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Radiopharmaceutical Chemistry and Radiotherapy
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Radiopharmaceutical Chemistry and Radiotherapy

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

Deadline for manuscript submissions: closed (15 April 2021) | Viewed by 31181

Special Issue Editor

Dr. Thaddeus J. Wadas

E-Mail Website
Guest Editor
Department of Radiology, University of Iowa, Iowa City, IA 52242, USA
Interests: radiotherapy; positron emission tomography; molecular imaging; zirconium-89; actinium-225; pancreatic cancer; prostate cancer; breast cancer; sarcoma; lung cancer

Special Issue Information

Dear Colleagues,

This Special Issue is related to recent developments in the field of radiopharmaceutical chemistry with a special emphasis on radiotherapy.

As part of their clinical care, physicians recommend radiation therapy as primary, neo-adjuvant, adjuvant, or palliative treatments to more than half of all cancer patients. Radiation therapy uses the intense energy associated with ionizing radiation to destroy cancerous cells. This radiation can be administered from an external source, through brachytherapy, or by using the systemic circulation to deliver therapeutic radiopharmaceuticals, which are designed to exploit dysregulated physiological processes and protein overexpression that cancer cells use to survive. Recently, several systemic radiotherapies have demonstrated efficacy in the clinic or in clinical trials; these successes have renewed interest in their development and integration into precision medicine strategies for cancer care. This Special Issue seeks to highlight the creative collaborations among researchers in the physical, biological, and health sciences that are conducting innovative preclinical or clinical radiotherapy research. All researchers working in the field are cordially invited to contribute original research papers or reviews to this Special Issue of Molecules.

Dr. Thaddeus J. Wadas
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. 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

  • Production and radiochemistry
  • Dosimetry
  • Auger therapy
  • Beta minus (β-) therapy
  • Alpha particle (α2+) therapy
  • Theranostic pairs
  • Image guided radiotherapy
  • Radiotherapy clinical trials
  • Regulatory aspects relating to radiotherapy
  • Radionuclide generators

Published Papers (7 papers)

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Research

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11 pages, 3011 KiB  
Article
TiO2 Decorated Low-Molecular Chitosan a Microsized Adsorbent for a 68Ge/68Ga Generator System
by Jun-Young Lee, Pyeong-Seok Choi, Seung-Dae Yang and Jeong-Hoon Park
Molecules 2021, 26(11), 3185; https://doi.org/10.3390/molecules26113185 - 26 May 2021
Cited by 1 | Viewed by 2288
Abstract
We report column material for a 68Ge/68Ga generator with acid resistance and excellent adsorption and desorption capacity of 68Ge and 68Ga, respectively. Despite being a core element of the 68Ge/68Ga generator system, research on this [...] Read more.
We report column material for a 68Ge/68Ga generator with acid resistance and excellent adsorption and desorption capacity of 68Ge and 68Ga, respectively. Despite being a core element of the 68Ge/68Ga generator system, research on this has been insufficient. Therefore, we synthesized a low molecular chitosan-based TiO2 (LC-TiO2) adsorbent via a physical trapping method as a durable 68Ge/68Ga generator column material. The adsorption/desorption studies exhibited a higher separation factor of 68Ge/68Ga in the concentration range of HCl examined (0.01 M to 1.0 M). The prepared LC-TiO2 adsorbent showed acid resistance capabilities with >93% of 68Ga elution yield and 1.6 × 10−4% of 68Ge breakthrough. In particular, the labeling efficiency of DOTA and NOTA, by using the generator eluted 68Ga, was quite encouraging and confirmed to be 99.65 and 99.69%, respectively. Accordingly, the resulting behavior of LC-TiO2 towards 68Ge/68Ga adsorption/desorption capacity and stability with aqueous HCl exhibited a high potential for ion-exchange solid-phase extraction for the 68Ge/68Ga generator column material. Full article
(This article belongs to the Special Issue Radiopharmaceutical Chemistry and Radiotherapy)
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15 pages, 4238 KiB  
Article
Imaging of Fibroblast Activation Protein Alpha Expression in a Preclinical Mouse Model of Glioma Using Positron Emission Tomography
by Darpan N. Pandya, Akesh Sinha, Hong Yuan, Lysette Mutkus, Kristina Stumpf, Frank C. Marini and Thaddeus J. Wadas
Molecules 2020, 25(16), 3672; https://doi.org/10.3390/molecules25163672 - 12 Aug 2020
Cited by 20 | Viewed by 3861
Abstract
Glioblastoma multiforme (GBM) is the most aggressive glioma of the primary central nervous system. Due to the lack of effective treatment options, the prognosis for patients remains bleak. Fibroblast activation protein alpha (FAP), a 170 kDa type II transmembrane serine protease was observed [...] Read more.
Glioblastoma multiforme (GBM) is the most aggressive glioma of the primary central nervous system. Due to the lack of effective treatment options, the prognosis for patients remains bleak. Fibroblast activation protein alpha (FAP), a 170 kDa type II transmembrane serine protease was observed to be expressed on glioma cells and within the glioma tumor microenvironment. To understand the utility of targeting FAP in this tumor type, the immuno-PET radiopharmaceutical [89Zr]Zr-Df-Bz-F19 mAb was prepared and Lindmo analysis was used for its in vitro evaluation using the U87MG cell line, which expresses FAP endogenously. Lindmo analysis revealed an association constant (Ka) of 10−8 M−1 and an immunoreactivity of 52%. Biodistribution studies in U87MG tumor-bearing mice revealed increasing radiotracer retention in tumors over time, leading to average tumor-to-muscle ratios of 3.1, 7.3, 7.2, and 8.3 at 2, 24, 48 and 72 h, respectively. Small animal PET corroborated the biodistribution studies; tumor-to-muscle ratios at 2, 24, 48, and 72 h were 2.0, 5.0, 6.1 and 7.8, respectively. Autoradiography demonstrated accumulated activity throughout the interior of FAP+ tumors, while sequential tumor sections stained positively for FAP expression. Conversely, FAP− tissues retained minimal radioactivity and were negative for FAP expression by immunohistochemistry. These results demonstrate FAP as a promising biomarker that may be exploited to diagnose and potentially treat GBM and other neuroepithelial cancers. Full article
(This article belongs to the Special Issue Radiopharmaceutical Chemistry and Radiotherapy)
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13 pages, 4183 KiB  
Article
Tumor Targeting Effect of Triphenylphosphonium Cations and Folic Acid Coated with Zr-89-Labeled Silica Nanoparticles
by Gun Gyun Kim, Jun Young Lee, Pyeong Seok Choi, Sang Wook Kim and Jeong Hoon Park
Molecules 2020, 25(12), 2922; https://doi.org/10.3390/molecules25122922 - 25 Jun 2020
Cited by 10 | Viewed by 2516
Abstract
In this study, we investigated the tumor targeting effect in cancer cells using triphenylphosphonium (TPP) cations, which are accumulated by differences in membrane potential, and folic acid (FA), which is selectively bound to overexpressed receptors on various cancer cells. We used Food and [...] Read more.
In this study, we investigated the tumor targeting effect in cancer cells using triphenylphosphonium (TPP) cations, which are accumulated by differences in membrane potential, and folic acid (FA), which is selectively bound to overexpressed receptors on various cancer cells. We used Food and Drug Administration (FDA)-approved silica nanoparticles (SNPs) as drug carriers, and SNPs conjugated with TPP and FA (STFs) samples were prepared by introducing different amounts of TPP and FA onto the nanoparticle surfaces. STF-1, 2, 3, 4 and 5 are named according to the combination ratio of TPP and FA on the particle surface. To confirm the tumor targeting effect, 89Zr (t1/2 = 3.3 days) was coordinated directly to the silanol group of SNP surfaces without chelators. It was shown that the radiochemical yield was 69% and radiochemical purity was >99%. In the cellular uptake evaluation, SNPs with the most TPP (SFT-5) and FA (SFT-1) attached indicated similar uptake tendencies for mouse colon cancer cells (CT-26). However, the results of the cell internalization assay and measurement of positron emission tomography (PET) images showed that SFT-5 had more affinity for the CT-26 tumor than other samples the TPP ratio of which was lower. Consequently, we confirmed that TPP ligands affect target cancer cells more than FA, which means that cell membrane potential is significantly effective for tumor targeting. Full article
(This article belongs to the Special Issue Radiopharmaceutical Chemistry and Radiotherapy)
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Graphical abstract

13 pages, 787 KiB  
Article
Observations on the Effects of Residualization and Dehalogenation on the Utility of N-Succinimidyl Ester Acylation Agents for Radioiodination of the Internalizing Antibody Trastuzumab
by Satish K. Chitneni, Eftychia Koumarianou, Ganesan Vaidyanathan and Michael R. Zalutsky
Molecules 2019, 24(21), 3907; https://doi.org/10.3390/molecules24213907 - 30 Oct 2019
Cited by 7 | Viewed by 2807
Abstract
Trastuzumab is an antibody used for the treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancers. Since trastuzumab is an internalizing antibody, two factors could play an important role in achieving high uptake and prolonged retention of radioactivity in HER2-positive tumors [...] Read more.
Trastuzumab is an antibody used for the treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancers. Since trastuzumab is an internalizing antibody, two factors could play an important role in achieving high uptake and prolonged retention of radioactivity in HER2-positive tumors after radioiodination—residualizing capacity after receptor-mediated internalization and susceptibility to dehalogenation. To evaluate the contribution of these two factors, trastuzumab was radiolabeled using the residualizing reagent N-succinimidyl 4-guanidinomethyl-3-[*I]iodobenzoate ([*I]SGMIB) and the nonresidualizing reagent N-succinimidyl-3-[*I]iodobenzoate ([*I]SIB), both of which are highly dehalogenation-resistant. Paired-label uptake and intracellular retention of [125I]SGMIB-trastuzumab and [131I]SIB-trastuzumab was compared on HER2-expressing BT474 human breast carcinoma cells. Tumor uptake and normal tissue distribution characteristics for the two labeled conjugates were assessed in mice bearing BT474M1 xenografts. The internalization and intracellular retention of initially-bound radioactivity in BT474 cells was similar for the two labeled conjugates up to 4 h, but were significantly higher for [125I]SGMIB-trastuzumab at 6 and 24 h. Similarly, [*I]SGMIB labeling resulted in significantly higher uptake and retention of radioactivity in BT474M1 xenografts at all studied time points. Moreover, tumor-to-tissue ratios for [125I]SGMIB-trastuzumab were consistently higher than those for [131I]SIB-trastuzumab starting at 12 h postinjection. Thus, optimal targeting of HER2-positive breast cancers with a radioiodinated trastuzumab conjugate requires an acylation agent that imparts residualizing capacity in addition to high stability towards dehalogenation in vivo. Full article
(This article belongs to the Special Issue Radiopharmaceutical Chemistry and Radiotherapy)
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15 pages, 3678 KiB  
Article
A Monte Carlo Method for Determining the Response Relationship between Two Commonly Used Detectors to Indirectly Measure Alpha Particle Radiation Activity
by Christopher J. Tichacek, Mikalai M. Budzevich, Thaddeus J. Wadas, David L. Morse and Eduardo G. Moros
Molecules 2019, 24(18), 3397; https://doi.org/10.3390/molecules24183397 - 19 Sep 2019
Cited by 10 | Viewed by 3907
Abstract
Using targeted ligands to deliver alpha-emitting radionuclides directly to tumor cells has become a promising therapeutic strategy. To calculate the radiation dose to patients, activities of parent and daughter radionuclides must be measured. Scintillation detectors can be used to quantify these activities; however, [...] Read more.
Using targeted ligands to deliver alpha-emitting radionuclides directly to tumor cells has become a promising therapeutic strategy. To calculate the radiation dose to patients, activities of parent and daughter radionuclides must be measured. Scintillation detectors can be used to quantify these activities; however, activities found in pre-clinical and clinical studies can exceed their optimal performance range. Therefore, a method of correcting scintillation detector measurements at higher activities was developed using Monte Carlo modeling. Because there are currently no National Institute of Standards and Technology traceable Actinium-225 (225Ac) standards available, a well-type ionization chamber was used to measure 70.3 ± 7.0, 144.3 ± 14.4, 222.0 ± 22.2, 299.7 ± 30.0, 370.0 ± 37.0, and 447.7 ± 44.7 kBq samples of 225Ac obtained from Oak Ridge National Lab. Samples were then placed in a well-type NaI(Tl) scintillation detector and spectra were obtained. Alpha particle activity for each species was calculated using gamma abundance per alpha decay. MCNP6 Monte Carlo software was used to simulate the 4π-geometry of the NaI(Tl) detector. Using the ionization chamber reading as activity input to the Monte Carlo model, spectra were obtained and compared to NaI(Tl) spectra. Successive simulations of different activities were run until a spectrum minimizing the mean percent difference between the two was identified. This was repeated for each sample activity. Ionization chamber calibration measurements showed increase in error from 3% to 10% as activities decreased, resulting from decreasing detection efficiency. Measurements of 225Ac using both detector types agreed within 7% of Oak Ridge stated activities. Simulated Monte Carlo spectra of 225Ac were successfully generated. Activities obtained from these spectra differed with ionization chamber readings up to 156% at 147.7 kBq. Simulated spectra were then adjusted to correct NaI(Tl) measurements to be within 1%. These were compared to ionization chamber readings and a response relationship was determined between the two instruments. Measurements of 225Ac and daughter activity were conducted using a NaI(Tl) scintillation detector calibrated for energy and efficiency and an ionization chamber calibrated for efficiency using a surrogate calibration reference. Corrections provided by Monte Carlo modeling improve the accuracy of activity quantification for alpha-particle emitting radiopharmaceuticals in pre-clinical and clinical studies. Full article
(This article belongs to the Special Issue Radiopharmaceutical Chemistry and Radiotherapy)
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Review

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18 pages, 1219 KiB  
Review
Progress in Targeted Alpha-Particle-Emitting Radiopharmaceuticals as Treatments for Prostate Cancer Patients with Bone Metastases
by Chirayu M. Patel, Thaddeus J. Wadas and Yusuke Shiozawa
Molecules 2021, 26(8), 2162; https://doi.org/10.3390/molecules26082162 - 09 Apr 2021
Cited by 2 | Viewed by 3431
Abstract
Bone metastasis remains a major cause of death in cancer patients, and current therapies for bone metastatic disease are mainly palliative. Bone metastases arise after cancer cells have colonized the bone and co-opted the normal bone remodeling process. In addition to bone-targeted therapies [...] Read more.
Bone metastasis remains a major cause of death in cancer patients, and current therapies for bone metastatic disease are mainly palliative. Bone metastases arise after cancer cells have colonized the bone and co-opted the normal bone remodeling process. In addition to bone-targeted therapies (e.g., bisphosphonate and denosumab), hormone therapy, chemotherapy, external beam radiation therapy, and surgical intervention, attempts have been made to use systemic radiotherapy as a means of delivering cytocidal radiation to every bone metastatic lesion. Initially, several bone-seeking beta-minus-particle-emitting radiopharmaceuticals were incorporated into the treatment for bone metastases, but they failed to extend the overall survival in patients. However, recent clinical trials indicate that radium-223 dichloride (223RaCl2), an alpha-particle-emitting radiopharmaceutical, improves the overall survival of prostate cancer patients with bone metastases. This success has renewed interest in targeted alpha-particle therapy development for visceral and bone metastasis. This review will discuss (i) the biology of bone metastasis, especially focusing on the vicious cycle of bone metastasis, (ii) how bone remodeling has been exploited to administer systemic radiotherapies, and (iii) targeted radiotherapy development and progress in the development of targeted alpha-particle therapy for the treatment of prostate cancer bone metastasis. Full article
(This article belongs to the Special Issue Radiopharmaceutical Chemistry and Radiotherapy)
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48 pages, 2017 KiB  
Review
Development of Targeted Alpha Particle Therapy for Solid Tumors
by Narges K. Tafreshi, Michael L. Doligalski, Christopher J. Tichacek, Darpan N. Pandya, Mikalai M. Budzevich, Ghassan El-Haddad, Nikhil I. Khushalani, Eduardo G. Moros, Mark L. McLaughlin, Thaddeus J. Wadas and David L. Morse
Molecules 2019, 24(23), 4314; https://doi.org/10.3390/molecules24234314 - 26 Nov 2019
Cited by 74 | Viewed by 11724
Abstract
Targeted alpha-particle therapy (TAT) aims to selectively deliver radionuclides emitting α-particles (cytotoxic payload) to tumors by chelation to monoclonal antibodies, peptides or small molecules that recognize tumor-associated antigens or cell-surface receptors. Because of the high linear energy transfer (LET) and short range of [...] Read more.
Targeted alpha-particle therapy (TAT) aims to selectively deliver radionuclides emitting α-particles (cytotoxic payload) to tumors by chelation to monoclonal antibodies, peptides or small molecules that recognize tumor-associated antigens or cell-surface receptors. Because of the high linear energy transfer (LET) and short range of alpha (α) particles in tissue, cancer cells can be significantly damaged while causing minimal toxicity to surrounding healthy cells. Recent clinical studies have demonstrated the remarkable efficacy of TAT in the treatment of metastatic, castration-resistant prostate cancer. In this comprehensive review, we discuss the current consensus regarding the properties of the α-particle-emitting radionuclides that are potentially relevant for use in the clinic; the TAT-mediated mechanisms responsible for cell death; the different classes of targeting moieties and radiometal chelators available for TAT development; current approaches to calculating radiation dosimetry for TATs; and lead optimization via medicinal chemistry to improve the TAT radiopharmaceutical properties. We have also summarized the use of TATs in pre-clinical and clinical studies to date. Full article
(This article belongs to the Special Issue Radiopharmaceutical Chemistry and Radiotherapy)
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