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Radionuclides in Diagnostics and Therapy of Malignant Tumors: New Development

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Survivorship and Quality of Life".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 42349

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Prof. Dr. Vladimir Tolmachev

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Department of Immunology, Genetics and Pathology (IGP), Dag Hammarskjölds väg 20 Uppsala University, SE-751 85 Uppsala, Sweden
Interests: radionuclide; targeting; imaging; therapy; scaffold proteins; antibody; peptide; pretargeting
Special Issues, Collections and Topics in MDPI journals

Dr. Anzhelika Vorobyeva

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Guest Editor

Department of Immunology, Genetics and Pathology (IGP), Dag Hammarskjölds väg 20 Uppsala University, Se-751 85 Uppsala, Sweden
Interests: radionuclide imaging; radionuclide therapy; targeted therapy; scaffold proteins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

The area of radionuclide applications in medicine is developing rapidly. Novel radionuclide imaging probes are developed to visualize molecular therapeutic targets, opening a way for a new exciting area, theranostics. New promising data suggest that radionuclide therapy might be efficient not only in hematologic malignancies but also in solid tumors. A progress in hardware development improves quantification accuracy of SPECT and enables its use for a patient-specific dosimetry. This creates an opportunity to make cancer treatment more personalized and, therefore, more efficient.

This Special Issue aims at highlighting current progress in all aspects of development of methodology for application of radionuclides in therapy and diagnostics of malignant tumors.

Prof. Dr. Vladimir Tolmachev
Dr. Anzhelika Vorobyeva
Guest Editors

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Keywords

targeted radionuclide therapy
theranostics
molecular radionuclide imaging
response monitoring
predictive imaging

Published Papers (13 papers)

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Editorial

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5 pages, 198 KiB

Open AccessEditorial

Radionuclides in Diagnostics and Therapy of Malignant Tumors: New Development

by Vladimir Tolmachev and Anzhelika Vorobyeva

Cancers 2022, 14(2), 297; https://doi.org/10.3390/cancers14020297 - 7 Jan 2022

Cited by 4 | Viewed by 1629

Abstract

The interest in using targeted radiopharmaceuticals in nuclear oncology has increased in recent years and continues to grow [...] Full article

(This article belongs to the Special Issue Radionuclides in Diagnostics and Therapy of Malignant Tumors: New Development)

Research

Jump to: Editorial, Review

15 pages, 5477 KiB

Open AccessArticle

Hyperfractionated Treatment with ¹⁷⁷Lu-Octreotate Increases Tumor Response in Human Small-Intestine Neuroendocrine GOT1 Tumor Model

by Mikael Elvborn, Emman Shubbar and Eva Forssell-Aronsson

Cancers 2022, 14(1), 235; https://doi.org/10.3390/cancers14010235 - 4 Jan 2022

Cited by 2 | Viewed by 2325

Abstract

Radionuclide treatment of patients with neuroendocrine tumors has advanced in the last decades with favorable results using ¹⁷⁷Lu-octreotate. However, the gap between the high cure rate in animal studies vs. patient studies indicates a potential to increase the curation of patients. The aim of this study was to investigate the tumor response for different fractionation schemes with ¹⁷⁷Lu-octreotate. BALB/c mice bearing a human small-intestine neuroendocrine GOT1 tumor were either mock treated with saline or injected intravenously with a total of 30–120 MBq of ¹⁷⁷Lu-octreotate: 1 × 30, 2 × 15, 1 × 60, 2 × 30, 1 × 120, 2 × 60, or 3 × 40 MBq. The tumor volume was measured twice per week until the end of the experiment. The mean tumor volume for mice that received 2 × 15 = 30 and 1 × 30 MBq ¹⁷⁷Lu-octreotate was reduced by 61% and 52%, respectively. The mean tumor volume was reduced by 91% and 44% for mice that received 2 × 30 = 60 and 1 × 60 MBq ¹⁷⁷Lu-octreotate, respectively. After 120 MBq ¹⁷⁷Lu-octreotate, given as 1–3 fractions, the mean tumor volume was reduced by 91–97%. Multiple fractions resulted in delayed regrowth and prolonged overall survival by 20–25% for the 120 MBq groups and by 45% for lower total activities, relative to one fraction. The results indicate that fractionation and hyperfractionation of ¹⁷⁷Lu-octreotate are beneficial for tumor reduction and prolongs the time to regrowth. Full article

(This article belongs to the Special Issue Radionuclides in Diagnostics and Therapy of Malignant Tumors: New Development)

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14 pages, 2327 KiB

Open AccessArticle

[^99mTc]Tc-DB15 in GRPR-Targeted Tumor Imaging with SPECT: From Preclinical Evaluation to the First Clinical Outcomes

by Berthold A. Nock, Aikaterini Kaloudi, Panagiotis Kanellopoulos, Barbara Janota, Barbara Bromińska, Dariusz Iżycki, Renata Mikołajczak, Rafał Czepczynski and Theodosia Maina

Cancers 2021, 13(20), 5093; https://doi.org/10.3390/cancers13205093 - 12 Oct 2021

Cited by 15 | Viewed by 2020

Abstract

Diagnostic imaging and radionuclide therapy of prostate (PC) and breast cancer (BC) using radiolabeled gastrin-releasing peptide receptor (GRPR)-antagonists represents a promising approach. We herein propose the GRPR-antagonist based radiotracer [^99mTc]Tc-DB15 ([^99mTc]Tc-N₄-AMA-DGA-_DPhe⁶,Sar¹¹,LeuNHEt¹³]BBN(6-13); N₄: 6-carboxy-1,4,8,11-tetraazaundecane, AMA: aminomethyl-aniline, DGA: diglycolic acid) as a new diagnostic tool for GRPR-positive tumors applying SPECT/CT. The uptake of [^99mTc]Tc-DB15 was tested in vitro in mammary (T-47D) and prostate cancer (PC-3) cells and in vivo in T-47D or PC-3 xenograft-bearing mice as well as in BC patients. DB15 showed high GRPR-affinity (IC₅₀ = 0.37 ± 0.03 nM) and [^99mTc]Tc-DB15 strongly bound to the cell-membrane of T-47D and PC-3 cells, according to a radiolabeled antagonist profile. In mice, the radiotracer showed high and prolonged GRPR-specific uptake in PC-3 (e.g., 25.56 ± 2.78 %IA/g vs. 0.72 ± 0.12 %IA/g in block; 4 h pi) and T-47D (e.g., 15.82 ± 3.20 %IA/g vs. 3.82 ± 0.30 %IA/g in block; 4 h pi) tumors, while rapidly clearing from background. In patients with advanced BC, the tracer could reveal several bone and soft tissue metastases on SPECT/CT. The attractive pharmacokinetic profile of [^99mTc]DB15 in mice and its capability to target GRPR-positive BC lesions in patients highlight its prospects for a broader clinical use, an option currently being explored by ongoing clinical studies. Full article

(This article belongs to the Special Issue Radionuclides in Diagnostics and Therapy of Malignant Tumors: New Development)

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19 pages, 4047 KiB

Open AccessArticle

HER3 PET Imaging: ⁶⁸Ga-Labeled Affibody Molecules Provide Superior HER3 Contrast to ⁸⁹Zr-Labeled Antibody and Antibody-Fragment-Based Tracers

by Sara S. Rinne, Charles Dahlsson Leitao, Ayman Abouzayed, Anzhelika Vorobyeva, Vladimir Tolmachev, Stefan Ståhl, John Löfblom and Anna Orlova

Cancers 2021, 13(19), 4791; https://doi.org/10.3390/cancers13194791 - 24 Sep 2021

Cited by 6 | Viewed by 3142

Abstract

HER3 (human epidermal growth factor receptor type 3) is a challenging target for diagnostic radionuclide molecular imaging due to the relatively modest overexpression in tumors and substantial expression in healthy organs. In this study, we compared four HER3-targeting PET tracers based on different types of targeting molecules in a preclinical model: the ⁸⁹Zr-labeled therapeutic antibody seribantumab, a seribantumab-derived F(ab)₂-fragment labeled with ⁸⁹Zr and ⁶⁸Ga, and the ⁶⁸Ga-labeled affibody molecule [⁶⁸Ga]Ga-Z_HER3. The novel conjugates were radiolabeled and characterized in vitro using HER3-expressing BxPC-3 and DU145 human cancer cells. Biodistribution was studied using Balb/c nu/nu mice bearing BxPC-3 xenografts. HER3-negative RAMOS xenografts were used to demonstrate binding specificity in vivo. Autoradiography was conducted on the excised tumors. nanoPET/CT imaging was performed. New conjugates specifically bound to HER3 in vitro and in vivo. [⁶⁸Ga]Ga-DFO-seribantumab-F(ab’)₂ was considered unsuitable for imaging due to the low stability and high uptake in normal organs. The highest tumor-to-non-tumor contrast with [⁸⁹Zr]Zr-DFO-seribantumab and [⁸⁹Zr]Zr-DFO-seribantumab-F(ab’)₂ was achieved at 96 h and 48 h pi, respectively. Despite lower tumor uptake, [⁶⁸Ga]Ga-Z_HER3 provided the best imaging contrast due to the fastest clearance from blood and normal organs. The results of our study suggest that affibody-based tracers are more suitable for PET imaging of HER3 expression than antibody- and antibody-fragment-based tracers. Full article

(This article belongs to the Special Issue Radionuclides in Diagnostics and Therapy of Malignant Tumors: New Development)

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20 pages, 9093 KiB

Open AccessArticle

Influence of the Position and Composition of Radiometals and Radioiodine Labels on Imaging of Epcam Expression in Prostate Cancer Model Using the DARPin Ec1

by Sergey M. Deyev, Tianqi Xu, Yongsheng Liu, Alexey Schulga, Elena Konovalova, Javad Garousi, Sara S. Rinne, Maria Larkina, Haozhong Ding, Torbjörn Gräslund, Anna Orlova, Vladimir Tolmachev and Anzhelika Vorobyeva

Cancers 2021, 13(14), 3589; https://doi.org/10.3390/cancers13143589 - 17 Jul 2021

Cited by 9 | Viewed by 3378

Abstract

The epithelial cell adhesion molecule (EpCAM) is intensively overexpressed in 40–60% of prostate cancer (PCa) cases and can be used as a target for the delivery of drugs and toxins. The designed ankyrin repeat protein (DARPin) Ec1 has a high affinity to EpCAM (68 pM) and a small size (18 kDa). Radiolabeled Ec1 might be used as a companion diagnostic for the selection of PCa patients for therapy. The study aimed to investigate the influence of radiolabel position (N- or C-terminal) and composition on the targeting and imaging properties of Ec1. Two variants, having an N- or C-terminal cysteine, were produced, site-specifically conjugated to a DOTA chelator and labeled with cobalt-57, gallium-68 or indium-111. Site-specific radioiodination was performed using ((4-hydroxyphenyl)-ethyl)maleimide (HPEM). Biodistribution of eight radiolabeled Ec1-probes was measured in nude mice bearing PCa DU145 xenografts. In all cases, positioning of a label at the C-terminus provided the best tumor-to-organ ratios. The non-residualizing [¹²⁵I]I-HPEM label provided the highest tumor-to-muscle and tumor-to-bone ratios and is more suitable for EpCAM imaging in early-stage PCa. Among the radiometals, indium-111 provided the highest tumor-to-blood, tumor-to-lung and tumor-to-liver ratios and could be used at late-stage PCa. In conclusion, label position and composition are important for the DARPin Ec1. Full article

(This article belongs to the Special Issue Radionuclides in Diagnostics and Therapy of Malignant Tumors: New Development)

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16 pages, 1649 KiB

Open AccessArticle

A Conjugation Strategy to Modulate Antigen Binding and FcRn Interaction Leads to Improved Tumor Targeting and Radioimmunotherapy Efficacy with an Antibody Targeting Prostate-Specific Antigen

by Oskar Vilhelmsson Timmermand, Anders Örbom, Mohamed Altai, Wahed Zedan, Bo Holmqvist, Marcella Safi, Thuy A. Tran, Sven-Erik Strand and Joanna Strand

Cancers 2021, 13(14), 3469; https://doi.org/10.3390/cancers13143469 - 11 Jul 2021

Cited by 6 | Viewed by 2737

Abstract

Background: The humanized monoclonal antibody (mAb) hu5A10 specifically targets and internalizes prostate cancer cells by binding to prostate specific antigen (PSA). Preclinical evaluations have shown that hu5A10 is an excellent vehicle for prostate cancer (PCa) radiotheranostics. We studied the impact of different chelates and conjugation ratios on hu5A10′s target affinity, neonatal fc-receptor interaction on in vivo targeting efficacy, and possible enhanced therapeutic efficacy. Methods: In our experiment, humanized 5A10 (hu5A10) was conjugated with DOTA or DTPA at a molar ratio of 3:1, 6:1, and 12:1. Surface plasmon resonance (SPR) was used to study antigen and FcRn binding to the antibody conjugates. [¹¹¹In]hu5A10 radio-immunoconjugates were administered intravenously into BALB/c mice carrying subcutaneous LNCaP xenografts. Serial Single-photon emission computed tomography (SPECT) images were obtained during the first week. Tumors were harvested and radionuclide distribution was analyzed by autoradiography along with microanatomy and immunohistochemistry. Results: As seen by SPR, the binding to PSA was clearly affected by the chelate-to-antibody ratio. Similarly, FcRn (neonatal fc-receptor) interacted less with antibodies conjugated at high ratios of chelator, which was more pronounced for DOTA conjugates. The autoradiography data indicated a higher distribution of radioactivity to the rim of the tumor for lower ratios and a more homogenous distribution at higher ratios. Mice injected with ratio 3:1 ¹¹¹In-DOTA-hu5A10 showed no significant difference in tumor volume when compared to mice given vehicle over a time period of 3 weeks. Mice given a similar injection of ratio 6:1 ¹¹¹In-DOTA-hu5A10 or 6:1 ¹¹¹In-DTPA-hu5A10 or 12:1 ¹¹¹In-DTPA-hu5A10 showed significant tumor growth retardation. Conclusions: The present study demonstrated that the radiolabeling strategy could positively modify the hu5A10′s capacity to bind PSA and complex with the FcRn-receptor, which resulted in more homogenous activity distribution in tumors and enhanced therapy efficacy. Full article

(This article belongs to the Special Issue Radionuclides in Diagnostics and Therapy of Malignant Tumors: New Development)

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12 pages, 2985 KiB

Open AccessArticle

Improved Tumor-Targeting with Peptidomimetic Analogs of Minigastrin ¹⁷⁷Lu-PP-F11N

by Nathalie M. Grob, Roger Schibli, Martin Béhé and Thomas L. Mindt

Cancers 2021, 13(11), 2629; https://doi.org/10.3390/cancers13112629 - 27 May 2021

Cited by 9 | Viewed by 2964

Abstract

The cholecystokinin-2 receptor (CCK2R) is an attractive target in nuclear medicine due to its overexpression by different tumors. Several radiolabeled peptidic ligands targeting the CCK2R have been investigated in the past; however, their low stability against proteases can limit their uptake in tumors and metastases. Substitution of single or multiple amide bonds with metabolically stable 1,4-disubstituted 1,2,3-triazoles as amide bond bioisosteres proved a promising strategy for improving the tumor-targeting properties of a truncated analog of minigastrin. In this study, we applied the previously studied structural modifications to improve the pharmacokinetic and pharmacodynamic properties of PP-F11N, a minigastrin analog currently in clinical trials. Novel minigastrins (NMGs) as analogs of PP-F11N with one or two amide bonds substituted by 1,2,3-triazoles were synthesized, radiolabeled with ¹⁷⁷Lu³⁺, and subjected to full evaluation in vitro (cell internalization, receptor affinity, stability in blood plasma) and in vivo (stability, biodistribution, SPECT/CT imaging). NMGs with triazoles inserted between the amino acids DGlu¹⁰-Ala¹¹ and/or Tyr¹²-Gly¹³ showed a significantly increased cellular uptake and affinity toward the CCK2R in vitro. Resistance against the metabolic degradation of the NMGs was comparable to those of the clinical candidate PP-F11N. Imaging by SPECT/CT and biodistribution studies demonstrated a higher uptake in CCK2R-positive tumors but also in the CCK2R-positive stomach. The peptidomimetic compounds showed a slow tumor washout and high tumor-to-kidney ratios. The structural modifications led to the identification of analogs with promising properties for progression to clinical applications in the diagnosis and therapy of CCK2R-positive neoplasms. Full article

(This article belongs to the Special Issue Radionuclides in Diagnostics and Therapy of Malignant Tumors: New Development)

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16 pages, 5134 KiB

Open AccessArticle

Novel Human Antibodies to Insulin Growth Factor 2 Receptor (IGF2R) for Radioimmunoimaging and Therapy of Canine and Human Osteosarcoma

by Jaline Broqueza, Chandra B. Prabaharan, Samitha Andrahennadi, Kevin J. H. Allen, Ryan Dickinson, Valerie MacDonald-Dickinson, Ekaterina Dadachova and Maruti Uppalapati

Cancers 2021, 13(9), 2208; https://doi.org/10.3390/cancers13092208 - 4 May 2021

Cited by 9 | Viewed by 3078

Abstract

Etiological and genetic drivers of osteosarcoma (OS) are not well studied and vary from one tumor to another; making it challenging to pursue conventional targeted therapy. Recent studies have shown that cation independent mannose-6-phosphate/insulin-like growth factor-2 receptor (IGF2R) is consistently overexpressed in almost all of standard and patient-derived OS cell lines, making it an ideal therapeutic target for development of antibody-based drugs. Monoclonal antibodies, targeting IGF2R, can be conjugated with alpha- or beta-emitter radionuclides to deliver cytocidal doses of radiation to target IGF2R expression in OS. This approach known as radioimmunotherapy (RIT) can therefore be developed as a novel treatment for OS. In addition, OS is one of the common cancers in companion dogs and very closely resembles human OS in clinical presentation and molecular aberrations. In this study, we have developed human antibodies that cross-react with similar affinities to IGF2R proteins of human, canine and murine origin. We used naïve and synthetic antibody Fab-format phage display libraries to develop antibodies to a conserved region on IGF2R. The generated antibodies were radiolabeled and characterized in vitro and in vivo using human and canine OS patient-derived tumors in SCID mouse models. We demonstrate specific binding to IGF2R and tumor uptake in these models, as well as binding to tumor tissue of canine OS patients, making these antibodies suitable for further development of RIT for OS Full article

(This article belongs to the Special Issue Radionuclides in Diagnostics and Therapy of Malignant Tumors: New Development)

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13 pages, 2187 KiB

Open AccessArticle

Dosimetric Analysis of the Short-Ranged Particle Emitter ¹⁶¹Tb for Radionuclide Therapy of Metastatic Prostate Cancer

by Peter Bernhardt, Johanna Svensson, Jens Hemmingsson, Nicholas P. van der Meulen, Jan Rijn Zeevaart, Mark W. Konijnenberg, Cristina Müller and Jon Kindblom

Cancers 2021, 13(9), 2011; https://doi.org/10.3390/cancers13092011 - 22 Apr 2021

Cited by 21 | Viewed by 3136

Abstract

The aim of this study was to analyze the required absorbed doses to detectable metastases (D_req) when using radionuclides with prostate specific membrane antigen (PSMA)-targeting radioligands to achieve a high probability for metastatic control. The Monte Carlo based analysis was performed for the clinically-used radionuclides yttrium-90, iodine-131, lutetium-177, and actinium-225, and the newly-proposed low-energy electron emitter terbium-161. It was demonstrated that metastatic formation rate highly influenced the metastatic distribution. Lower values generated few large detectable metastases, as in the case with oligo metastases, while high values generated a distribution of multiple small detectable metastases, as observed in patients with diffused visualized metastases. With equal number of detectable metastases, the total metastatic volume burden was 4–6 times higher in the oligo metastatic scenario compared to the diffusely visualized scenario. The D_req was around 30% higher for the situations with 20 detectable metastases compared to one detectable metastasis. The D_req for iodine-131 and yttrium-90 was high (920–3300 Gy). The D_req for lutetium-177 was between 560 and 780 Gy and considerably lower D_req were obtained for actinium-225 and terbium-161, with 240–330 Gy and 210–280 Gy, respectively. In conclusion, the simulations demonstrated that terbium-161 has the potential for being a more effective targeted radionuclide therapy for metastases using PSMA ligands. Full article

(This article belongs to the Special Issue Radionuclides in Diagnostics and Therapy of Malignant Tumors: New Development)

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20 pages, 2344 KiB

Open AccessArticle

Comparative Evaluation of Novel ¹⁷⁷Lu-Labeled PNA Probes for Affibody-Mediated PNA-Based Pretargeting

by Hanna Tano, Maryam Oroujeni, Anzhelika Vorobyeva, Kristina Westerlund, Yongsheng Liu, Tianqi Xu, Daniel Vasconcelos, Anna Orlova, Amelie Eriksson Karlström and Vladimir Tolmachev

Cancers 2021, 13(3), 500; https://doi.org/10.3390/cancers13030500 - 28 Jan 2021

Cited by 13 | Viewed by 4053

Abstract

Affibody-mediated PNA-based pretargeting is a promising approach to radionuclide therapy of HER2-expressing tumors. In this study, we test the hypothesis that shortening the PNA pretargeting probes would increase the tumor-to-kidney dose ratio. The primary probe Z_HER2:342-SR-HP15 and the complementary secondary probes HP16, HP17, and HP18, containing 9, 12, and 15 nucleobases, respectively, and carrying a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator were designed, synthesized, characterized in vitro, and labeled with ¹⁷⁷Lu. In vitro pretargeting was studied in HER2-expressing SKOV3 and BT474 cell lines. The biodistribution of these novel probes was evaluated in immunodeficient mice bearing SKOV3 xenografts and compared to the previously studied [¹⁷⁷Lu]Lu-HP2. Characterization confirmed the formation of high-affinity duplexes between HP15 and the secondary probes, with the affinity correlating with the length of the complementary PNA sequences. All the PNA-based probes were bound specifically to HER2-expressing cells in vitro. In vivo studies demonstrated HER2-specific uptake of all ¹⁷⁷Lu-labeled probes in xenografts in a pretargeting setting. The ratio of cumulated radioactivity in the tumor to the radioactivity in kidneys was dependent on the secondary probe’s size and decreased with an increased number of nucleobases. The shortest PNA probe, [¹⁷⁷Lu]Lu-HP16, showed the highest tumor-to-kidney ratio. [¹⁷⁷Lu]Lu-HP16 is the most promising secondary probe for affibody-mediated tumor pretargeting. Full article

(This article belongs to the Special Issue Radionuclides in Diagnostics and Therapy of Malignant Tumors: New Development)

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15 pages, 2878 KiB

Open AccessArticle

Site-Specific Dual-Labeling of a VHH with a Chelator and a Photosensitizer for Nuclear Imaging and Targeted Photodynamic Therapy of EGFR-Positive Tumors

by Emma Renard, Estel Collado Camps, Coline Canovas, Annemarie Kip, Martin Gotthardt, Mark Rijpkema, Franck Denat, Victor Goncalves and Sanne A. M. van Lith

Cancers 2021, 13(3), 428; https://doi.org/10.3390/cancers13030428 - 23 Jan 2021

Cited by 19 | Viewed by 3124

Abstract

Variable domains of heavy chain only antibodies (VHHs) are valuable agents for application in tumor theranostics upon conjugation to both a diagnostic probe and a therapeutic compound. Here, we optimized site-specific conjugation of the chelator DTPA and the photosensitizer IRDye700DX to anti-epidermal growth factor receptor (EGFR) VHH 7D12, for applications in nuclear imaging and photodynamic therapy. 7D12 was site-specifically equipped with bimodal probe DTPA-tetrazine-IRDye700DX using the dichlorotetrazine conjugation platform. Binding, internalization and light-induced toxicity of DTPA-IRDye700DX-7D12 were determined using EGFR-overexpressing A431 cells. Finally, ex vivo biodistribution of DTPA-IRDye700DX-7D12 in A431 tumor-bearing mice was performed, and tumor homing was visualized with SPECT and fluorescence imaging. DTPA-IRDye700DX-7D12 was retrieved with a protein recovery of 43%, and a degree of labeling of 0.56. Spectral properties of the IRDye700DX were retained upon conjugation. ¹¹¹In-labeled DTPA-IRDye700DX-7D12 bound specifically to A431 cells, and they were effectively killed upon illumination. DTPA-IRDye700DX-7D12 homed to A431 xenografts in vivo, and this could be visualized with both SPECT and fluorescence imaging. In conclusion, the dichlorotetrazine platform offers a feasible method for site-specific dual-labeling of VHH 7D12, retaining binding affinity and therapeutic efficacy. The flexibility of the described approach makes it easy to vary the nature of the probes for other combinations of diagnostic and therapeutic compounds. Full article

(This article belongs to the Special Issue Radionuclides in Diagnostics and Therapy of Malignant Tumors: New Development)

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Review

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23 pages, 2997 KiB

Open AccessReview

The Race for Hydroxamate-Based Zirconium-89 Chelators

by Irene V. J. Feiner, Marie Brandt, Joseph Cowell, Tori Demuth, Daniëlle Vugts, Gilles Gasser and Thomas L. Mindt

Cancers 2021, 13(17), 4466; https://doi.org/10.3390/cancers13174466 - 4 Sep 2021

Cited by 26 | Viewed by 3796

Abstract

Metallic radionuclides conjugated to biological vectors via an appropriate chelator are employed in nuclear medicine for the diagnosis (imaging) and radiotherapy of diseases. For the application of radiolabeled antibodies using positron emission tomography (immunoPET), zirconium-89 has gained increasing interest over the last decades as its physical properties (t_1/2 = 78.4 h, 22.6% β⁺ decay) match well with the slow pharmacokinetics of antibodies (t_biol. = days to weeks) allowing for late time point imaging. The most commonly used chelator for ⁸⁹Zr in this context is desferrioxamine (DFO). However, it has been shown in preclinical studies that the hexadentate DFO ligand does not provide ⁸⁹Zr-complexes of sufficient stability in vivo and unspecific uptake of the osteophilic radiometal in bones is observed. For clinical applications, this might be of concern not only because of an unnecessary dose to the patient but also an increased background signal. As a consequence, next generation chelators based on hydroxamate scaffolds for more stable coordination of ⁸⁹Zr have been developed by different research groups. In this review, we describe the progress in this research field until end of 2020, including promising examples of new candidates of chelators currently in advanced stages for clinical translation that outrun the performance of the current gold standard DFO. Full article

(This article belongs to the Special Issue Radionuclides in Diagnostics and Therapy of Malignant Tumors: New Development)

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18 pages, 2786 KiB

Open AccessReview

Cancer-Associated Fibroblasts as Players in Cancer Development and Progression and Their Role in Targeted Radionuclide Imaging and Therapy

by Sofia Koustoulidou, Mark W. H. Hoorens, Simone U. Dalm, Shweta Mahajan, Reno Debets, Yann Seimbille and Marion de Jong

Cancers 2021, 13(5), 1100; https://doi.org/10.3390/cancers13051100 - 4 Mar 2021

Cited by 31 | Viewed by 5426

Abstract

Cancer Associated Fibroblasts (CAFs) form a major component of the tumour microenvironment, they have a complex origin and execute diverse functions in tumour development and progression. As such, CAFs constitute an attractive target for novel therapeutic interventions that will aid both diagnosis and treatment of various cancers. There are, however, a few limitations in reaching successful translation of CAF targeted interventions from bench to bedside. Several approaches targeting CAFs have been investigated so far and a few CAF-targeting tracers have successfully been developed and applied. This includes tracers targeting Fibroblast Activation Protein (FAP) on CAFs. A number of FAP-targeting tracers have shown great promise in the clinic. In this review, we summarize our current knowledge of the functional heterogeneity and biology of CAFs in cancer. Moreover, we highlight the latest developments towards theranostic applications that will help tumour characterization, radioligand therapy and staging in cancers with a distinct CAF population. Full article

(This article belongs to the Special Issue Radionuclides in Diagnostics and Therapy of Malignant Tumors: New Development)

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