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Targeted Radionuclide Therapy: Theranostic Applications and Advances in Personalized Therapy

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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 November 2022) | Viewed by 19620

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Special Issue Editors

Dr. Carolina de Aguiar Ferreira

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Guest Editor

Department of Medical Physics, University of Wisconsin-Madison, Madison, WI 53705, USA
Interests: targeted radionuclide therapy; molecular imaging; theranostics; radiotherapy; cancer therapy
Special Issues, Collections and Topics in MDPI journals

Dr. Leonardo Lima Fuscaldi

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Guest Editor

Department of Physiological Sciences, Santa Casa de Sao Paulo School of Medical Sciences, Sao Paulo, SP 01221-020, Brazil
Interests: molecular imaging; radiopharmaceuticals; radiolabeled peptides; radiotheranostic agents; targeted radionuclide therapy

Special Issue Information

Dear Colleagues,

Targeted radionuclide therapy (TRT) is a radiation therapy modality consisting of systemic delivery of radioactive atoms to induce DNA damage in tumor cells. TRT agents target specific receptors or molecular cues overexpressed in tumor cells or the microenvironment. Recent developments in understanding of radionuclide chemistry and physical characteristics of radionuclides, as well as biological insights on appropriate and specific molecular targets, have promoted increased use of TRT, especially within a theranostic approach. Herein, we aim at highlighting the most recent applications of targeted radionuclide therapy through the use of different ligands and tumor targeting agents, in combination with diagnostic approaches or other cancer therapies for personalized cancer treatment.

Dr. Carolina de Aguiar Ferreira
Dr. Leonardo Lima Fuscaldi
Guest Editors

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Keywords

theranostics
targeted radionuclide therapy
TRT
molecular imaging
cancer therapy
radiotherapy
personalized medicine

Published Papers (7 papers)

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Research

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17 pages, 2504 KiB

Open AccessArticle

Preclinical Evaluation of a Lead Specific Chelator (PSC) Conjugated to Radiopeptides for ²⁰³Pb and ²¹²Pb-Based Theranostics

by Mengshi Li, Nicholas J. Baumhover, Dijie Liu, Brianna S. Cagle, Frédéric Boschetti, Guillaume Paulin, Dongyoul Lee, Zhiming Dai, Ephraim R. Obot, Brenna M. Marks, Ibrahim Okeil, Edwin A. Sagastume, Moustafa Gabr, F. Christopher Pigge, Frances L. Johnson and Michael K. Schultz

Pharmaceutics 2023, 15(2), 414; https://doi.org/10.3390/pharmaceutics15020414 - 26 Jan 2023

Cited by 9 | Viewed by 3098

Abstract

²⁰³Pb and ²¹²Pb have emerged as promising theranostic isotopes for image-guided α-particle radionuclide therapy for cancers. Here, we report a cyclen-based Pb specific chelator (PSC) that is conjugated to tyr³-octreotide via a PEG₂ linker (PSC-PEG-T) targeting somatostatin receptor subtype 2 (SSTR2). PSC-PEG-T could be labeled efficiently to purified ²¹²Pb at 25 °C and also to ²¹²Bi at 80 °C. Efficient radiolabeling of mixed ²¹²Pb and ²¹²Bi in PSC-PEG-T was also observed at 80 °C. Post radiolabeling, stable Pb(II) and Bi(III) radiometal complexes in saline were observed after incubating [²⁰³Pb]Pb-PSC-PEG-T for 72 h and [²¹²Bi]Bi-PSC-PEG-T for 5 h. Stable [²¹²Pb]Pb-PSC-PEG-T and progeny [²¹²Bi]Bi-PSC-PEG-T were identified after storage in saline for 24 h. In serum, stable radiometal/radiopeptide were observed after incubating [²⁰³Pb]Pb-PSC-PEG-T for 55 h and [²¹²Pb]Pb-PSC-PEG-T for 24 h. In vivo biodistribution of [²¹²Pb]Pb-PSC-PEG-T in tumor-free CD-1 Elite mice and athymic mice bearing AR42J xenografts revealed rapid tumor accumulation, excellent tumor retention and fast renal clearance of both ²¹²Pb and ²¹²Bi, with no in vivo redistribution of progeny ²¹²Bi. Single-photon emission computed tomography (SPECT) imaging of [²⁰³Pb]Pb-PSC-PEG-T and [²¹²Pb]Pb-PSC-PEG-T in mice also demonstrated comparable accumulation in AR42J xenografts and renal clearance, confirming the theranostic potential of the elementally identical ²⁰³Pb/²¹²Pb radionuclide pair. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy: Theranostic Applications and Advances in Personalized Therapy)

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12 pages, 1673 KiB

Open AccessArticle

Effect of Polar Head Group Modifications on the Tumor Retention of Phospholipid Ether Analogs: Role of the Quaternary Nitrogen

by Anatoly N. Pinchuk, Mark A. Rampy, Marc A. Longino, Ben Y. Durkee, Raymond E. Counsell and Jamey P. Weichert

Pharmaceutics 2023, 15(1), 171; https://doi.org/10.3390/pharmaceutics15010171 - 3 Jan 2023

Cited by 1 | Viewed by 1382

Abstract

We have previously described the remarkable capacity of radioiodinated alkyl phospholipids to be sequestered and retained by a variety of tumors in vivo. We have already established the influence of certain structural parameters of iodinated alkyl phospholipids on tumor avidity, such as stereochemistry at the sn-2 carbon of alkylglycerol phosphocholines, meta-or para-position of iodine in the aromatic ring of phenylalkyl phosphocholines, and the length of the alkyl chain in alkyl phospholipids. In order to determine the additional structural requirements for tumor uptake and retention, three new radioiodinated alkylphospholipid analogs, 2–4, were synthesized as potential tumor imaging agents. Polar head groups were modified to determine structure-tumor avidity relationships. The trimethylammonio group in 1 was substituted with a hydrogen atom in 2, an ammonio group in 3 and a tertiary butyl group in 4. All analogs were separately labeled with iodine-125 or iodine-124 and administered to Walker 256 tumor-bearing rats or human PC-3 tumor-bearing SCID mice, respectively. Tumor uptake was assessed by gamma-camera scintigraphy (for [I-125]-labeled compounds) and high-resolution micro-PET scanning (for [I-124]-labeled compounds). It was found that structural modifications in the polar head group of alkyl phospholipids strongly influenced the tumor uptake and tissue distribution of these compounds in tumor-bearing animals. Phosphoethanolamine analog 3 (NM401) displayed a very slight accumulation in tumor as compared with phosphocholine analog 1 (NM346). Analogs 2 (NM400) and 4 (NM402) lacking the positively charged nitrogen atom failed to display any tumor uptake and localized primarily in the liver. This study provided important insights regarding structural requirements for tumor uptake and retention. Replacement of the quaternary nitrogen in the alkyl phospholipid head group with non-polar substituents resulted in loss of tumor avidity. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy: Theranostic Applications and Advances in Personalized Therapy)

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12 pages, 3142 KiB

Open AccessArticle

Immune Checkpoint Inhibitor-Mediated Cancer Theranostics with Radiolabeled Anti-Granzyme B Peptide

by Carolina de Aguiar Ferreira, Pedram Heidari, Bahar Ataeinia, Nicoleta Sinevici, Alyssa Granito, Hritik Mahajan Kumar, Eric Wehrenberg-Klee and Umar Mahmood

Pharmaceutics 2022, 14(7), 1460; https://doi.org/10.3390/pharmaceutics14071460 - 13 Jul 2022

Cited by 3 | Viewed by 2501

Abstract

Although immune checkpoint inhibitors (ICI) have revolutionized cancer management, patient response can be heterogeneous, and the development of ICI resistance is increasingly reported. Novel treatment strategies are necessary not only to expand the use of ICI to previously unresponsive tumor types but also to overcome resistance. Targeted radionuclide therapy may synergize well with ICIs since it can promote a pro-inflammatory tumor microenvironment. We investigated the use of a granzyme B targeted peptide (GZP) as a cancer theranostic agent, radiolabeled with ⁶⁸Ga (⁶⁸Ga-GZP) as a PET imaging agent and radiolabeled with ⁹⁰Y (⁹⁰Y-GZP) as a targeted radionuclide therapy agent for combinational therapy with ICI in murine models of colon cancer. Our results demonstrate that GZP increasingly accumulates in tumor tissue after ICI and that the combination of ICI with ⁹⁰Y-GZP promotes a dose-dependent response, achieving curative response in some settings and increased overall survival. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy: Theranostic Applications and Advances in Personalized Therapy)

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Review

Jump to: Research

16 pages, 3776 KiB

Open AccessReview

Intra-Arterial Delivery of Radiopharmaceuticals in Oncology: Current Trends and the Future of Alpha-Particle Therapeutics

by Nathan Kauffman, James Morrison, Kevin O’Brien, Jinda Fan and Kurt R. Zinn

Pharmaceutics 2023, 15(4), 1138; https://doi.org/10.3390/pharmaceutics15041138 - 4 Apr 2023

Cited by 5 | Viewed by 2411

Abstract

A paradigm shift is underway in cancer diagnosis and therapy using radioactivity-based agents called radiopharmaceuticals. In the new strategy, diagnostic imaging measures the tumor uptake of radioactive agent “X” in a patient’s specific cancer, and if uptake metrics are realized, the patient can be selected for therapy with radioactive agent “Y”. The X and Y represent different radioisotopes that are optimized for each application. X–Y pairs are known as radiotheranostics, with the currently approved route of therapy being intravenous administration. The field is now evaluating the potential of intra-arterial dosing of radiotheranostics. In this manner, a higher initial concentration can be achieved at the cancer site, which could potentially enhance tumor-to-background targeting and lead to improved imaging and therapy. Numerous clinical trials are underway to evaluate these new therapeutic approaches that can be performed via interventional radiology. Of further interest is changing the therapeutic radioisotope that provides radiation therapy by β- emission to radioisotopes that also decay by α-particle emissions. Alpha (α)-particle emissions provide high energy transfer to the tumors and have distinct advantages. This review discusses the current landscape of intra-arterially delivered radiopharmaceuticals and the future of α-particle therapy with short-lived radioisotopes. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy: Theranostic Applications and Advances in Personalized Therapy)

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24 pages, 520 KiB

Open AccessReview

Lutathera^® Orphans: State of the Art and Future Application of Radioligand Therapy with ¹⁷⁷Lu-DOTATATE

by Luca Urso, Alberto Nieri, Licia Uccelli, Angelo Castello, Paolo Artioli, Corrado Cittanti, Maria Cristina Marzola, Luigia Florimonte, Massimo Castellani, Sergio Bissoli, Francesca Porto, Alessandra Boschi, Laura Evangelista and Mirco Bartolomei

Pharmaceutics 2023, 15(4), 1110; https://doi.org/10.3390/pharmaceutics15041110 - 31 Mar 2023

Cited by 8 | Viewed by 2857

Abstract

Lutathera^® is the first EMA- and FDA-approved radiopharmaceutical for radioligand therapy (RLT). Currently, on the legacy of the NETTER1 trial, only adult patients with progressive unresectable somatostatin receptor (SSTR) positive gastroenteropancreatic (GEP) neuroendocrine neoplasms (NET) can be treated with Lutathera^®. Conversely, patients with SSTR-positive disease arising from outside the gastroenteric region do not currently have access to Lutathera^® treatment despite several papers in the literature reporting the effectiveness and safety of RLT in these settings. Moreover, patients with well-differentiated G3 GEP-NET are also still “Lutathera orphans”, and retreatment with RLT in patients with disease relapse is currently not approved. The aim of this critical review is to summarize current literature evidence assessing the role of Lutathera^® outside the approved indications. Moreover, ongoing clinical trials evaluating new possible applications of Lutathera^® will be considered and discussed to provide an updated picture of future investigations. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy: Theranostic Applications and Advances in Personalized Therapy)

20 pages, 358 KiB

Open AccessReview

Targeted Radiation and Immune Therapies—Advances and Opportunities for the Treatment of Prostate Cancer

by Anusha Muralidhar, Hemanth K. Potluri, Tanya Jaiswal and Douglas G. McNeel

Pharmaceutics 2023, 15(1), 252; https://doi.org/10.3390/pharmaceutics15010252 - 11 Jan 2023

Cited by 4 | Viewed by 2425

Abstract

Prostate cancer is the most diagnosed malignancy in men in the United States and the second leading cause of cancer-related death. For localized disease, radiation therapy is a standard treatment that is often curative. For metastatic disease, radiation therapy has been primarily used for palliation, however, several newer systemic radiation therapies have been demonstrated to significantly improve patient outcomes and improve survival. In particular, several targeted radionuclide therapies have been approved for the treatment of advanced-stage cancer, including strontium-89, samarium-153, and radium-223 for bone-metastatic disease, and lutetium-177-labeled PSMA-617 for patients with prostate-specific membrane antigen (PSMA)-expressing metastatic castration-resistant prostate cancer (mCRPC). Contrarily, immune-based treatments have generally demonstrated little activity in advanced prostate cancer, with the exception of the autologous cellular vaccine, sipuleucel-T. This has been attributed to the presence of an immune-suppressive prostate cancer microenvironment. The ability of radiation therapy to not only eradicate tumor cells but also potentially other immune-regulatory cells within the tumor immune microenvironment suggests that targeted radionuclide therapies may be well poised to combine with immune-targeted therapies to eliminate prostate cancer metastases more effectively. This review provides an overview of the recent advances of targeted radiation agents currently approved for prostate cancer, and those being investigated in combination with immunotherapy, and discusses the challenges as well as the opportunities in this field. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy: Theranostic Applications and Advances in Personalized Therapy)

15 pages, 1108 KiB

Open AccessEditor’s ChoiceReview

Developments in Combining Targeted Radionuclide Therapies and Immunotherapies for Cancer Treatment

by Caroline P. Kerr, Joseph J. Grudzinski, Thanh Phuong Nguyen, Reinier Hernandez, Jamey P. Weichert and Zachary S. Morris

Pharmaceutics 2023, 15(1), 128; https://doi.org/10.3390/pharmaceutics15010128 - 30 Dec 2022

Cited by 9 | Viewed by 3917

Abstract

Targeted radionuclide therapy (TRT) and immunotherapy are rapidly growing classes of cancer treatments. Basic, translational, and clinical research are now investigating therapeutic combinations of these agents. In comparison to external beam radiation therapy (EBRT), TRT has the unique advantage of treating all disease sites following intravenous injection and selective tumor uptake and retention—a particularly beneficial property in metastatic disease settings. The therapeutic value of combining radiation therapy with immune checkpoint blockade to treat metastases has been demonstrated in preclinical studies, whereas results of clinical studies have been mixed. Several clinical trials combining TRT and immune checkpoint blockade have been initiated based on preclinical studies combining these with EBRT and/or TRT. Despite the interest in translation of TRT and immunotherapy combinations, many questions remain surrounding the mechanisms of interaction and the optimal approach to clinical implementation of these combinations. This review highlights the mechanisms of interaction between anti-tumor immunity and radiation therapy and the status of basic and translational research and clinical trials investigating combinations of TRT and immunotherapies. Full article

(This article belongs to the Special Issue Targeted Radionuclide Therapy: Theranostic Applications and Advances in Personalized Therapy)

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