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Targeted Alpha Therapy: Progress in Radionuclide Production, Radiochemistry, and Applications

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Targeted Alpha Therapy: Progress in Radionuclide Production, Radiochemistry, and Applications pharmaceutics Review Targeted Alpha Therapy: Progress in Radionuclide Production, Radiochemistry, and Applications Bryce J. B. Nelson 1, Jan D. Andersson 1,2 and Frank Wuest 1,* 1 Department of Oncology, University of Alberta, 11560 University Ave, Edmonton, AB T6G 1Z2, Canada; [email protected] (B.J.B.N.); [email protected] (J.D.A.) 2 Edmonton Radiopharmaceutical Center, Alberta Health Services, 11560 University Ave, Edmonton, AB T6G 1Z2, Canada * Correspondence: [email protected]; Tel.: +1-780-391-7666; Fax: +1-780-432-8483 Abstract: This review outlines the accomplishments and potential developments of targeted alpha (α) particle therapy (TAT). It discusses the therapeutic advantages of the short and highly ionizing path of α-particle emissions; the ability of TAT to complement and provide superior efficacy over existing forms of radiotherapy; the physical decay properties and radiochemistry of common α-emitters, including 225Ac, 213Bi, 224Ra, 212Pb, 227Th, 223Ra, 211At, and 149Tb; the production techniques and proper handling of α-emitters in a radiopharmacy; recent preclinical developments; ongoing and completed clinical trials; and an outlook on the future of TAT. Keywords: targeted alpha therapy; alpha particle therapy; targeted radionuclide therapy; theranos- tics; actinium-225; bismuth-213; astatine-211; radium-223; thorium-227; terbium-149 1. Introduction Radionuclide therapy has been employed frequently in the past several decades Citation: Nelson, B.J.B.; Andersson, for disease control, curative therapy, and pain management applications [1]. Targeted J.D.; Wuest, F. Targeted Alpha radionuclide therapy (TRT) is advantageous as it delivers a highly concentrated dose to a Therapy: Progress in Radionuclide tumor site—either directly to the tumor cells or to its microenvironment—while sparing Production, Radiochemistry, and the healthy surrounding tissues. It has been clinically demonstrated using a variety of Applications. Pharmaceutics 2021, 13, radionuclides to treat malignancies, including polycythemia, cystic craniopharyngioma, 49. https://doi.org/10.3390/ hyperthyroidism, synovitis and arthritis, and numerous cancers, such as thyroid cancer, pharmaceutics13010049 bone tumors and metastasis, hepatic metastasis, ovarian cancer, neuroendocrine tumors, Received: 2 December 2020 leukemia, lymphoma, and metastatic prostate cancer [2–4]. Since radionuclide therapy Accepted: 23 December 2020 targets diseases at the cellular level, it has advantages for treating systemic malignancies Published: 31 December 2020 such as tumor metastases over other forms of therapy such as external beam therapy, where full body irradiation is impossible. In addition to being minimally invasive, radionuclide Publisher’s Note: MDPI stays neu- therapy can be shorter in duration than chemotherapy [2]. − tral with regard to jurisdictional clai- In TRT, therapeutic radionuclides including alpha (α), beta (β ), and Auger electron ms in published maps and institutio- emitters are typically conjugated to a targeting vector such as monoclonal antibodies, nal affiliations. biomolecules, peptides, nanocarriers, and small-molecule inhibitors. To maximize the therapeutic efficacy of a TRT radiopharmaceutical, its radionuclide decay pathway, particle emission range, and relative biological effectiveness should be matched appropriately for a given tumor mass, size, radiosensitivity, and heterogeneity [1]. Copyright: © 2020 by the authors. Li- This review focuses on targeted alpha therapy (TAT), outlined by the graphical ab- censee MDPI, Basel, Switzerland. stract in Figure1. A detailed overview of α-emitting radionuclides currently employed This article is an open access article in radiotherapy is presented and compared to radionuclides with different emissions, distributed under the terms and con- including β− particle and auger electron emitters. Production techniques for α-emitters ditions of the Creative Commons At- tribution (CC BY) license (https:// are outlined, including their separation and unique handling requirements, followed by creativecommons.org/licenses/by/ their radiochemistry and targeting characteristics. Preclinical developments and clinical 4.0/). Pharmaceutics 2021, 13, 49. https://doi.org/10.3390/pharmaceutics13010049 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2021, 13, x FOR PEER REVIEW 2 of 28 radiochemistry and targeting characteristics. Preclinical developments and clinical appli- cations of α-emitters are discussed along with current limitations, potential areas for im- provement, and anticipated applications. Pharmaceutics 2021, 13, 49 2 of 26 applications of α-emitters are discussed along with current limitations, potential areas for improvement, and anticipated applications. (a) Radionuclide Production and Automated Processing (b) Radiolabeling (c) Targeted Alpha Radiotherapy Figure 1. Key aspects of targeted alpha therapy: (a) radionuclide production via cyclotron, nuclear reactor or generator decay, and shielded automated processing; (b) radiolabeling the alpha-emitting radionuclide to a suitable targeting vector to form a bioconjugate; andFigure (c) targeted1. Key aspects alpha radiotherapyof targeted alpha precisely therapy: destroys (a) radionuclide tumor cells while production sparing via surrounding cyclotron, nuclear healthy tissue. reactor or generator decay, and shielded automated processing; (b) radiolabeling the alpha-emit- ting radionuclide to a suitable targeting vector to form a bioconjugate; and (c) targeted alpha radi- otherapy2. Selecting precisely Radionuclides destroys tumor for Radiotherapycells while sparing surrounding healthy tissue. When selecting a radionuclide for clinical application, the physical and biochemical 2. characteristicsSelecting Radionuclides must be considered. for Radiotherapy Physical characteristics include physical half-life, typeWhen of emissions, selecting energya radionuclide of the emissions, for clinical daughter application, products, the methodphysical of and production, biochemical characteristicsand radionuclidic must purity.be considered. Biochemical Physical characteristics characteristics include include tissue targeting,physical half-life, retention type of ofemissions, radioactivity energy in the of the tumor, emissions,in vivo stability,daughter and products, toxicity method [2]. For of radiotherapy, production, it and is ra- dionuclidicdesirable to purity. have a highBiochemical linear energy characteristics transfer (LET), include where tissue there istargeting, a high ionization retention energy of radi- oactivitydeposited in the per tumor, unit length in vivo of travel. stability, Radionuclides and toxicity with [2]. aFor high radiotherapy, LET deposit it radioactive is desirable to emission energy within a small range of tissue, thereby sparing surrounding healthy tissue have a high linear energy transfer (LET), where there is a high ionization energy deposited and keeping the radioactive dose within, as much as possible, the patient’s organ to be pertreated. unit length It can alsoof travel. be advantageous Radionuclides for the with therapeutic a high LET radionuclide, deposit radioactive or a complementary emission en- ergytheranostic within a radionuclide,small range of to tissue, emit positrons thereby sparing (β+) or gammasurrounding (γ) radiation. healthy Thistissue enables and keep- ingpositron the radioactive emission dose tomography within, (PET)as much or singleas possible, photon the emission patient’s tomography organ to be (SPECT) treated. It imaging and visualization of radiopharmaceutical distribution within a patient’s body, permitting treatment monitoring. Table1 outlines key characteristics of α, β−, and auger electron emitters, and some clinical applications for cancer TRT that have been explored. Pharmaceutics 2021, 13, 49 3 of 26 Table 1. Key characteristics of α, β−, and auger electron emitters and their clinical applications. Radioactive Particle Decay Characteristics Clinical Cancer Applications Reference Metastatic castration resistant prostate cancer, Emission energy per decay: 50–2300 keV acute myeloid leukemia, neuroendocrine Beta particle(β−) Range: 0.05–12 mm tumors, acute lymphocytic leukemia, ovarian [1,3,4] Linear Energy Transfer (LET): 0.2 keV/µm carcinomas, gliomas, metastatic melanoma, colon cancer, bone metastases Advanced pancreatic cancer with resistant neoplastic meningitis, advanced sst-2 positive Emission energy per decay: 0.2–200 keV neuroendocrine and liver malignancies, Auger electron (AE) Range: 2–500 nm [1,5] metastatic epidermal growth factor receptor LET: 4–26 keV/µm (EGFR)-positive breast cancer, glioblastoma multiforme Metastatic castration resistant prostate cancer, relapsed or refractory CD-22-positive Emission energy per decay: 5–9 MeV non-Hodgkin lymphoma, acute myeloid Alpha particle (α) Range: 40–100 µm [1,3,4] leukemia, neuroendocrine tumors, ovarian LET: 80 keV/µm carcinoma, gliomas, intralesional and systemic melanoma, colon cancer, bone metastases β− emitting radioisotopes have a relatively long pathlength (≤12 mm) and a lower LET of ~0.2 keV/µm, giving them effectiveness in medium–large tumors [1]. However, they lack success in solid cancers with microscopic tumor burden. This may be attributed to their emissions releasing the majority of their energy along a several millimeter long electron track, irradiating the surrounding healthy tissue instead of depositing their main energy into the micro-metastatic tumor cells where the radionuclide was delivered [6]. Clinical success
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