Concepts to Improve Targeted Radionuclide Therapy in Cancer: Ligand Design Optimization and Application of Emerging Radionuclides and Combination Therapies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 18354

Special Issue Editor


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Guest Editor
Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen-PSI, and ETH Zurich, Department of Chemistry and Applied Biosciences, 8093 Zurich, Switzerland
Interests: targeted radionuclide therapy; nonstandard radionuclides; albumin-binder concept; PSMA targeting; folate receptor targeting
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Special Issue Information

Dear Colleagues,

The field of nuclear oncology has become increasingly important in cancer therapy mainly due to the successful application of peptide-receptor radionuclide therapy using somatostatin analogues and PSMA ligand-based radioligand therapy.

It will thus be of paramount interest to develop innovative concepts of novel radionuclide therapies and improve existing ones to allow a broader range of applications. The goal of this Special Issue is to present a collection of research studies describing ligand design optimization (e.g., through linker modification or the use of albumin binders or cleavable linkers) as well as the application of nonstandard radionuclides (e.g., alpha-particle/Auger electron emitters) and investigations of combination therapies.

I am pleased to invite you to contribute to this Special Issue “Concepts to Improve Targeted Radionuclide Therapy in Cancer: Ligand Design Optimization and Application of Emerging Radionuclides and Combination Therapies”. Original research articles and communications as well as review articles are welcome.

We look forward to receiving your contributions.

Prof. Dr. Cristina Müller
Guest Editor

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Keywords

  • radionuclide therapy
  • nonstandard radionuclides
  • linker modification
  • albumin binders
  • small-molecule radioligands
  • radiopeptides
  • radiosensitizers
  • combination therapies
  • 3D in vitro systems
  • tumor mouse models

Published Papers (7 papers)

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Research

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13 pages, 3091 KiB  
Article
Design and Preclinical Evaluation of a Novel Prostate-Specific Membrane Antigen Radioligand Modified with a Transthyretin Binder
by Christian Vaccarin, Ana Katrina Mapanao, Luisa M. Deberle, Anna E. Becker, Francesca Borgna, Giovanni Marzaro, Roger Schibli and Cristina Müller
Cancers 2024, 16(7), 1262; https://doi.org/10.3390/cancers16071262 - 23 Mar 2024
Viewed by 888
Abstract
Transthyretin binders have previously been used to improve the pharmacokinetic properties of small-molecule drug conjugates and could, thus, be utilized for radiopharmaceuticals as an alternative to the widely explored “albumin binder concept”. In this study, a novel PSMA ligand modified with a transthyretin-binding [...] Read more.
Transthyretin binders have previously been used to improve the pharmacokinetic properties of small-molecule drug conjugates and could, thus, be utilized for radiopharmaceuticals as an alternative to the widely explored “albumin binder concept”. In this study, a novel PSMA ligand modified with a transthyretin-binding entity (TB-01) was synthesized and labeled with lutetium-177 to obtain [177Lu]Lu-PSMA-TB-01. A high and specific uptake of [177Lu]Lu-PSMA-TB-01 was found in PSMA-positive PC-3 PIP cells (69 ± 3% after 4 h incubation), while uptake in PSMA-negative PC-3 flu cells was negligible (<1%). In vitro binding studies showed a 174-fold stronger affinity of [177Lu]Lu-PSMA-TB-01 to transthyretin than to human serum albumin. Biodistribution studies in PC-3 PIP/flu tumor-bearing mice confirmed the enhanced blood retention of [177Lu]Lu-PSMA-TB-01 (16 ± 1% IA/g at 1 h p.i.), which translated to a high tumor uptake (69 ± 13% IA/g at 4 h p.i.) with only slow wash-out over time (31 ± 8% IA/g at 96 h p.i.), while accumulation in the PC-3 flu tumor and non-targeted normal tissue was reasonably low. Further optimization of the radioligand design would be necessary to fine-tune the biodistribution and enable its use for therapeutic purposes. This study was the first of this kind and could motivate the use of the “transthyretin binder concept” for the development of future radiopharmaceuticals. Full article
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19 pages, 3290 KiB  
Article
Investigations Using Albumin Binders to Modify the Tissue Distribution Profile of Radiopharmaceuticals Exemplified with Folate Radioconjugates
by Sarah D. Busslinger, Anna E. Becker, Christian Vaccarin, Luisa M. Deberle, Marie-Luise Renz, Viola Groehn, Roger Schibli and Cristina Müller
Cancers 2023, 15(17), 4259; https://doi.org/10.3390/cancers15174259 - 25 Aug 2023
Cited by 5 | Viewed by 1264
Abstract
Introducing an albumin-binding entity into otherwise short-lived radiopharmaceuticals can be an effective means to improve their pharmacokinetic properties due to enhanced blood residence time. In the current study, DOTA-derivatized albumin binders based on 4-(p-iodophenyl)butanoate (DOTA-ALB-1 and DOTA-ALB-3) and 5-(p-iodophenyl)pentanoate [...] Read more.
Introducing an albumin-binding entity into otherwise short-lived radiopharmaceuticals can be an effective means to improve their pharmacokinetic properties due to enhanced blood residence time. In the current study, DOTA-derivatized albumin binders based on 4-(p-iodophenyl)butanoate (DOTA-ALB-1 and DOTA-ALB-3) and 5-(p-iodophenyl)pentanoate entities (DOTA-ALB-24 and DOTA-ALB-25) without and with a hydrophobic 4-(aminomethyl)benzoic acid (AMBA) linker unit, respectively, were synthesized and labeled with lutetium-177 for in vitro and in vivo comparison. Overall, [177Lu]Lu-DOTA-ALB-1 demonstrated ~3-fold stronger in vitro albumin-binding affinity and a longer blood residence time (T50%IA ~8 h) than [177Lu]Lu-DOTA-ALB-24 (T50%IA ~0.8 h). Introducing an AMBA linker enhanced the albumin-binding affinity, resulting in a T50%IA of ~24 h for [177Lu]Lu-DOTA-ALB-3 and ~2 h for [177Lu]Lu-DOTA-ALB-25. The same albumin binders without or with the AMBA linker were incorporated into 6R- and 6S-5-methyltetrahydrofolate-based DOTA-conjugates (177Lu-RedFols). Biodistribution studies in mice performed with both diastereoisomers of [177Lu]Lu-RedFol-1 and [177Lu]Lu-RedFol-3, which comprised the 4-(p-iodophenyl)butanoate moiety, demonstrated a slower accumulation in KB tumors than those of [177Lu]Lu-RedFol-24 and [177Lu]Lu-RedFol-25 with the 5-(p-iodophenyl)pentanoate entity. In all cases, the tumor uptake was high (30–45% IA/g) 24 h after injection. Both diastereoisomers of [177Lu]Lu-RedFol-1 and [177Lu]Lu-RedFol-3 demonstrated high blood retention (3.8–8.7% IA/g, 24 h p.i.) and a 2- to 4-fold lower kidney uptake than the corresponding diastereoisomers of [177Lu]Lu-RedFol-24 and [177Lu]Lu-RedFol-25, which were more rapidly cleared from the blood (<0.2% IA/g, 24 h after injection). Kidney retention of the 6S-diastereoisomers of all 177Lu-RedFols was consistently higher than that of the respective 6R-diastereoisomers, irrespective of the albumin binder and linker unit used. It was demonstrated that the blood clearance data obtained with 177Lu-DOTA-ALBs had predictive value for the blood retention times of the respective folate radioconjugates. The use of these albumin-binding entities without or with an AMBA linker may serve for fine-tuning the blood retention of folate radioconjugates and also other radiopharmaceuticals and, hence, optimize their tissue distribution profiles. Dosimetry estimations based on patient data obtained with one of the most promising folate radioconjugates will be crucial to identify the dose-limiting organ, which will allow for selecting the most suitable folate radioconjugate for therapeutic purposes. Full article
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13 pages, 2872 KiB  
Article
Correlations between [68Ga]Ga-DOTA-TOC Uptake and Absorbed Dose from [177Lu]Lu-DOTA-TATE
by Ragnar Bruvoll, Johan Blakkisrud, Lars Tore Mikalsen, James Connelly and Caroline Stokke
Cancers 2023, 15(4), 1134; https://doi.org/10.3390/cancers15041134 - 10 Feb 2023
Cited by 5 | Viewed by 1425
Abstract
Purpose: The aim of this paper was to investigate correlations between pre- therapeutic [68Ga]Ga-DOTA-TOC uptake and absorbed dose to tumours from therapy with [177Lu]Lu-DOTA-TATE. Methods: This retrospective study included 301 tumours from 54 GEP-NET patients. The tumours were segmented [...] Read more.
Purpose: The aim of this paper was to investigate correlations between pre- therapeutic [68Ga]Ga-DOTA-TOC uptake and absorbed dose to tumours from therapy with [177Lu]Lu-DOTA-TATE. Methods: This retrospective study included 301 tumours from 54 GEP-NET patients. The tumours were segmented on pre-therapeutic [68Ga]Ga-DOTA-TOC PET/CT, and post-therapy [177Lu]Lu-DOTA-TATE SPECT/CT images, using a fixed 40% threshold. The SPECT/CT images were used for absorbed dose calculations by assuming a linear build-up from time zero to day one, and mono-exponential wash-out after that. Both SUVmean and SUVmax were measured from the PET images. A linear absorbed-dose prediction model was formed with SUVmean as the independent variable, and the accuracy was tested with a split 70–30 training-test set. Results: Mean SUVmean and SUVmax from [68Ga]Ga-DOTA-TOC PET was 24.0 (3.6–84.4) and 41.0 (6.7–146.5), and the mean absorbed dose from [177Lu]Lu-DOTA-TATE was 26.9 Gy (2.4–101.9). A linear relationship between SUVmean and [177Lu]Lu-DOTA-TATE activity concentration at 24 h post injection was found (R2 = 0.44, p < 0.05). In the prediction model, a root mean squared error and a mean absolute error of 1.77 and 1.33 Gy/GBq, respectively, were found for the test set. Conclusions: There was a high inter- and intra-patient variability in tumour measurements, both for [68Ga]Ga-DOTA-TOC SUVs and absorbed doses from [177Lu]Lu-DOTA-TATE. Depending on the required accuracy, [68Ga]Ga-DOTA-TOC PET imaging may estimate the [177Lu]Lu-DOTA-TATE uptake. However, there could be a high variance between predicted and actual absorbed doses. Full article
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16 pages, 2526 KiB  
Article
[225Ac]Ac-SibuDAB for Targeted Alpha Therapy of Prostate Cancer: Preclinical Evaluation and Comparison with [225Ac]Ac-PSMA-617
by Sarah D. Busslinger, Viviane J. Tschan, Olivia K. Richard, Zeynep Talip, Roger Schibli and Cristina Müller
Cancers 2022, 14(22), 5651; https://doi.org/10.3390/cancers14225651 - 17 Nov 2022
Cited by 17 | Viewed by 2444
Abstract
In the present study, SibuDAB, an albumin-binding PSMA ligand, was investigated in combination with actinium-225 and the data were compared with those of [225Ac]Ac-PSMA-617. In vitro, [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617 showed similar tumor cell uptake and PSMA-binding affinities [...] Read more.
In the present study, SibuDAB, an albumin-binding PSMA ligand, was investigated in combination with actinium-225 and the data were compared with those of [225Ac]Ac-PSMA-617. In vitro, [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617 showed similar tumor cell uptake and PSMA-binding affinities as their 177Lu-labeled counterparts. The in vitro binding to serum albumin in mouse and human blood plasma, respectively, was 2.8-fold and 1.4-fold increased for [225Ac]Ac-SibuDAB as compared to [177Lu]Lu-SibuDAB. In vivo, this characteristic was reflected by the longer retention of [225Ac]Ac-SibuDAB in the blood than previously seen for [177Lu]Lu-SibuDAB. Similar to [225Ac]Ac-PSMA-617, [225Ac]Ac-SibuDAB was well tolerated at 30 kBq per mouse. Differences in blood cell counts were observed between treated mice and untreated controls, but no major variations were observed between values obtained for [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617. [225Ac]Ac-SibuDAB was considerably more effective to treat PSMA-positive tumor xenografts than [225Ac]Ac-PSMA-617. Only 5 kBq per mouse were sufficient to eradicate the tumors, whereas tumor regrowth was observed for mice treated with 5 kBq [225Ac]Ac-PSMA-617 and only one out of six mice survived until the end of the study. The enhanced therapeutic efficacy of [225Ac]Ac-SibuDAB as compared to that of [225Ac]Ac-PSMA-617 and reasonable safety data qualify this novel radioligand as a candidate for targeted α-therapy of prostate cancer. Full article
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Review

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12 pages, 800 KiB  
Review
Peptide Receptor Radionuclide Therapy (PRRT): Innovations and Improvements
by Elettra Merola and Chiara Maria Grana
Cancers 2023, 15(11), 2975; https://doi.org/10.3390/cancers15112975 - 30 May 2023
Cited by 9 | Viewed by 2185
Abstract
Neuroendocrine neoplasms (NENs) are tumors originating from neuroendocrine cells distributed throughout the human body. With an increasing incidence over the past few decades, they represent a highly heterogeneous group of neoplasms, mostly expressing somatostatin receptors (SSTRs) on their cell surface. Peptide receptor radionuclide [...] Read more.
Neuroendocrine neoplasms (NENs) are tumors originating from neuroendocrine cells distributed throughout the human body. With an increasing incidence over the past few decades, they represent a highly heterogeneous group of neoplasms, mostly expressing somatostatin receptors (SSTRs) on their cell surface. Peptide receptor radionuclide therapy (PRRT) has emerged as a crucial strategy for treating advanced, unresectable neuroendocrine tumors by administering radiolabeled somatostatin analogs intravenously to target SSTRs. This article will focus on the multidisciplinary theranostic approach, treatment effectiveness (such as response rates and symptom relief), patient outcomes, and toxicity profile of PRRT for NEN patients. We will review the most significant studies, such as the phase III NETTER-1 trial, and discuss promising new radiopharmaceuticals, including alpha-emitting radionuclide-labeled somatostatin analogs and SSTR antagonists. Full article
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21 pages, 864 KiB  
Review
The Effects of Peptide Receptor Radionuclide Therapy on the Neoplastic and Normal Pituitary
by Pedro Marques
Cancers 2023, 15(10), 2710; https://doi.org/10.3390/cancers15102710 - 11 May 2023
Cited by 3 | Viewed by 1935
Abstract
Pituitary neuroendocrine tumours (PitNETs) are usually benign and slow-growing; however, in some cases, they may behave aggressively and become resistant to conventional treatments. Therapeutic options for aggressive or metastatic PitNETs are limited, and currently mainly consist of temozolomide, with little experience of other [...] Read more.
Pituitary neuroendocrine tumours (PitNETs) are usually benign and slow-growing; however, in some cases, they may behave aggressively and become resistant to conventional treatments. Therapeutic options for aggressive or metastatic PitNETs are limited, and currently mainly consist of temozolomide, with little experience of other emerging approaches, including peptide receptor radionuclide therapy (PRRT). Somatostatin receptor expression in PitNETs explains the effectiveness of somatostatin analogues for treating PitNETs, particularly those hypersecreting pituitary hormones, such as growth hormone or adrenocorticotropic hormone. The expression of such receptors in pituitary tumour cells has provided the rationale for using PRRT to treat patients with aggressive or metastatic PitNETs. However, the PRRT efficacy in this setting remains unestablished, as knowledge on this today is based only on few case reports and small series of cases, which are reviewed here. A total of 30 PRRT-treated patients have been thus far reported: 23 aggressive PitNETs, 5 carcinomas, and 2 of malignancy status unspecified. Of the 27 published cases with information regarding the response to PRRT, 5 (18%) showed a partial response, 8 (30%) had stable disease, and 14 (52%) had progressive disease. No major adverse effects have been reported, and there is also no increased risk of clinically relevant hypopituitarism in patients with pituitary or non-pituitary neuroendocrine tumours following PRRT. PRRT may be regarded as a safe option for patients with aggressive or metastatic PitNETs if other treatment approaches are not feasible or have failed in controlling the disease progression, with tumour shrinkage occurring in up to a fifth of cases, while about a third of aggressive pituitary tumours may achieve stable disease. Here, the data on PRRT in the management of patients with aggressive pituitary tumours are reviewed, as well as the effects of PRRT on the pituitary function in other PRRT-treated cancer patients. Full article
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25 pages, 1780 KiB  
Review
The Tumor Microenvironment in Tumorigenesis and Therapy Resistance Revisited
by Kevin Dzobo, Dimakatso A. Senthebane and Collet Dandara
Cancers 2023, 15(2), 376; https://doi.org/10.3390/cancers15020376 - 6 Jan 2023
Cited by 47 | Viewed by 7366
Abstract
Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis, [...] Read more.
Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis, and highlight various ways through which tumor cells reprogram normal cells into phenotypes that are pro-tumorigenic, including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to the transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells, including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic, but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to the formation of new vascular networks in order to actively promote and sustain tumor growth via the supply of oxygen and nutrients, whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to the targeting of tumor cells. The reprogramming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centered therapies under investigation. Full article
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