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Novel Targeted Radiopharmaceuticals for Diagnosis and Therapy

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 31 July 2024 | Viewed by 12128

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Special Issue Editors

Dr. Kristina Djanashvili

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Guest Editor

Department of Biotechnology, Delft University of Technology, Delft, The Netherlands
Interests: multimodal imaging; nanotechnology; organic synthesis; theranostics; lanthanides; radioisotopes; tumor targeting; hyperthermia

Dr. Sara Lacerda

E-Mail Website
Guest Editor

Center of Molecular Biophysics, CNRS, Orléans, France
Interests: molecular Imaging; targeted contrast agents; multimodal imaging; theranostics; radiolabeling; radioimaging; lanthanides

Special Issue Information

Dear Colleagues,

The development of new radiopharmaceuticals designed for the diagnosis and therapy of various diseases is a rapidly growing field of research towards precision health solutions. As a result, the remarkable clinical potential of radiolabeled probes is currently receiving increased attention from clinicians and pharmaceutical companies. However, a challenging aspect in the acceptance of the novel probes remains the multidisciplinary nature of the research that requires expertise in (radio)chemistry, radiobiology, medicine, and medical physics, which consequently necessitates collaborative approaches.

The favorable features of the radiopharmaceutical probes include the versatility of radionuclides in terms of their decay properties (half-life and energy) and the possibility for the conjugation of biomolecules, which eventually results in targeted imaging, therapy and combinations thereof.

This Special Issue of Molecules is open for articles (reviews, research papers and communications) with a focus on strategies for the synthesis and radiolabeling of novel targeted radiopharmaceuticals as well as in vitro and in vivo evaluations of their diagnostic and therapeutic performances. Subjects might include but are not limited to designs of new chelators for various radiometals, targeting vectors and linkers for their conjugation, or the introduction of radiohalogens into the structure of biomolecules.

Dr. Kristina Djanashvili
Dr. Sara Lacerda
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. Molecules is an international peer-reviewed open access semimonthly 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 2700 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

radiochemistry
radiolabeling
multimodal imaging
molecular imaging
theranostics
targeting vectors
nuclear medicine
local delivery

Published Papers (7 papers)

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Research

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37 pages, 9132 KiB

Open AccessArticle

¹⁷⁷Lu-Labeled Iron Oxide Nanoparticles Functionalized with Doxorubicin and Bevacizumab as Nanobrachytherapy Agents against Breast Cancer

by Evangelia-Alexandra Salvanou, Argiris Kolokithas-Ntoukas, Danai Prokopiou, Maria Theodosiou, Eleni Efthimiadou, Przemysław Koźmiński, Stavros Xanthopoulos, Konstantinos Avgoustakis and Penelope Bouziotis

Molecules 2024, 29(5), 1030; https://doi.org/10.3390/molecules29051030 - 27 Feb 2024

Viewed by 757

Abstract

The use of conventional methods for the treatment of cancer, such as chemotherapy or radiotherapy, and approaches such as brachytherapy in conjunction with the unique properties of nanoparticles could enable the development of novel theranostic agents. The aim of our current study was to evaluate the potential of iron oxide nanoparticles, coated with alginic acid and polyethylene glycol, functionalized with the chemotherapeutic agent doxorubicin and the monoclonal antibody bevacizumab, to serve as a nanoradiopharmaceutical agent against breast cancer. Direct radiolabeling with the therapeutic isotope Lutetium-177 (¹⁷⁷Lu) resulted in an additional therapeutic effect. Functionalization was accomplished at high percentages and radiolabeling was robust. The high cytotoxic effect of our radiolabeled and non-radiolabeled nanostructures was proven in vitro against five different breast cancer cell lines. The ex vivo biodistribution in tumor-bearing mice was investigated with three different ways of administration. The intratumoral administration of our functionalized radionanoconjugates showed high tumor accumulation and retention at the tumor site. Finally, our therapeutic efficacy study performed over a 50-day period against an aggressive triple-negative breast cancer cell line (4T1) demonstrated enhanced tumor growth retention, thus identifying the developed nanoparticles as a promising nanobrachytherapy agent against breast cancer. Full article

(This article belongs to the Special Issue Novel Targeted Radiopharmaceuticals for Diagnosis and Therapy)

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12 pages, 1803 KiB

Open AccessArticle

Efficient Synthesis and HPLC-Based Characterization for Developing Vanadium-48-Labeled Vanadyl Acetylacetonate as a Novel Cancer Radiotracer for PET Imaging

by Brittany A. Broder, Mohammed Bhuiyan, Richard Freifelder, David A. Rotsch, Satish K. Chitneni, Marvin W. Makinen and Chin-Tu Chen

Molecules 2024, 29(4), 799; https://doi.org/10.3390/molecules29040799 - 09 Feb 2024

Viewed by 877

Abstract

Bis(acetylacetonato)oxidovanadium(IV) [(VO(acac)₂], generally known as vanadyl acetylacetonate, has been shown to be preferentially sequestered in malignant tissue. Vanadium-48 (⁴⁸V) generated with a compact medical cyclotron has been used to label VO(acac)₂ as a potential radiotracer in positron emission tomography (PET) imaging for the detection of cancer, but requires lengthy synthesis. Current literature protocols for the characterization of VO(acac)₂ require macroscale quantities of reactants and solvents to identify products by color and to enable crystallization that are not readily adaptable to the needs of radiotracer synthesis. We present an improved method to produce vanadium-48-labeled VO(acac)₂, [⁴⁸V]VO(acac)₂, and characterize it using high-performance liquid chromatography (HPLC) with radiation detection in combination with UV detection. The approach is suitable for radiotracer-level quantities of material. These methods are readily applicable for production of [⁴⁸V]VO(acac)₂. Preliminary results of preclinical, small-animal PET studies are presented. Full article

(This article belongs to the Special Issue Novel Targeted Radiopharmaceuticals for Diagnosis and Therapy)

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20 pages, 5543 KiB

Open AccessArticle

Preclinical Evaluation of a PSMA-Targeting Homodimer with an Optimized Linker for Imaging of Prostate Cancer

by Erika Murce, Savanne Beekman, Evelien Spaan, Maryana Handula, Debra Stuurman, Corrina de Ridder and Yann Seimbille

Molecules 2023, 28(10), 4022; https://doi.org/10.3390/molecules28104022 - 11 May 2023

Cited by 3 | Viewed by 2201

Abstract

Prostate-specific membrane antigen (PSMA) targeting radiopharmaceuticals have been successfully used for diagnosis and therapy of prostate cancer. Optimization of the available agents is desirable to improve tumor uptake and reduce side effects to non-target organs. This can be achieved, for instance, via linker modifications or multimerization approaches. In this study, we evaluated a small library of PSMA-targeting derivatives with modified linker residues, and selected the best candidate based on its binding affinity to PSMA. The lead compound was coupled to a chelator for radiolabeling, and subject to dimerization. The resulting molecules, 22 and 30, were highly PSMA specific (IC₅₀ = 1.0–1.6 nM) and stable when radiolabeled with indium-111 (>90% stable in PBS and mouse serum up to 24 h). Moreover, [¹¹¹In]In-30 presented a high uptake in PSMA expressing LS174T cells, with 92.6% internalization compared to 34.1% for PSMA-617. Biodistribution studies in LS174T mice xenograft models showed that [¹¹¹In]In-30 had a higher tumor and kidney uptake compared to [¹¹¹In]In-PSMA-617, but increasing T/K and T/M ratios at 24 h p.i. Tumors could be clearly visualized at 1 h p.i. by SPECT/CT after administration of [¹¹¹In]In-22 and [¹¹¹In]In-PSMA-617, while [¹¹¹In]In-30 showed a clear signal at later time-points (e.g., 24 h p.i.). Full article

(This article belongs to the Special Issue Novel Targeted Radiopharmaceuticals for Diagnosis and Therapy)

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15 pages, 1944 KiB

Open AccessArticle

Radiolabelling of Polyclonally Expanded Human Regulatory T Cells (Treg) with ⁸⁹Zr-oxine for Medium-Term In Vivo Cell Tracking

by Jacinta Jacob, Alessia Volpe, Qi Peng, Robert I. Lechler, Lesley A. Smyth, Giovanna Lombardi and Gilbert O. Fruhwirth

Molecules 2023, 28(3), 1482; https://doi.org/10.3390/molecules28031482 - 03 Feb 2023

Cited by 3 | Viewed by 2225

Abstract

Regulatory T cells (Tregs) are a promising candidate cell therapy to treat autoimmune diseases and aid the longevity of transplanted solid organs. Despite increasing numbers of clinical trials using human Treg therapy, important questions pertaining to their in vivo fate, distribution, and function remain unanswered. Treg accumulation in relevant tissues was found to be crucial for Treg therapy efficacy, but existing blood-borne biomarkers are unlikely to accurately reflect the tissue state. Non-invasive Treg tracking by whole-body imaging is a promising alternative and can be achieved by direct radiolabelling of Tregs and following the radiolabelled cells with positron emission tomography (PET). Our goal was to evaluate the radiolabelling of polyclonal Tregs with ⁸⁹Zr to permit their in vivo tracking by PET/CT for longer than one week with current preclinical PET instrumentation. We used [⁸⁹Zr]Zr(oxinate)₄ as the cell-labelling agent and achieved successful radiolabelling efficiency of human Tregs spanning 0.1–11.1 Bq ⁸⁹Zr/Treg cell, which would be compatible with PET tracking beyond one week. We characterized the ⁸⁹Zr-Tregs, assessing their phenotypes, and found that they were not tolerating these intracellular ⁸⁹Zr amounts, as they failed to survive or expand in a ⁸⁹Zr-dose-dependent manner. Even at 0.1 Bq ⁸⁹Zr per Treg cell, while ⁸⁹Zr-Tregs remained functional as determined by a five-day-long effector T cell suppression assay, they failed to expand beyond day 3 in vitro. Moreover, PET imaging revealed signs of ⁸⁹Zr-Treg death after adoptive transfer in vivo. In summary, ⁸⁹Zr labelling of Tregs at intracellular radioisotope amounts compatible with cell tracking over several weeks did not achieve the desired outcomes, as ⁸⁹Zr-Tregs failed to expand and survive. Consequently, we conclude that indirect Treg labelling is likely to be the most effective alternative method to satisfy the requirements of this cell tracking scenario. Full article

(This article belongs to the Special Issue Novel Targeted Radiopharmaceuticals for Diagnosis and Therapy)

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19 pages, 3988 KiB

Open AccessArticle

Engineered rHDL Nanoparticles as a Suitable Platform for Theranostic Applications

by Liliana Aranda-Lara, Keila Isaac-Olivé, Blanca Ocampo-García, Guillermina Ferro-Flores, Carlos González-Romero, Alfredo Mercado-López, Rodrigo García-Marín, Clara Santos-Cuevas, José A. Estrada and Enrique Morales-Avila

Molecules 2022, 27(20), 7046; https://doi.org/10.3390/molecules27207046 - 19 Oct 2022

Cited by 3 | Viewed by 1425

Abstract

Reconstituted high-density lipoproteins (rHDLs) can transport and specifically release drugs and imaging agents, mediated by the Scavenger Receptor Type B1 (SR-B1) present in a wide variety of tumor cells, providing convenient platforms for developing theranostic systems. Usually, phospholipids or Apo-A1 lipoproteins on the particle surfaces are the motifs used to conjugate molecules for the multifunctional purposes of the rHDL nanoparticles. Cholesterol has been less addressed as a region to bind molecules or functional groups to the rHDL surface. To maximize the efficacy and improve the radiolabeling of rHDL theranostic systems, we synthesized compounds with bifunctional agents covalently linked to cholesterol. This strategy means that the radionuclide was bound to the surface, while the therapeutic agent was encapsulated in the lipophilic core. In this research, HYNIC-S-(CH₂)₃-S-Cholesterol and DOTA-benzene-p-SC-NH-(CH₂)₂-NH-Cholesterol derivatives were synthesized to prepare nanoparticles (NPs) of HYNIC-rHDL and DOTA-rHDL, which can subsequently be linked to radionuclides for SPECT/PET imaging or targeted radiotherapy. HYNIC is used to complexing ^99mTc and DOTA for labeling molecules with ^{111, 113m}In, ^{67, 68}Ga, ¹⁷⁷Lu, ¹⁶¹Tb, ²²⁵Ac, and ⁶⁴Cu, among others. In vitro studies showed that the NPs of HYNIC-rHDL and DOTA-rHDL maintain specific recognition by SR-B1 and the ability to internalize and release, in the cytosol of cancer cells, the molecules carried in their core. The biodistribution in mice showed a similar behavior between rHDL (without surface modification) and HYNIC-rHDL, while DOTA-rHDL exhibited a different biodistribution pattern due to the significant reduction in the lipophilicity of the modified cholesterol molecule. Both systems demonstrated characteristics for the development of suitable theranostic platforms for personalized cancer treatment. Full article

(This article belongs to the Special Issue Novel Targeted Radiopharmaceuticals for Diagnosis and Therapy)

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10 pages, 1293 KiB

Open AccessArticle

Photonuclear Alchemy: Obtaining Medical Isotopes of Gold from Mercury Irradiated on Electron Accelerators

by Andrey G. Kazakov, Julia S. Babenya, Taisya Y. Ekatova, Sergey S. Belyshev, Vadim V. Khankin, Omar Albaghdadi, Alexander A. Kuznetsov, Illarion I. Dovhyi, Nikolay A. Bezhin and Ivan G. Tananaev

Molecules 2022, 27(17), 5532; https://doi.org/10.3390/molecules27175532 - 28 Aug 2022

Viewed by 1604

Abstract

In our work, the photonuclear production of ^198,199Au isotopes for nuclear medicine purposes was studied, and a method for their recovery from irradiated mercury was developed. The yields of the corresponding nuclear reactions were determined, and a comparison of various methods of obtaining gold radioisotopes was provided. New sorbents based on benzo-15-crown-5, which selectively binds gold, were studied, and the optimal conditions for Au recovery with a high degree of purification from mercury were found. It was established that, for the fast and quantitative recovery of Au isotopes, it was necessary to add at least 0.1 mg of the carrier. As a result, the developed method can be regularly used to obtain ^198,199Au for the research of radiopharmaceuticals based on them. Full article

(This article belongs to the Special Issue Novel Targeted Radiopharmaceuticals for Diagnosis and Therapy)

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Review

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46 pages, 67524 KiB

Open AccessReview

Mutated Isocitrate Dehydrogenase (mIDH) as Target for PET Imaging in Gliomas

by Felix Neumaier, Boris D. Zlatopolskiy and Bernd Neumaier

Molecules 2023, 28(7), 2890; https://doi.org/10.3390/molecules28072890 - 23 Mar 2023

Cited by 3 | Viewed by 1991

Abstract

Gliomas are the most common primary brain tumors in adults. A diffuse infiltrative growth pattern and high resistance to therapy make them largely incurable, but there are significant differences in the prognosis of patients with different subtypes of glioma. Mutations in isocitrate dehydrogenase (IDH) have been recognized as an important biomarker for glioma classification and a potential therapeutic target. However, current clinical methods for detecting mutated IDH (mIDH) require invasive tissue sampling and cannot be used for follow-up examinations or longitudinal studies. PET imaging could be a promising approach for non-invasive assessment of the IDH status in gliomas, owing to the availability of various mIDH-selective inhibitors as potential leads for the development of PET tracers. In the present review, we summarize the rationale for the development of mIDH-selective PET probes, describe their potential applications beyond the assessment of the IDH status and highlight potential challenges that may complicate tracer development. In addition, we compile the major chemical classes of mIDH-selective inhibitors that have been described to date and briefly consider possible strategies for radiolabeling of the most promising candidates. Where available, we also summarize previous studies with radiolabeled analogs of mIDH inhibitors and assess their suitability for PET imaging in gliomas. Full article

(This article belongs to the Special Issue Novel Targeted Radiopharmaceuticals for Diagnosis and Therapy)

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