Forward Thinking towards Theranostic (Radio)ligands Targeting the Tumor Microenvironment (TME)

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

Deadline for manuscript submissions: closed (18 March 2022) | Viewed by 27424

Special Issue Editors

Helmholtz-Zentrum Dresden-Rossendorf (HZDR) e.V., Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany
Interests: radiopharmaceutical sciences; medicinal chemistry; labeling chemistry; organic chemistry; chemical biology; PET tracers; radiopharmaceuticals for diagnostics and endoradiotherapy; small molecules; peptides

Special Issue Information

Dear Colleagues,

The tumor microenvironment is a very dynamic immunosuppressive network, comprising a range of T cells, B cells, and NK cells which, together with endothelia, associate with the extracellular matrix and cancer cells. Within that network, adipocytes, regulatory T (Treg) cells, fibroblasts, macrophages, and cytokines promote cellular proliferation in all stages of cancer. Therefore, these cellular components represent interesting targets for the therapy of cancers. In addition, they can serve as imaging biomarkers for early detection of tumor disease and monitoring treatment response. In recent years, immune checkpoint inhibitor therapy has become a promising new cancer treatment option. However, on average only 30% of patients respond after checkpoint inhibitor monotherapy. In order to identify such patients prior to therapy, molecular imaging techniques such as PET and SPECT are advantageous over classical immunohistochemistry methods, because they can fully address the issue of heterogeneous expression of checkpoints over time, e.g., PD-L1 or CTLA-4. Providing clinicians with a diagnostic tool for supporting therapy decisions is therefore very attractive and should fuel the development of new radiotracers targeting the tumor microenvironment. Additionally, theranostic approaches including endoradiotherapy and (radio)immunotherapy as well as cellular therapies for addressing targets within the tumor microenvironment hold the potential for treating patients. 

We would like to invite you to contribute reviews or original research articles covering the different facets of the emerging field of tumor-microenvironment-targeting (radio)ligands, which will be published as part of a Special Issue entitled “Forward Thinking towards Theranostic (Radio)ligands Targeting the Tumor Microenvironment (TME)”.

Areas of interest include, but are not limited to:

  • Development of small (non-peptide)-molecule-derived theranostic radioligands, (oligo)peptides and peptidomimetic radioligands targeting receptors within the tumor microenvironment for imaging and therapy, such as checkpoint inhibitors (e.g., PD-L1, CTLA-4);
  • Antibodies and derivatives thereof, fragments, affibodies, diabodies radiolabeled with diagnostic and/or therapeutic radionuclides for imaging and/or therapy within the tumor microenvironment;
  • (Radio)immunotherapy and cellular therapy such as CAR T cell therapy approaches applying the immune protein or immune cells as a therapeutic agent;
  • Preclinical in vitro and in vivo evaluations of the aforementioned radioligands;
  • Clinical evaluation in clinical research and clinical trials.

Dr. Sven Stadlbauer
Dr. Klaus Kopka
Guest Editors

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Keywords

  • molecular imaging (PET, SPECT)
  • theranostics
  • (radio)immunotherapy
  • checkpoint inhibitors
  • tumor microenvironment
  • cellular therapy
  • nuclear medicine

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Published Papers (6 papers)

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Research

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14 pages, 1967 KiB  
Article
From Automated Synthesis to In Vivo Application in Multiple Types of Cancer—Clinical Results with [68Ga]Ga-DATA5m.SA.FAPi
by Lukas Greifenstein, Carsten S. Kramer, Euy Sung Moon, Frank Rösch, Andre Klega, Christian Landvogt, Corinna Müller and Richard P. Baum
Pharmaceuticals 2022, 15(8), 1000; https://doi.org/10.3390/ph15081000 - 14 Aug 2022
Cited by 10 | Viewed by 2749
Abstract
Radiolabeled FAPI (fibroblast activation protein inhibitors) recently gained attention as widely applicable imaging and potential therapeutic compounds targeting CAF (cancer-associated fibroblasts) or DAF (disease-associated fibroblasts in benign disorders). Moreover, the use of FAPI has distinct advantages compared to FDG (e.g., increased sensitivity in [...] Read more.
Radiolabeled FAPI (fibroblast activation protein inhibitors) recently gained attention as widely applicable imaging and potential therapeutic compounds targeting CAF (cancer-associated fibroblasts) or DAF (disease-associated fibroblasts in benign disorders). Moreover, the use of FAPI has distinct advantages compared to FDG (e.g., increased sensitivity in regions with high glucose metabolism, no need for fasting, and rapid imaging). In this study, we wanted to evaluate the radiochemical synthesis and the clinical properties of the new CAF-targeting tracer [68Ga]Ga-DATA5m.SA.FAPi. The compound consists of a (radio)chemically easy to use hybrid chelate DATA.SA, which can be labeled at low temperatures, making it an interesting molecule for ‘instant kit-type’ labeling, and a squaric acid moiety that provides distinct advantages for synthesis and radiolabeling. Our work demonstrates that automatic synthesis of the FAP inhibitor [68Ga]Ga-DATA5m.SA.FAPi is feasible and reproducible, providing convenient access to this new hybrid chelator-based tracer. Our studies demonstrated the diagnostic usability of [68Ga]Ga-DATA5m.SA.FAPi for the unambiguous detection of cancer-associated fibroblasts of various carcinomas and their metastases (NSCLC, liposarcoma, parotid tumors, prostate cancer, and pancreas adenocarcinoma), while physiological uptake in brain, liver, intestine, bone, and lungs was very low. Full article
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13 pages, 1210 KiB  
Article
Preparation and Bioevaluation of Novel 99mTc-Labeled Complexes with a 2-Nitroimidazole HYNIC Derivative for Imaging Tumor Hypoxia
by Qing Ruan, Qianqian Gan, Xuran Zhang, Si’an Fang and Junbo Zhang
Pharmaceuticals 2021, 14(2), 158; https://doi.org/10.3390/ph14020158 - 15 Feb 2021
Cited by 5 | Viewed by 2725
Abstract
To develop novel 99mTc-labeled single-photon emission computed tomography (SPECT) radiotracers for imaging hypoxia, a novel HYNICNM ligand (6-hydrazinonicotinamide (HYNIC) 2-nitroimidazole derivative) was designed and synthesized. It was radiolabeled with technetium-99m using tricine/trisodium triphenylphosphine-3,3′,3′′-trisulfonate (TPPTS), tricine/sodium triphenylphosphine-3-monosulfonate (TPPMS) and tricine as co-ligands to [...] Read more.
To develop novel 99mTc-labeled single-photon emission computed tomography (SPECT) radiotracers for imaging hypoxia, a novel HYNICNM ligand (6-hydrazinonicotinamide (HYNIC) 2-nitroimidazole derivative) was designed and synthesized. It was radiolabeled with technetium-99m using tricine/trisodium triphenylphosphine-3,3′,3′′-trisulfonate (TPPTS), tricine/sodium triphenylphosphine-3-monosulfonate (TPPMS) and tricine as co-ligands to obtain [99mTc]Tc-tricine-TPPTS-HYNICNM, [99mTc]Tc-tricine-TPPMS-HYNICNM, and [99mTc]Tc-(tricine)2-HYNICNM, respectively. The three technetium-99m complexes were radiolabeled in one step with a high yield (95%) and had good stability in saline and mouse serum. In vitro cellular uptake results showed that these complexes exhibited good hypoxic selectivity. The partition coefficient indicated that they were good hydrophilic complexes, and [99mTc]Tc-tricine-TPPTS-HYNICNM displayed the highest hydrophilicity (−3.02 ± 0.08). The biodistribution in mice bearing S180 tumors showed that [99mTc]Tc-tricine-TPPTS-HYNICNM exhibited higher tumor uptake (1.05 ± 0.27% IA/g); more rapid clearance from the liver, blood, muscle, and other non-target organs; and a higher tumor/non-target ratio, especially for the tumor/liver ratio (1.95), than [99mTc]Tc-tricine-TPPMS-HYNICNM and [99mTc]Tc-(tricine)2-HYNICNM. The results of single-photon emission computed tomography (SPECT) imaging studies of [99mTc]Tc-tricine-TPPTS-HYNICNM were in accordance with the biodistribution results, which suggested that [99mTc]Tc-tricine-TPPTS-HYNICNM is a promising agent for imaging tumor hypoxia. Full article
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Review

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34 pages, 4071 KiB  
Review
Development of Radiotracers for Imaging of the PD-1/PD-L1 Axis
by Fabian Krutzek, Klaus Kopka and Sven Stadlbauer
Pharmaceuticals 2022, 15(6), 747; https://doi.org/10.3390/ph15060747 - 14 Jun 2022
Cited by 20 | Viewed by 4148
Abstract
Immune checkpoint inhibitor (ICI) therapy has emerged as a major treatment option for a variety of cancers. Among the immune checkpoints addressed, the programmed death receptor 1 (PD-1) and its ligand PD-L1 are the key targets for an ICI. PD-L1 has especially been [...] Read more.
Immune checkpoint inhibitor (ICI) therapy has emerged as a major treatment option for a variety of cancers. Among the immune checkpoints addressed, the programmed death receptor 1 (PD-1) and its ligand PD-L1 are the key targets for an ICI. PD-L1 has especially been proven to be a reproducible biomarker allowing for therapy decisions and monitoring therapy success. However, the expression of PD-L1 is not only heterogeneous among and within tumor lesions, but the expression is very dynamic and changes over time. Immunohistochemistry, which is the standard diagnostic tool, can only inadequately address these challenges. On the other hand, molecular imaging techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) provide the advantage of a whole-body scan and therefore fully address the issue of the heterogeneous expression of checkpoints over time. Here, we provide an overview of existing PET, SPECT, and optical imaging (OI) (radio)tracers for the imaging of the upregulation levels of PD-1 and PD-L1. We summarize the preclinical and clinical data of the different molecule classes of radiotracers and discuss their respective advantages and disadvantages. At the end, we show possible future directions for developing new radiotracers for the imaging of PD-1/PD-L1 status in cancer patients. Full article
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20 pages, 1276 KiB  
Review
Expanding Theranostic Radiopharmaceuticals for Tumor Diagnosis and Therapy
by Cristina Barca, Christoph M. Griessinger, Andreas Faust, Dominic Depke, Markus Essler, Albert D. Windhorst, Nick Devoogdt, Kevin M. Brindle, Michael Schäfers, Bastian Zinnhardt and Andreas H. Jacobs
Pharmaceuticals 2022, 15(1), 13; https://doi.org/10.3390/ph15010013 - 22 Dec 2021
Cited by 18 | Viewed by 6197
Abstract
Radioligand theranostics (RT) in oncology use cancer-type specific biomarkers and molecular imaging (MI), including positron emission tomography (PET), single-photon emission computed tomography (SPECT) and planar scintigraphy, for patient diagnosis, therapy, and personalized management. While the definition of theranostics was initially restricted to a [...] Read more.
Radioligand theranostics (RT) in oncology use cancer-type specific biomarkers and molecular imaging (MI), including positron emission tomography (PET), single-photon emission computed tomography (SPECT) and planar scintigraphy, for patient diagnosis, therapy, and personalized management. While the definition of theranostics was initially restricted to a single compound allowing visualization and therapy simultaneously, the concept has been widened with the development of theranostic pairs and the combination of nuclear medicine with different types of cancer therapies. Here, we review the clinical applications of different theranostic radiopharmaceuticals in managing different tumor types (differentiated thyroid, neuroendocrine prostate, and breast cancer) that support the combination of innovative oncological therapies such as gene and cell-based therapies with RT. Full article
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30 pages, 4961 KiB  
Review
New Frontiers in Cancer Imaging and Therapy Based on Radiolabeled Fibroblast Activation Protein Inhibitors: A Rational Review and Current Progress
by Surachet Imlimthan, Euy Sung Moon, Hendrik Rathke, Ali Afshar-Oromieh, Frank Rösch, Axel Rominger and Eleni Gourni
Pharmaceuticals 2021, 14(10), 1023; https://doi.org/10.3390/ph14101023 - 05 Oct 2021
Cited by 36 | Viewed by 6444
Abstract
Over the past decade, the tumor microenvironment (TME) has become a new paradigm of cancer diagnosis and therapy due to its unique biological features, mainly the interconnection between cancer and stromal cells. Within the TME, cancer-associated fibroblasts (CAFs) demonstrate as one of the [...] Read more.
Over the past decade, the tumor microenvironment (TME) has become a new paradigm of cancer diagnosis and therapy due to its unique biological features, mainly the interconnection between cancer and stromal cells. Within the TME, cancer-associated fibroblasts (CAFs) demonstrate as one of the most critical stromal cells that regulate tumor cell growth, progression, immunosuppression, and metastasis. CAFs are identified by various biomarkers that are expressed on their surfaces, such as fibroblast activation protein (FAP), which could be utilized as a useful target for diagnostic imaging and treatment. One of the advantages of targeting FAP-expressing CAFs is the absence of FAP expression in quiescent fibroblasts, leading to a controlled targetability of diagnostic and therapeutic compounds to the malignant tumor stromal area using radiolabeled FAP-based ligands. FAP-based radiopharmaceuticals have been investigated strenuously for the visualization of malignancies and delivery of theranostic radiopharmaceuticals to the TME. This review provides an overview of the state of the art in TME compositions, particularly CAFs and FAP, and their roles in cancer biology. Moreover, relevant reports on radiolabeled FAP inhibitors until the year 2021 are highlighted—as well as the current limitations, challenges, and requirements for those radiolabeled FAP inhibitors in clinical translation. Full article
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31 pages, 2691 KiB  
Review
Current State of Radiolabeled Heterobivalent Peptidic Ligands in Tumor Imaging and Therapy
by Benedikt Judmann, Diana Braun, Björn Wängler, Ralf Schirrmacher, Gert Fricker and Carmen Wängler
Pharmaceuticals 2020, 13(8), 173; https://doi.org/10.3390/ph13080173 - 30 Jul 2020
Cited by 16 | Viewed by 3705
Abstract
Over the past few years, an approach emerged that combines different receptor-specific peptide radioligands able to bind different target structures on tumor cells concomitantly or separately. The reason for the growing interest in this special field of radiopharmaceutical development is rooted in the [...] Read more.
Over the past few years, an approach emerged that combines different receptor-specific peptide radioligands able to bind different target structures on tumor cells concomitantly or separately. The reason for the growing interest in this special field of radiopharmaceutical development is rooted in the fact that bispecific peptide heterodimers can exhibit a strongly increased target cell avidity and specificity compared to their corresponding monospecific counterparts by being able to bind to two different target structures that are overexpressed on the cell surface of several malignancies. This increase of avidity is most pronounced in the case of concomitant binding of both peptides to their respective targets but is also observed in cases of heterogeneously expressed receptors within a tumor entity. Furthermore, the application of a radiolabeled heterobivalent agent can solve the ubiquitous problem of limited tumor visualization sensitivity caused by differential receptor expression on different tumor lesions. In this article, the concept of heterobivalent targeting and the general advantages of using radiolabeled bispecific peptidic ligands for tumor imaging or therapy as well as the influence of molecular design and the receptors on the tumor cell surface are explained, and an overview is given of the radiolabeled heterobivalent peptides described thus far. Full article
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