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Pharmaceuticals
Special Issues
Development of Radiolabeled Peptides
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Development of Radiolabeled Peptides

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

Deadline for manuscript submissions: 25 May 2024 | Viewed by 6132

Special Issue Editor

Dr. Noeen Malik

E-Mail Website
Guest Editor
1201 Welch Road, Lucas Expansion Center, CRF (Cyclotron and Radiochemistry Facility), Department of Radiology, Stanford Medicine (School of Medicine), Stanford, CA, USA
Interests: development and commercialization of theragnostic radiopharmaceuticals in oncology and neuroscience

Special Issue Information

Dear Colleagues,

Over the past 50 years, the development of radiopharmaceuticals for oncology has been quite significant. For both diagnostic and therapeutic purposes, imaging modalities such as PET/CT, PET/MRI, and SPECT have proven vital over the years. As a diagnostic tool (PET/CT/MRI), functional imaging is not only valuable when reflecting on the progress of cancer, but it also determines the impact of therapeutic procedures. From a therapeutic standpoint, pharmaceuticals are tagged with α- or β-emitting radionuclides to deliver targeted radiations, such as in case of metastatic cancers.

Novel radiopharmaceuticals are developed by integrating bench research with clinical diagnostic applications and therapeutic approaches. In terms of the development process, antibodies and peptides account for the largest segment of the market due to their clinical importance. However, unlike antibodies, small molecules and peptides can target and clear rapidly. Nonetheless, another important factor is internalization, which contributes to a longer radionuclide retention time.

A significant trend toward radionuclide-tagged peptides has emerged over the past two decades, both as diagnostic tools and therapeutics. The inclination to use radiometals-labeled peptides (for diagnostics: 64Cu, 68Ga, 89Zr; For therapeutics: 177Lu, 111In, 225Ac) rather than 18F-labeled small molecules is greater as the latter involves no change in chemical structure and thus maintains somewhat similar kinetics in diagnostics and therapeutics.  

The journal Pharmaceuticals invites both reviews and original articles to highlight recent developments in research on radiolabeled peptides, both in oncology and neuroscience. The collection of manuscripts will be published as a Special Issue of the journal.

Dr. Noeen Malik
Guest Editor

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. Pharmaceuticals 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

  • radiometals
  • peptides
  • PET/CT/MRI
  • functional imaging
  • oncology
  • diagnosis
  • therapy

Published Papers (4 papers)

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Research

14 pages, 813 KiB  
Article
Preparation, Radiolabeling with 68Ga/177Lu and Preclinical Evaluation of Novel Angiotensin Peptide Analog: A New Class of Peptides for Breast Cancer Targeting
by Subhani M. Okarvi
Pharmaceuticals 2023, 16(11), 1550; https://doi.org/10.3390/ph16111550 - 02 Nov 2023
Viewed by 929
Abstract
Aim: Angiotensin II (AngII) is known to play a significant part in the development of breast cancer by triggering cell propagation of breast cancer, tumor angiogenesis, and regulating tumor invasion and cell migration. AngII arbitrates its action via two G-protein-coupled receptors, AngII type [...] Read more.
Aim: Angiotensin II (AngII) is known to play a significant part in the development of breast cancer by triggering cell propagation of breast cancer, tumor angiogenesis, and regulating tumor invasion and cell migration. AngII arbitrates its action via two G-protein-coupled receptors, AngII type 1 receptor (AT1) and AngII type 2 receptor (AT2). Overexpression of the AT1 receptor in breast cancer cells seems to promote tumor growth and angiogenesis, thus targeting the AT1 receptor using AngII peptide would facilitate the detection of breast carcinoma. We developed an AngII peptide intending to assess whether the peptide of the renin–angiotensin system holds the ability to target AT1 receptor-overexpressing breast cancer in vivo. Methods: DOTA-coupled AngII peptide was synthesized by conventional solid-phase peptide synthesis according to Fmoc/HATU chemistry. 68Ga/177Lu labeled AngII peptide was evaluated for its binding with TNBC MDA-MB-231 and ER+ MCF7 cell lines. Pharmacokinetics was studied in healthy balb/c mice and in vivo tumor targeting in nude mice with MDA-MB-231 tumors xenografts. Results: DOTA-AngII peptide was labeled efficiently with 68Ga/177Lu with high labeling efficiency (≥90%). The stability of the radiopeptide in human plasma was found to be high. The AngII peptide analog showed nanomolar (<40 nM) AT1 receptor-specific binding affinity. The radioactivity internalized into MDA-MBA-231 and MCF7 cells were 14.97% and 11.75%, respectively. In vivo, biodistribution in balb/c mice exhibited efficient clearance of 68Ga/177Lu-DOTA-AngII peptide from the blood and elimination predominantly by the renal system due to its hydrophilic nature. A low amount of radioactivity was seen in the major organs including lungs, liver, stomach, spleen, and intestines (<3% ID/g) except the kidneys. A high renal-urinary excretion was observed for the radiotracer. In the TNBC MDA-MB-231 xenografts model, radiolabeled AngII peptide exhibited specific and effective AT1-based targeting in vivo. A rapid and efficient tumor targeting (2.18% ID/g at 45 min p.i.) together with fast renal excretion (~67% ID) highlights the tumor-targeting potential of the radiotracer. The AT1 receptor specificity of the radiotracer was validated by blocking assays. Furthermore, PET imaging provided sufficient visualization of MDA-MB-231 tumors in nude mice. Conclusion: Our findings suggest that 68Ga/177Lu-DOTA-AngII peptide can be useful for the theranostic application of breast carcinomas. This study suggests the potential of this innovative class of peptides for rapid and efficient targeting of tumors and warrants further evaluation. Full article
(This article belongs to the Special Issue Development of Radiolabeled Peptides)
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17 pages, 9142 KiB  
Article
Investigation of the Effect on the Albumin Binding Moiety for the Pharmacokinetic Properties of 68Ga-, 205/206Bi-, and 177Lu-Labeled NAPamide-Based Radiopharmaceuticals
by Dániel Szücs, Judit P. Szabó, Viktória Arató, Barbara Gyuricza, Dezső Szikra, Imre Tóth, Zita Képes, György Trencsényi and Anikó Fekete
Pharmaceuticals 2023, 16(9), 1280; https://doi.org/10.3390/ph16091280 - 11 Sep 2023
Cited by 1 | Viewed by 811
Abstract
Although radiolabeled alpha-melanocyte stimulating hormone-analogue NAPamide derivatives are valuable melanoma-specific diagnostic probes, their rapid elimination kinetics and high renal uptake may preclude them from being used in clinical settings. We aimed at improving the pharmacokinetics of radiolabeled DOTA-NAPamide compounds by incorporating a 4-(p-iodo-phenyl)-butanoic [...] Read more.
Although radiolabeled alpha-melanocyte stimulating hormone-analogue NAPamide derivatives are valuable melanoma-specific diagnostic probes, their rapid elimination kinetics and high renal uptake may preclude them from being used in clinical settings. We aimed at improving the pharmacokinetics of radiolabeled DOTA-NAPamide compounds by incorporating a 4-(p-iodo-phenyl)-butanoic acid (IPB) into the molecules. Followed by 68Ga-, 205/206Bi-, and 177Lu-labelling, the radiopharmaceuticals ([68Ga]Ga-DOTA-IPB-NAPamide, [205/206Bi]Bi-DOTA-IPB-NAPamide, [177Lu]Lu-DOTA-IPB-NAPamide) were characterized in vitro. To test the imaging behavior of the IPB-containing probes, B16F10 tumor-bearing C57BL/6 mice were subjected to in vivo microPET/microSPECT/CT imaging and ex vivo biodistribution studies. All tracers were stable in vitro, with radiochemical purity exceeding 98%. The use of albumin-binding moiety lengthened the in vivo biological half-life of the IPB-carrying radiopharmaceuticals, resulting in elevated tumor accumulation. Both [68Ga]Ga-DOTA-IPB-NAPamide (5.06 ± 1.08 %ID/g) and [205/206Bi]Bi-DOTA-IPB-NAPamide (4.50 ± 0.98 %ID/g) exhibited higher B16F10 tumor concentrations than their matches without the albumin-binding residue ([68Ga]Ga-DOTA-NAPamide and [205/206Bi]Bi-DOTA-NAPamide: 1.18 ± 0.27 %ID/g and 3.14 ± 0.32; respectively), however; the large amounts of off-target radioactivity do not confirm the benefits of half-life extension for short-lived isotopes. Enhanced [177Lu]Lu-DOTA-IPB-NAPamide tumor uptake even 24 h post-injection proved the advantage of IPB-based prolonged circulation time regarding long-lived radionuclides, although the significant background noise must be addressed in this case as well. Full article
(This article belongs to the Special Issue Development of Radiolabeled Peptides)
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19 pages, 2813 KiB  
Article
[212Pb]Pb-eSOMA-01: A Promising Radioligand for Targeted Alpha Therapy of Neuroendocrine Tumors
by Dylan Chapeau, Sofia Koustoulidou, Maryana Handula, Savanne Beekman, Corrina de Ridder, Debra Stuurman, Erik de Blois, Yulia Buchatskaya, Karlijn van der Schilden, Marion de Jong, Mark W. Konijnenberg and Yann Seimbille
Pharmaceuticals 2023, 16(7), 985; https://doi.org/10.3390/ph16070985 - 10 Jul 2023
Cited by 3 | Viewed by 2523
Abstract
Peptide receptor radionuclide therapy (PRRT) has been applied to the treatment of neuroendocrine tumors (NETs) for over two decades. However, improvement is still needed, and targeted alpha therapy (TAT) with alpha emitters such as lead-212 (212Pb) represents a promising avenue. A [...] Read more.
Peptide receptor radionuclide therapy (PRRT) has been applied to the treatment of neuroendocrine tumors (NETs) for over two decades. However, improvement is still needed, and targeted alpha therapy (TAT) with alpha emitters such as lead-212 (212Pb) represents a promising avenue. A series of ligands based on octreotate was developed. Lead-203 was used as an imaging surrogate for the selection of the best candidate for the studies with lead-212. 203/212Pb radiolabeling and in vitro assays were carried out, followed by SPECT/CT imaging and ex vivo biodistribution in NCI-H69 tumor-bearing mice. High radiochemical yields (≥99%) and purity (≥96%) were obtained for all ligands. [203Pb]Pb-eSOMA-01 and [203Pb]Pb-eSOMA-02 showed high stability in PBS and mouse serum up to 24 h, whereas [203Pb]Pb-eSOMA-03 was unstable in those conditions. All compounds exhibited a nanomolar affinity (2.5–3.1 nM) for SSTR2. SPECT/CT images revealed high tumor uptake at 1, 4, and 24 h post-injection of [203Pb]Pb-eSOMA-01/02. Ex vivo biodistribution studies confirmed that the highest uptake in tumors was observed with [212Pb]Pb-eSOMA-01. [212Pb]Pb-eESOMA-01 displayed the highest absorbed dose in the tumor (35.49 Gy/MBq) and the lowest absorbed dose in the kidneys (121.73 Gy/MBq) among the three tested radioligands. [212Pb]Pb-eSOMA-01 is a promising candidate for targeted alpha therapy of NETs. Further investigations are required to confirm its potential. Full article
(This article belongs to the Special Issue Development of Radiolabeled Peptides)
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14 pages, 2082 KiB  
Article
Validation of Freshly Isolated Rat Renal Cells as a Tool for Preclinical Assessment of Radiolabeled Receptor-Specific Peptide Uptake in the Kidney
by Pavel Barta, Petr Nachtigal, Jana Maixnerova, Lenka Zemankova and Frantisek Trejtnar
Pharmaceuticals 2023, 16(5), 696; https://doi.org/10.3390/ph16050696 - 04 May 2023
Viewed by 1283
Abstract
The synthetic analogs of regulatory peptides radiolabeled with adequate radionuclides are perspective tools in nuclear medicine. However, undesirable uptake and retention in the kidney limit their application. Specific in vitro methods are used to evaluate undesirable renal accumulation. Therefore, we investigated the usefulness [...] Read more.
The synthetic analogs of regulatory peptides radiolabeled with adequate radionuclides are perspective tools in nuclear medicine. However, undesirable uptake and retention in the kidney limit their application. Specific in vitro methods are used to evaluate undesirable renal accumulation. Therefore, we investigated the usefulness of freshly isolated rat renal cells for evaluating renal cellular uptake of receptor-specific peptide analogs. Special attention was given to megalin as this transport system is an important contributor to the active renal uptake of the peptides. Freshly isolated renal cells were obtained from native rat kidneys by the collagenase method. Compounds with known accumulation in renal cells were used to verify the viability of cellular transport systems. Megalin expressions in isolated rat renal cells were compared to two other potential renal cell models by Western blotting. Specific tubular cell markers were used to confirm the presence of proximal tubular cells expressing megalin in isolated rat renal cell preparations by immunohistochemistry. Colocalization experiments on isolated rat kidney cells confirmed the presence of proximal tubular cells bearing megalin in preparations. The applicability of the method was tested by an accumulation study with several analogs of somatostatin and gastrin labeled with indium-111 or lutetium-177. Therefore, isolated rat renal cells may be an effective screening tool for in vitro analyses of renal uptake and comparative renal accumulation studies of radiolabeled peptides or other radiolabeled compounds with potential nephrotoxicity. Full article
(This article belongs to the Special Issue Development of Radiolabeled Peptides)
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