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Pharmaceutics
Special Issues
Molecular Imaging of the Immune System
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Molecular Imaging of the Immune System

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (30 August 2024) | Viewed by 15120

Special Issue Editors

Prof. Dr. Steve J. Archibald

E-Mail Website
Guest Editor
Positron Emission Tomography Research Centre, Department of Chemistry, University of Hull, Hull HU6 7RX, UK
Interests: synthesis; inorganic chemistry; nanotechnology; macrocycles; coordination chemistry; medical imaging; transition metal; medicinal chemistry; medical and biomedical image processing; PET; radiochemistry
Dr. Louis Allott

E-Mail Website
Guest Editor
Department of Biomedical Sciences, University of Hull, Cottingham Road, Kingston upon Hull HU6 7RX, UK
Interests: PET radiochemistry; drug and radiopharmaceutical discovery; clinical translation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The development of molecular imaging agents for interrogating the immune system is an important area of research with potential applications in a variety of fields. This includes, but is not limited to, understanding inflammation and the ageing immune system (“inflammaging”), interrogating biological responses to bacterial and viral infection, as well as monitoring cancer patients’ response to immunotherapy. A greater understanding of our immune system, and tools to interrogate immune response in patients, could open possibilities for new therapeutics for a range of immune-related diseases and conditions, in addition to imaging biomarkers. 

We are pleased to invite you to contribute original research articles and reviews to our Special Issue. We aim to form a collection of the latest advancements in the field and hope the Issue will transcend scientific disciplines and imaging modalities.

We look forward to receiving your contributions.

Prof. Dr. Steve J. Archibald
Dr. Louis Allott
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. Pharmaceutics 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

  • immunotherapy
  • immunology
  • immune response
  • probe development
  • positron emission tomography (PET)
  • clinical imaging
  • preclinical imaging

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Published Papers (6 papers)

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Research

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19 pages, 1720 KiB  
Article
Rigid Macrocycle Metal Complexes as CXCR4 Chemokine Receptor Antagonists: Influence of Ring Size
by Isaline Renard, Thomas D’huys, Benjamin P. Burke, Trisha Ajoleza, Amy N. Cain, Neil L. Funwie, Abid Khan, Danny L. Maples, Randall D. Maples, Dallas L. Matz, Graeme McRobbie, Robert Ullom, Timothy J. Prior, Douglas P. Linder, Tom Van Loy, Timothy J. Hubin, Dominique Schols and Stephen J. Archibald
Pharmaceutics 2024, 16(8), 1000; https://doi.org/10.3390/pharmaceutics16081000 - 28 Jul 2024
Viewed by 1208
Abstract
Understanding the role of chemokine receptors in health and disease has been of increasing interest in recent years. Chemokine receptor CXCR4 has been extensively studied because of its defined role in immune cell trafficking, HIV infection, inflammatory diseases, and cancer progression. We have [...] Read more.
Understanding the role of chemokine receptors in health and disease has been of increasing interest in recent years. Chemokine receptor CXCR4 has been extensively studied because of its defined role in immune cell trafficking, HIV infection, inflammatory diseases, and cancer progression. We have developed high affinity rigidified CXCR4 antagonists that incorporate metal ions to optimize the binding interactions with the aspartate side chains at the extracellular surface of the CXCR4 chemokine receptor and increase the residence time. Cross- and side-bridged tetraazamacrocylic complexes offer significant advantages over the non-bridged molecular structures in terms of receptor affinity, potential for radiolabelling, and use in therapeutic applications. Our investigation has been extended to the influence of the ring size on bridged tetraazamacrocyclic compounds with the addition of two novel chelators (bis-cross-bridged homocyclen and bis-cross-bridged cyclen) to compare to the bis-bridged cyclam, along with novel metal complexes formed with copper(II) or zinc(II). The in vitro biological assays showed that all of the zinc(II) complexes are high affinity antagonists with a marked increase in CXCR4 selectivity for the bis-cross-bridged cyclen complex, whereas the properties of the copper(II) complexes are highly dependent on metal ion geometry. X-ray crystal structural data and DFT computational studies allow for the rationalisation of the relative affinities and the aspartate residue interactions on the protein surface. Changing the ring size from 14-membered can increase the selectivity for the CXCR4 receptor whilst retaining potent inhibitory activity, improving the key pharmacological characteristics. Full article
(This article belongs to the Special Issue Molecular Imaging of the Immune System)
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13 pages, 2460 KiB  
Article
Curcumin Enhances the Abscopal Effect in Mice with Colorectal Cancer by Acting as an Immunomodulator
by Kuang-Chung Shih, Hui-Wen Chan, Chun-Yi Wu and Hui-Yen Chuang
Pharmaceutics 2023, 15(5), 1519; https://doi.org/10.3390/pharmaceutics15051519 - 17 May 2023
Cited by 2 | Viewed by 1909
Abstract
Radiotherapy (RT) is an effective cancer treatment. The abscopal effect, referring to the unexpected shrinkage observed in non-irradiated tumors after radiation therapy, is thought to be mediated by systemic immune activation. However, it has low incidence and is unpredictable. Here, RT was combined [...] Read more.
Radiotherapy (RT) is an effective cancer treatment. The abscopal effect, referring to the unexpected shrinkage observed in non-irradiated tumors after radiation therapy, is thought to be mediated by systemic immune activation. However, it has low incidence and is unpredictable. Here, RT was combined with curcumin to investigate how curcumin affects RT-induced abscopal effects in mice with bilateral CT26 colorectal tumors. Indium 111-labeled DOTA-anti-OX40 mAb was synthesized to detect the activated T cell accumulations in primary and secondary tumors correlating with the changes in protein expressions and tumor growth to understand the overall effects of the combination of RT and curcumin. The combination treatment caused the most significant tumor suppression in both primary and secondary tumors, accompanied by the highest 111In-DOTA-OX40 mAb tumor accumulations. The combination treatment elevated expressions of proapoptotic proteins (Bax and cleaved caspase-3) and proinflammatory proteins (granzyme B, IL-6, and IL-1β) in both primary and secondary tumors. Based on the biodistribution of 111In-DOTA-OX40 mAb, tumor growth inhibition, and anti-tumor protein expression, our findings suggest that curcumin could act as an immune booster to augment RT-induced anti-tumor and abscopal effects effectively. Full article
(This article belongs to the Special Issue Molecular Imaging of the Immune System)
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10 pages, 3176 KiB  
Article
Peptide-Based [68Ga]Ga Labeled PET Tracer for Tumor Imaging by Targeting Tumor-Associated Macrophages
by Mingxing Huang, Rang Wang, Mufeng Li, Huawei Cai and Rong Tian
Pharmaceutics 2022, 14(11), 2511; https://doi.org/10.3390/pharmaceutics14112511 - 18 Nov 2022
Cited by 3 | Viewed by 1893
Abstract
Tumor-associated macrophages (TAMs) are known to promote cancer development and metastasis. In this study, a TAMs-targeting peptide named M2pep was selected to investigate the feasibility of [68Ga]Ga-labeled M2pep as a noninvasive probe in targeted TAMs imaging. The peptide M2pep was conjugated [...] Read more.
Tumor-associated macrophages (TAMs) are known to promote cancer development and metastasis. In this study, a TAMs-targeting peptide named M2pep was selected to investigate the feasibility of [68Ga]Ga-labeled M2pep as a noninvasive probe in targeted TAMs imaging. The peptide M2pep was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with 68Ga. The cellular uptake and binding assay were assessed in M2 macrophages and in the B16F10 cell line. Micro-PET imaging and a biodistribution study were performed on B16F10 tumor-bearing mice. High radiochemical purity [68Ga]Ga-DOTA-M2pep (>95%) was prepared and was stabilized in saline and bovine serum at 37 °C for 2 h. In vitro studies demonstrated high uptake of [68Ga]Ga-DOTA-M2pep in M2 macrophages, which was effectively blocked by the “cold” M2pep (free peptide). The micro-PET imaging and biodistribution study revealed that [68Ga]Ga-DOTA-M2pep reached the tumor site rapidly and showed high accumulation in the tumor at 1 h post-injection. In addition, the probe was rapidly cleared from the blood and mainly excreted via the kidneys, resulting in a high tumor/background ratio. Preclinical studies have shown that [68Ga]Ga-DOTA-M2pep specifically targets TAMs and might be a promising molecular probe for the noninvasive visualization of TAMs expression. Full article
(This article belongs to the Special Issue Molecular Imaging of the Immune System)
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17 pages, 2774 KiB  
Article
Preclinical PET Imaging of Granzyme B Shows Promotion of Immunological Response Following Combination Paclitaxel and Immune Checkpoint Inhibition in Triple Negative Breast Cancer
by Tiara S. Napier, Chanelle L. Hunter, Patrick N. Song, Benjamin M. Larimer and Anna G. Sorace
Pharmaceutics 2022, 14(2), 440; https://doi.org/10.3390/pharmaceutics14020440 - 18 Feb 2022
Cited by 12 | Viewed by 3314
Abstract
Advancements in monitoring and predicting of patient-specific response of triple negative breast cancer (TNBC) to immunotherapy (IMT) with and without chemotherapy are needed. Using granzyme B-specific positron emission tomography (GZP-PET) imaging, we aimed to monitor changes in effector cell activation in response to [...] Read more.
Advancements in monitoring and predicting of patient-specific response of triple negative breast cancer (TNBC) to immunotherapy (IMT) with and without chemotherapy are needed. Using granzyme B-specific positron emission tomography (GZP-PET) imaging, we aimed to monitor changes in effector cell activation in response to IMT with chemotherapy in TNBC. TNBC mouse models received the paclitaxel (PTX) ± immune checkpoint inhibitors anti-programmed death 1 (anti-PD1) and anti-cytotoxic T-lymphocyte 4 (anti-CTLA4). GZP-PET imaging was performed on treatment days 0, 3, and 6. Mean standard uptake value (SUVmean), effector cell fractions, and SUV histograms were compared. Mice were sacrificed at early imaging timepoints for cytokine and histological analyses. GZP-PET imaging data revealed differences prior to tumor volume changes. By day six, responders had SUVmean ≥ 2.2-fold higher (p < 0.0037) and effector cell fractions ≥ 1.9-fold higher (p = 0.03) compared to non-responders. IMT/PTX resulted in a significantly different SUV distribution compared to control, indicating broader distribution of activated intratumoral T-cells. IMT/PTX resulted in significantly more necrotic tumor tissue and increased levels of IL-2, 4, and 12 compared to control. Results implicate immunogenic cell death through upregulation of key Th1/Th2 cytokines by IMT/PTX. Noninvasive PET imaging can provide data on the TNBC tumor microenvironment, specifically intratumoral effector cell activation, predicting response to IMT plus chemotherapy. Full article
(This article belongs to the Special Issue Molecular Imaging of the Immune System)
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12 pages, 1397 KiB  
Article
Granzyme B PET Imaging in Response to In Situ Vaccine Therapy Combined with αPD1 in a Murine Colon Cancer Model
by Siddesh V. Hartimath, Boominathan Ramasamy, Tan Yun Xuan, Tang Jun Rong, Shivashankar Khanapur, Peter Cheng, You Yi Hwang, Edward G. Robins and Julian L. Goggi
Pharmaceutics 2022, 14(1), 150; https://doi.org/10.3390/pharmaceutics14010150 - 8 Jan 2022
Cited by 6 | Viewed by 2787
Abstract
Immune checkpoint inhibitors (ICIs) block checkpoint receptors that tumours use for immune evasion, allowing immune cells to target and destroy cancer cells. Despite rapid advancements in immunotherapy, durable response rates to ICIs remains low. To address this, combination clinical trials are underway assessing [...] Read more.
Immune checkpoint inhibitors (ICIs) block checkpoint receptors that tumours use for immune evasion, allowing immune cells to target and destroy cancer cells. Despite rapid advancements in immunotherapy, durable response rates to ICIs remains low. To address this, combination clinical trials are underway assessing whether adjuvants can enhance responsiveness by increasing tumour immunogenicity. CpG-oligodeoxynucleotides (CpG-ODN) are synthetic DNA fragments containing an unmethylated cysteine-guanosine motif that stimulate the innate and adaptive immune systems by engaging Toll-like receptor 9 (TLR9) present on the plasmacytoid dendritic cells (pDCs) and B cells. Here, we have assessed the ability of AlF-mNOTA-GZP, a peptide tracer targeting granzyme B, to serve as a PET imaging biomarker in response to CpG-ODN 1585 in situ vaccine therapy delivered intratumourally (IT) or intraperitoneally (IP) either as monotherapy or in combination with αPD1. [18F]AlF-mNOTA-GZP was able to differentiate treatment responders from non-responders based on tumour uptake. Furthermore, [18F]AlF-mNOTA-GZP showed positive associations with changes in tumour-associated lymphocytes expressing GZB, namely GZB+ CD8+ T cells, and decreases in suppressive F4/80+ cells. [18F]AlF-mNOTA-GZP tumour uptake was mediated by GZB expressing CD8+ cells and successfully stratifies therapy responders from non-responders, potentially acting as a non-invasive biomarker for ICIs and combination therapy evaluation in a clinical setting. Full article
(This article belongs to the Special Issue Molecular Imaging of the Immune System)
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Review

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31 pages, 4840 KiB  
Review
Positron Emission Tomography Probes for Imaging Cytotoxic Immune Cells
by Ala Amgheib, Ruisi Fu and Eric O. Aboagye
Pharmaceutics 2022, 14(10), 2040; https://doi.org/10.3390/pharmaceutics14102040 - 24 Sep 2022
Cited by 1 | Viewed by 2564
Abstract
Non-invasive positron emission tomography (PET) imaging of immune cells is a powerful approach for monitoring the dynamics of immune cells in response to immunotherapy. Despite the clinical success of many immunotherapeutic agents, their clinical efficacy is limited to a subgroup of patients. Conventional [...] Read more.
Non-invasive positron emission tomography (PET) imaging of immune cells is a powerful approach for monitoring the dynamics of immune cells in response to immunotherapy. Despite the clinical success of many immunotherapeutic agents, their clinical efficacy is limited to a subgroup of patients. Conventional imaging, as well as analysis of tissue biopsies and blood samples do not reflect the complex interaction between tumour and immune cells. Consequently, PET probes are being developed to capture the dynamics of such interactions, which may improve patient stratification and treatment evaluation. The clinical efficacy of cancer immunotherapy relies on both the infiltration and function of cytotoxic immune cells at the tumour site. Thus, various immune biomarkers have been investigated as potential targets for PET imaging of immune response. Herein, we provide an overview of the most recent developments in PET imaging of immune response, including the radiosynthesis approaches employed in their development. Full article
(This article belongs to the Special Issue Molecular Imaging of the Immune System)
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