of personalized medicine is increasing. This review is focused on the examples of targeted (radio)pharmaceuticals for the imaging and therapy of neuroendocrine neoplasms (NENs), prostate cancer, and breast cancer. These examples strongly demonstrate the tendency of nuclear medicine development towards personalized medicine. Full article
(This article belongs to the Special Issue The Future Direction of Radiopharmaceutical Development for Cancer Theranostics)
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38 pages, 2090 KiB  
Review
Radiolabelled Peptides for Positron Emission Tomography and Endoradiotherapy in Oncology
by Christine Rangger and Roland Haubner
Pharmaceuticals 2020, 13(2), 22; https://doi.org/10.3390/ph13020022 - 30 Jan 2020
Cited by 32 | Viewed by 6270
Abstract
This review deals with the development of peptide-based radiopharmaceuticals for the use with positron emission tomography and peptide receptor radiotherapy. It discusses the pros and cons of this class of radiopharmaceuticals as well as the different labelling strategies, and summarises approaches to optimise [...] Read more.
This review deals with the development of peptide-based radiopharmaceuticals for the use with positron emission tomography and peptide receptor radiotherapy. It discusses the pros and cons of this class of radiopharmaceuticals as well as the different labelling strategies, and summarises approaches to optimise metabolic stability. Additionally, it presents different target structures and addresses corresponding tracers, which are already used in clinical routine or are being investigated in clinical trials. Full article
(This article belongs to the Special Issue The Future Direction of Radiopharmaceutical Development for Cancer Theranostics)
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22 pages, 1952 KiB  
Review
Thermosensitive Nanosystems Associated with Hyperthermia for Cancer Treatment
by Isabela Pereira Gomes, Jaqueline Aparecida Duarte, Ana Luiza Chaves Maia, Domenico Rubello, Danyelle M. Townsend, André Luís Branco de Barros and Elaine Amaral Leite
Pharmaceuticals 2019, 12(4), 171; https://doi.org/10.3390/ph12040171 - 25 Nov 2019
Cited by 34 | Viewed by 6088
Abstract
Conventional chemotherapy regimens have limitations due to serious adverse effects. Targeted drug delivery systems to reduce systemic toxicity are a powerful drug development platform. Encapsulation of antitumor drug(s) in thermosensitive nanocarriers is an emerging approach with a promise to improve uptake and increase [...] Read more.
Conventional chemotherapy regimens have limitations due to serious adverse effects. Targeted drug delivery systems to reduce systemic toxicity are a powerful drug development platform. Encapsulation of antitumor drug(s) in thermosensitive nanocarriers is an emerging approach with a promise to improve uptake and increase therapeutic efficacy, as they can be activated by hyperthermia selectively at the tumor site. In this review, we focus on thermosensitive nanosystems associated with hyperthermia for the treatment of cancer, in preclinical and clinical use. Full article
(This article belongs to the Special Issue The Future Direction of Radiopharmaceutical Development for Cancer Theranostics)
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