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Pharmaceuticals
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Design, Synthesis and Biological Testing of Next Generation Theranostic Radiopharmaceuticals
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Design, Synthesis and Biological Testing of Next Generation Theranostic Radiopharmaceuticals

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

Deadline for manuscript submissions: closed (30 July 2022) | Viewed by 19164

Special Issue Editor

Dr. Andreas Ingemann Jensen

E-Mail Website
Guest Editor
Department of Health Technology, Technical University of Denmark (DTU), Kgs. Lyngby, Denmark
Interests: radiopharmaceutical chemistry; drug delivery systems; targeted radionuclide therapy; theranostics

Special Issue Information

Dear Colleagues,

In recent years, the radiopharmaceutical field has witnessed a surge in interest. This has, in particular, been spurred on by the successes of new drugs for targeted radionuclide therapy in oncology, such as PSMA-targeted compounds. Partly as a result of this, the interest in alpha-particle emitting radionuclides, such as actinium-225, thorium-227, and astatine-211, has also re-emerged and grown tremendously, together with the more established beta-particle emitters. In order to deploy these upcoming radiotherapeutics effectively, the development of new strategies for utilizing theranostic radionuclide pairs is essential. In this sense, “theranostics” refers to the use of the same chemical targeting vector or delivery system, but labeled with either a diagnostic or a therapeutic radionuclide. The diagnostic variant will first detect disease through imaging techniques such as positron emission tomography (PET) imaging, and verify that the targeting vector accumulates as desired. Second, the therapeutic variant will strike and eradicate the same lesions, with the diagnostic variant monitoring the efficacy of the therapy. The current standard is defined by radionuclide pairs such as gallium-68 (PET imaging) and lutetium-177 (beta-particle therapy). However, the rising availability of suitable therapeutic radionuclides, and the emergence of new targets and radiochemical strategies, are making the development of new theranostic platforms increasingly relevant. With this, researchers are invited to submit original and review articles of a basic, preclinical and clinical scope, focusing on the design, synthesis and biological testing of new radiotheranostic compounds and delivery systems, and their future potential. Work that only focuses on diagnostics or therapy should have a clear potential application in theranostics. Accepted submissions will be published in this Special Issue of Pharmaceuticals.

Dr. Andreas Ingemann Jensen
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

  • radiopharmaceuticals
  • radiochemistry
  • drug design
  • drug delivery
  • theranostics
  • radionuclide therapy

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Published Papers (4 papers)

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Research

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19 pages, 1594 KiB  
Article
64Cu-DOTHA2-PSMA, a Novel PSMA PET Radiotracer for Prostate Cancer with a Long Imaging Time Window
by Marie-Christine Milot, Ophélie Bélissant Benesty, Véronique Dumulon-Perreault, Samia Ait-Mohand, Patrick O. Richard, Étienne Rousseau and Brigitte Guérin
Pharmaceuticals 2022, 15(8), 996; https://doi.org/10.3390/ph15080996 - 13 Aug 2022
Cited by 7 | Viewed by 3012
Abstract
Prostate cancer imaging and late-stage management can be improved with prostate-specific membrane antigen (PSMA)-targeting radiotracers. We developed a PSMA positron emission tomography (PET) radiotracer, DOTHA2-PSMA radiolabeled with 64Cu (T1/2: 12.7 h), to leverage its large imaging time window. [...] Read more.
Prostate cancer imaging and late-stage management can be improved with prostate-specific membrane antigen (PSMA)-targeting radiotracers. We developed a PSMA positron emission tomography (PET) radiotracer, DOTHA2-PSMA radiolabeled with 64Cu (T1/2: 12.7 h), to leverage its large imaging time window. This preclinical study aimed to evaluate the biological and imaging properties of 64Cu-DOTHA2-PSMA. Its stability was assessed in plasma ex vivo and in mice. Cellular behavior was studied for up to 48 h in LNCaP cells. Biodistribution studies were performed in balb/c mice for up to 48 h. Dynamic (1 h) and static (4 h and 24 h) PET imaging was completed in LNCaP tumor-bearing mice. 64Cu-DOTHA2-PSMA was stable ex vivo in plasma and reached cellular internalization up to 34.1 ± 4.9% injected activity (IA)/106 cells at 48 h post-injection (p.i.). Biodistribution results showed significantly lower uptake in kidneys than 68Ga-PSMA-617, our reference PET tracer (p < 0.001), but higher liver uptake at 2 h p.i. (p < 0.001). PET images showed 64Cu-DOTHA2-PSMA’s highest tumoral uptake at 4 h p.i., with a significant difference between blocked and non-blocked groups from the time of injection to 24 h p.i. The high stability and tumor uptake with a long tumor imaging time window of 64Cu-DOTHA2-PSMA potentially contribute to the prostate cancer theranostic approach and its local recurrence detection. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Testing of Next Generation Theranostic Radiopharmaceuticals)
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12 pages, 1699 KiB  
Article
Humanization, Radiolabeling and Biodistribution Studies of an IgG1-Type Antibody Targeting Uncomplexed PSA for Theranostic Applications
by Joanna Strand, Kjell Sjöström, Urpo J. Lamminmaki, Oskar Vilhelmsson Timmermand, Sven-Erik Strand and Thuy A. Tran
Pharmaceuticals 2021, 14(12), 1251; https://doi.org/10.3390/ph14121251 - 1 Dec 2021
Cited by 1 | Viewed by 2409
Abstract
Metastatic castration-resistant prostate cancer is today incurable. Conventional imaging methods have limited detection, affecting their ability to give an accurate outcome prognosis, and current therapies for metastatic prostate cancer are insufficient. This inevitably leads to patients relapsing with castration-resistant prostate cancer. Targeting prostate-specific [...] Read more.
Metastatic castration-resistant prostate cancer is today incurable. Conventional imaging methods have limited detection, affecting their ability to give an accurate outcome prognosis, and current therapies for metastatic prostate cancer are insufficient. This inevitably leads to patients relapsing with castration-resistant prostate cancer. Targeting prostate-specific antigens whose expression is closely linked to the activity in the androgen receptor pathway, and thus the pathogenesis of prostate cancer, is a possible way to increase specificity and reduce off-target effects. We have humanized and evaluated radioimmunoconjugates of a previously murine antibody, m5A10, targeting PSA intended for theranostics of hormone-refractory prostate cancer. The humanized antibody h5A10 was expressed in mammalian HEK293 cells transfected with the nucleotide sequences for the heavy and light chains of the antibody. Cell culture medium was filtered and purified by Protein G chromatography, and the buffer was changed to PBS pH 7.4 by dialysis. Murine and humanized 5A10 were conjugated with p-SCN-Bn-CHX-A”-DTPA. Surface plasmon resonance was used to characterize the binding to PSA of the immunoconjugates. Immunoconjugates were labeled with either indium-111 or lutetium-177. Biodistribution studies of murine and humanized 5A10 were performed in mice with LNCaP xenografts. 5A10 was successfully humanized, and in vivo targeting showed specific binding in xenografts. The results thus give an excellent platform for further theranostic development of humanized 5A10 for clinical applications. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Testing of Next Generation Theranostic Radiopharmaceuticals)
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19 pages, 2849 KiB  
Article
Fusion-Based Neutron Generator Production of Tc-99m and Tc-101: A Prospective Avenue to Technetium Theranostics
by Edward J. Mausolf, Erik V. Johnstone, Natalia Mayordomo, David L. Williams, Eugene Yao Z. Guan and Charles K. Gary
Pharmaceuticals 2021, 14(9), 875; https://doi.org/10.3390/ph14090875 - 29 Aug 2021
Cited by 8 | Viewed by 8908
Abstract
Presented are the results of 99mTc and 101Tc production via neutron irradiation of natural isotopic molybdenum (Mo) with epithermal/resonance neutrons. Neutrons were produced using a deuterium-deuterium (D-D) neutron generator with an output of 2 × 1010 n/s. The separation of [...] Read more.
Presented are the results of 99mTc and 101Tc production via neutron irradiation of natural isotopic molybdenum (Mo) with epithermal/resonance neutrons. Neutrons were produced using a deuterium-deuterium (D-D) neutron generator with an output of 2 × 1010 n/s. The separation of Tc from an irradiated source of bulk, low-specific activity (LSA) Mo on activated carbon (AC) was demonstrated. The yields of 99mTc and 101Tc, together with their potential use in medical single-photon emission computed tomography (SPECT) procedures, have been evaluated from the perspective of commercial production, with a patient dose consisting of 740 MBq (20 mCi) of 99mTc. The number of neutron generators to meet the annual 40,000,000 world-wide procedures is estimated for each imaging modality: 99mTc versus 101Tc, D-D versus deuterium-tritium (D-T) neutron generator system outputs, and whether or not natural molybdenum or enriched targets are used for production. The financial implications for neutron generator production of these isotopes is also presented. The use of 101Tc as a diagnostic, therapeutic, and/or theranostic isotope for use in medical applications is proposed and compared to known commercial nuclear diagnostic and therapeutic isotopes. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Testing of Next Generation Theranostic Radiopharmaceuticals)
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Review

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30 pages, 5567 KiB  
Review
AAZTA-Derived Chelators for the Design of Innovative Radiopharmaceuticals with Theranostic Applications
by Cyril Fersing, Nicolas Masurier, Léa Rubira, Emmanuel Deshayes and Vincent Lisowski
Pharmaceuticals 2022, 15(2), 234; https://doi.org/10.3390/ph15020234 - 16 Feb 2022
Cited by 9 | Viewed by 3730
Abstract
With the development of 68Ga and 177Lu radiochemistry, theranostic approaches in modern nuclear medicine enabling patient-centered personalized medicine applications have been growing in the last decade. In conjunction with the search for new relevant molecular targets, the design of innovative chelating [...] Read more.
With the development of 68Ga and 177Lu radiochemistry, theranostic approaches in modern nuclear medicine enabling patient-centered personalized medicine applications have been growing in the last decade. In conjunction with the search for new relevant molecular targets, the design of innovative chelating agents to easily form stable complexes with various radiometals for theranostic applications has gained evident momentum. Initially conceived for magnetic resonance imaging applications, the chelating agent AAZTA features a mesocyclic seven-membered diazepane ring, conferring some of the properties of both acyclic and macrocyclic chelating agents. Described in the early 2000s, AAZTA and its derivatives exhibited interesting properties once complexed with metals and radiometals, combining a fast kinetic of formation with a slow kinetic of dissociation. Importantly, the extremely short coordination reaction times allowed by AAZTA derivatives were particularly suitable for short half-life radioelements (i.e., 68Ga). In view of these particular characteristics, the scope of this review is to provide a survey on the design, synthesis, and applications in the nuclear medicine/radiopharmacy field of AAZTA-derived chelators. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Testing of Next Generation Theranostic Radiopharmaceuticals)
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