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Targeted Radionuclide Therapy of Cancer and Infections
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Targeted Radionuclide Therapy of Cancer and Infections

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 17672

Special Issue Editors

Prof. Dr. Ekaterina Dadachova

E-Mail Website
Guest Editor
College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
Interests: radioimmunotherapy of cancer and infections; melanoma; osteosarcoma; blood cancers; radiobiology; radioprotection with melanin pigment
Dr. Bart C.H. van der Wal

E-Mail Website
Guest Editor
Department of Orthopedics, University Medical Center Utrecht, Utrecht, The Netherlands
Interests: hip revision; periprosthetic joint infection; targeted radionuclide therapy; antibacterial coating; hip dysplasia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Targeted radionuclide therapy (TRT) has been burgeoning world-wide with several radiopharmaceuticals for treatment of metastatic cancers being approved for clinical use. There are many promising novel radiopharmaceuticals currently in preclinical development and several are already being evaluated in Phase 0 or Phase 1 clinical trials. Many research groups are performing groundbreaking radiobiological mechanistic studies to elucidate the mechanisms underpinning the efficacy of TRT with the goal of making this modality more effective and safe. However, it seems that at least half of the effort in TRT is currently directed towards prostate cancer, thus leaving other very important indications much less developed. This Special Issues welcomes submissions focused on developing TRT approaches beyond prostate cancer as they are applied to both major oncological indications such as colon, lung, pancreatic, breast cancer etc. and orphan types of cancers which affects much smaller populations such as osteosarcoma. TRT with various “delivery vehicles”  such as small molecules, peptides, antibodies, proteins and nanoparticles will be considered. Inclusion of safety evaluation on TRT is very encouraged. Manuscripts focused on radiobiology of TRT are also welcome. In addition, the recent COVID-19 pandemic has demonstrated the need for “out of the box” thinking when it comes to novel therapeutics to combat emerging infectious diseases. In this regard, applying the principles of TRT to treatment of a whole plethora of infectious diseases seems to be an attractive approach. as well as to all types of infectious diseases.

Prof. Dr. Ekaterina Dadachova
Dr. Bart C.H. van der Wal
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • targeted radionuclide therapy
  • cancer
  • infectious diseases
  • radiobiology

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Published Papers (7 papers)

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Editorial

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3 pages, 156 KiB  
Editorial
Targeted Radionuclide Therapy of Cancer and Infections
by Bart C. H. van der Wal and Ekaterina Dadachova
Int. J. Mol. Sci. 2023, 24(10), 9081; https://doi.org/10.3390/ijms24109081 - 22 May 2023
Cited by 2 | Viewed by 1499
Abstract
Targeted radionuclide therapy (TRT) has been burgeoning worldwide, with several radiopharmaceuticals for the treatment of metastatic cancers being approved for clinical use [...] Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy of Cancer and Infections)

Research

Jump to: Editorial, Review

9 pages, 1744 KiB  
Article
Evaluating the Targeting of a Staphylococcus-aureus-Infected Implant with a Radiolabeled Antibody In Vivo
by Bruce van Dijk, J. Fred F. Hooning van Duyvenbode, Lisanne de Vor, F. Ruben H. A. Nurmohamed, Marnix G. E. H. Lam, Alex J. Poot, Ruud M. Ramakers, Sofia Koustoulidou, Freek J. Beekman, Jos van Strijp, Suzan H. M. Rooijakkers, Ekaterina Dadachova, H. Charles Vogely, Harrie Weinans and Bart C. H. van der Wal
Int. J. Mol. Sci. 2023, 24(5), 4374; https://doi.org/10.3390/ijms24054374 - 22 Feb 2023
Cited by 5 | Viewed by 2143
Abstract
Implant infections caused by Staphylococcus aureus are difficult to treat due to biofilm formation, which complicates surgical and antibiotic treatment. We introduce an alternative approach using monoclonal antibodies (mAbs) targeting S. aureus and provide evidence of the specificity and biodistribution of S.- [...] Read more.
Implant infections caused by Staphylococcus aureus are difficult to treat due to biofilm formation, which complicates surgical and antibiotic treatment. We introduce an alternative approach using monoclonal antibodies (mAbs) targeting S. aureus and provide evidence of the specificity and biodistribution of S.-aureus-targeting antibodies in a mouse implant infection model. The monoclonal antibody 4497-IgG1 targeting wall teichoic acid in S. aureus was labeled with indium-111 using CHX-A”-DTPA as a chelator. Single Photon Emission Computed Tomography/computed tomographyscans were performed at 24, 72 and 120 h after administration of the 111In-4497 mAb in Balb/cAnNCrl mice with a subcutaneous implant that was pre-colonized with S. aureus biofilm. The biodistribution of this labelled antibody over various organs was visualized and quantified using SPECT/CT imaging, and was compared to the uptake at the target tissue with the implanted infection. Uptake of the 111In-4497 mAbs at the infected implant gradually increased from 8.34 %ID/cm3 at 24 h to 9.22 %ID/cm3 at 120 h. Uptake at the heart/blood pool decreased over time from 11.60 to 7.58 %ID/cm3, whereas the uptake in the other organs decreased from 7.26 to less than 4.66 %ID/cm3 at 120 h. The effective half-life of 111In-4497 mAbs was determined to be 59 h. In conclusion, 111In-4497 mAbs were found to specifically detect S. aureus and its biofilm with excellent and prolonged accumulation at the site of the colonized implant. Therefore, it has the potential to serve as a drug delivery system for the diagnostic and bactericidal treatment of biofilm. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy of Cancer and Infections)
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16 pages, 2540 KiB  
Article
Preclinical Efficacy of a PARP-1 Targeted Auger-Emitting Radionuclide in Prostate Cancer
by Sreeja Sreekumar, Dong Zhou, Cedric Mpoy, Elsa Schenk, Jalen Scott, Jeffrey M. Arbeit, Jinbin Xu and Buck E. Rogers
Int. J. Mol. Sci. 2023, 24(4), 3083; https://doi.org/10.3390/ijms24043083 - 4 Feb 2023
Cited by 11 | Viewed by 2693
Abstract
There is an unmet need for better therapeutic strategies for advanced prostate cancer. Poly (ADP-ribose) polymerase-1 (PARP-1) is a chromatin-binding DNA repair enzyme overexpressed in prostate cancer. This study evaluates whether PARP-1, on account of its proximity to the cell’s DNA, would be [...] Read more.
There is an unmet need for better therapeutic strategies for advanced prostate cancer. Poly (ADP-ribose) polymerase-1 (PARP-1) is a chromatin-binding DNA repair enzyme overexpressed in prostate cancer. This study evaluates whether PARP-1, on account of its proximity to the cell’s DNA, would be a good target for delivering high-linear energy transfer Auger radiation to induce lethal DNA damage in prostate cancer cells. We analyzed the correlation between PARP-1 expression and Gleason score in a prostate cancer tissue microarray. A radio-brominated Auger emitting inhibitor ([77Br]Br-WC-DZ) targeting PARP-1 was synthesized. The ability of [77Br]Br-WC-DZ to induce cytotoxicity and DNA damage was assessed in vitro. The antitumor efficacy of [77Br]Br-WC-DZ was investigated in prostate cancer xenograft models. PARP-1 expression was found to be positively correlated with the Gleason score, thus making it an attractive target for Auger therapy in advanced diseases. The Auger emitter, [77Br]Br-WC-DZ, induced DNA damage, G2-M cell cycle phase arrest, and cytotoxicity in PC-3 and IGR-CaP1 prostate cancer cells. A single dose of [77Br]Br-WC-DZ inhibited the growth of prostate cancer xenografts and improved the survival of tumor-bearing mice. Our studies establish the fact that PARP-1 targeting Auger emitters could have therapeutic implications in advanced prostate cancer and provides a strong rationale for future clinical investigation. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy of Cancer and Infections)
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19 pages, 2268 KiB  
Article
Understanding the Radiobiological Mechanisms Induced by 177Lu-DOTATATE in Comparison to External Beam Radiation Therapy
by Wendy Delbart, Jirair Karabet, Gwennaëlle Marin, Sébastien Penninckx, Jonathan Derrien, Ghanem E. Ghanem, Patrick Flamen and Zéna Wimana
Int. J. Mol. Sci. 2022, 23(20), 12369; https://doi.org/10.3390/ijms232012369 - 15 Oct 2022
Cited by 9 | Viewed by 2578
Abstract
Radionuclide Therapy (RNT) with 177Lu-DOTATATE targeting somatostatin receptors (SSTRs) in neuroendocrine tumours (NET) has been successfully used in routine clinical practice, mainly leading to stable disease. Radiobiology holds promise for RNT improvement but is often extrapolated from external beam radiation therapy (EBRT) [...] Read more.
Radionuclide Therapy (RNT) with 177Lu-DOTATATE targeting somatostatin receptors (SSTRs) in neuroendocrine tumours (NET) has been successfully used in routine clinical practice, mainly leading to stable disease. Radiobiology holds promise for RNT improvement but is often extrapolated from external beam radiation therapy (EBRT) studies despite differences in these two radiation-based treatment modalities. In a panel of six human cancer cell lines expressing SSTRs, common radiobiological endpoints (i.e., cell survival, cell cycle, cell death, oxidative stress and DNA damage) were evaluated over time in 177Lu-DOTATATE- and EBRT-treated cells, as well as the radiosensitizing potential of poly (ADP-ribose) polymerase inhibition (PARPi). Our study showed that common radiobiological mechanisms were induced by both 177Lu-DOTATATE and EBRT, but to a different extent and/or with variable kinetics, including in the DNA damage response. A higher radiosensitizing potential of PARPi was observed for EBRT compared to 177Lu-DOTATATE. Our data reinforce the need for dedicated RNT radiobiology studies, in order to derive its maximum therapeutic benefit. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy of Cancer and Infections)
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16 pages, 1918 KiB  
Article
Oxidation of p-[125I]Iodobenzoic Acid and p-[211At]Astatobenzoic Acid Derivatives and Evaluation In Vivo
by Yawen Li, Ming-Kuan Chyan, Donald K. Hamlin, Holly Nguyen, Eva Corey and D. Scott Wilbur
Int. J. Mol. Sci. 2022, 23(18), 10655; https://doi.org/10.3390/ijms231810655 - 13 Sep 2022
Cited by 2 | Viewed by 1864
Abstract
The alpha particle-emitting radionuclide astatine-211 (211At) is of interest for targeted radiotherapy; however, low in vivo stability of many 211At-labeled cancer-targeting molecules has limited its potential. As an alternative labeling method, we evaluated whether a specific type of astatinated aryl [...] Read more.
The alpha particle-emitting radionuclide astatine-211 (211At) is of interest for targeted radiotherapy; however, low in vivo stability of many 211At-labeled cancer-targeting molecules has limited its potential. As an alternative labeling method, we evaluated whether a specific type of astatinated aryl compound that has the At atom in a higher oxidation state might be stable to in vivo deastatination. In the research effort, para-iodobenzoic acid methyl ester and dPEG4-amino acid methyl ester derivatives were prepared as HPLC standards. The corresponding para-stannylbenzoic acid derivatives were also prepared and labeled with 125I and 211At. Oxidization of the [125I]iodo- and [211At]astato-benzamidyl-dPEG4-acid methyl ester derivatives provided materials for in vivo evaluation. A biodistribution was conducted in mice with coinjected oxidized 125I- and 211At-labeled compounds. The oxidized radioiodinated derivative was stable to in vivo deiodination, but unfortunately the oxidized [211At]astatinated benzamide derivative was found to be unstable under the conditions of isolation by radio-HPLC (post animal injection). Another biodistribution study in mice evaluated the tissue concentrations of coinjected [211At]NaAtO3 and [125I]NaIO3. Comparison of the tissue concentrations of the isolated material from the oxidized [211At]benzamide derivative with those of [211At]astatate indicated the species obtained after isolation was likely [211At]astatate. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy of Cancer and Infections)
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Review

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14 pages, 2159 KiB  
Review
Targeting Melanin in Melanoma with Radionuclide Therapy
by Kevin J. H. Allen, Mackenzie E. Malo, Rubin Jiao and Ekaterina Dadachova
Int. J. Mol. Sci. 2022, 23(17), 9520; https://doi.org/10.3390/ijms23179520 - 23 Aug 2022
Cited by 8 | Viewed by 2811
Abstract
Nearly 100,000 individuals are expected to be diagnosed with melanoma in the United States in 2022. Treatment options for late-stage metastatic disease up until the 2010s were few and offered only slight improvement to the overall survival. The introduction of B-RAF inhibitors and [...] Read more.
Nearly 100,000 individuals are expected to be diagnosed with melanoma in the United States in 2022. Treatment options for late-stage metastatic disease up until the 2010s were few and offered only slight improvement to the overall survival. The introduction of B-RAF inhibitors and anti-CTLA4 and anti-PD-1/PD-L1 immunotherapies into standard of care brought measurable increases in the overall survival across all stages of melanoma. Despite the improvement in the survival statistics, patients treated with targeted therapies and immunotherapies are subject to very serious side effects, the development of drug resistance, and the high costs of treatment. This leaves room for the development of novel approaches as well as for the exploration of novel combination therapies for the treatment of metastatic melanoma. One such approach is targeting melanin pigment with radionuclide therapy. Advances in melanin-targeting radionuclide therapy of melanoma can be viewed from two spheres: (1) radioimmunotherapy (RIT) and (2) radiolabeled small molecules. The investigation of mechanisms of the action and efficacy of targeting melanin in melanoma treatment by RIT points to the involvement of the immune system such as complement dependent cytotoxicity. The combination of RIT with immunotherapy presents synergistic killing in mouse melanoma models. The field of radiolabeled small molecules is focused on radioiodinated compounds that have the ability to cross the cellular membranes to access intracellular melanin and can be applied in both therapy and imaging as theranostics. Clinical applications of targeting melanin with radionuclide therapies have produced encouraging results and clinical work is on-going. Continued work on targeting melanin with radionuclide therapy as a monotherapy, or possibly in combination with standard of care agents, has the potential to strengthen the current treatment options for melanoma patients. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy of Cancer and Infections)
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15 pages, 943 KiB  
Review
Dosing Therapeutic Radiopharmaceuticals in Obese Patients
by Merel van Nuland, Tessa F. Ververs and Marnix G. E. H. Lam
Int. J. Mol. Sci. 2022, 23(2), 818; https://doi.org/10.3390/ijms23020818 - 13 Jan 2022
Cited by 5 | Viewed by 3173
Abstract
The prevalence of obesity has increased dramatically in the Western population. Obesity is known to influence not only the proportion of adipose tissue but also physiological processes that could alter drug pharmacokinetics. Yet, there are no specific dosing recommendations for radiopharmaceuticals in this [...] Read more.
The prevalence of obesity has increased dramatically in the Western population. Obesity is known to influence not only the proportion of adipose tissue but also physiological processes that could alter drug pharmacokinetics. Yet, there are no specific dosing recommendations for radiopharmaceuticals in this patient population. This could potentially lead to underdosing and thus suboptimal treatment in obese patients, while it could also lead to drug toxicity due to high levels of radioactivity. In this review, relevant literature is summarized on radiopharmaceutical dosing and pharmacokinetic properties, and we aimed to translate these data into practical guidelines for dosing of radiopharmaceuticals in obese patients. For radium-223, dosing in obese patients is well established. Furthermore, for samarium-153-ethylenediaminetetramethylene (EDTMP), dose-escalation studies show that the maximum tolerated dose will probably not be reached in obese patients when dosing on MBq/kg. On the other hand, there is insufficient evidence to support dose recommendations in obese patients for rhenium-168-hydroxyethylidene diphosphonate (HEDP), sodium iodide-131, iodide 131-metaiodobenzylguanidine (MIBG), lutetium-177-dotatate, and lutetium-177-prostate-specific membrane antigen (PSMA). From a pharmacokinetic perspective, fixed dosing may be appropriate for these drugs. More research into obese patient populations is needed, especially in the light of increasing prevalence of obesity worldwide. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy of Cancer and Infections)
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