Towards Targeted Alpha Therapy with Actinium-225: Chelators for Mild Condition Radiolabeling and Targeting PSMA—A Proof of Concept Study

Currently, targeted alpha therapy is one of the most investigated topics in radiopharmaceutical cancer management. Especially, the alpha emitter 225Ac has excellent nuclear properties and is gaining increasing popularity for the treatment of various tumor entities. We herein report on the synthesis of two universal 225Ac-chelators for mild condition radiolabeling and binding to conjugate molecules of pharmacological interest via the copper-mediated click chemistry. A convenient radiolabeling procedure was investigated as well as the complex stability proved for both chelators and two PSMA (prostate-specific membrane antigen)-targeting model radioconjugates. Studies regarding affinity and cell survival were performed on LNCaP cells followed by biodistribution studies, which were performed using LNCaP tumor-bearing mice. High efficiency radiolabeling for all conjugates was demonstrated. Cell binding studies revealed a fourfold lower cell affinity for the PSMA radioconjugate with one targeting motif compared to the radioconjugate owing two targeting motifs. Additionally, these differences were verified by in vitro cell survival evaluation and biodistribution studies, both showing a higher cell killing efficiency for the same dose, a higher tumor uptake (15%ID/g) and a rapid whole body clearance after 24 h. The synthesized chelators will overcome obstacles of lacking stability and worse labeling needs regarding 225Ac complexation using the DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid) chelator. Moreover, the universal functionalization expands the coverage of these chelators in combination with any sensitive bio(macro)molecule, thus improving treatment of any addressable tumor target.

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Targeted Alpha Therapy Trial in Bangladesh: Promise for Advanced MUC1 – Expressing Tumors

Bangladesh Journal of Nuclear Medicine ◽

10.3329/bjnm.v19i1.35580 ◽

2018 ◽

Vol 19 (1) ◽

pp. 43-50

Author(s):

Lutfun Nisa ◽

Kamila Afroj Quadir ◽

Shamim MF Begum ◽

Raihan Hussain ◽

Mizanul Hasan

Keyword(s):

Clinical Trial ◽

Monoclonal Antibody ◽

Cancer Cells ◽

Advanced Technology ◽

Current Status ◽

Targeted Alpha Therapy ◽

Cancer Management ◽

Tolerance Dose ◽

Maximum Tolerance ◽

Alpha Therapy

Introduction: Targeted alpha therapy (TAT) is a new experimental therapy that targets cancer cells and tumor capillary endothelial cells through intravenous injection of an alpha immuneconjugate (AIC). The AIC is formed by labeling the cancer targeting vector (monoclonal antibody) with alpha emitting radioisotopes using a bifunctionalchelator. The monoclonal antibody (MAb) is raised against antigens (e.g. MUC1) over-expressed on the surface of certain cancer cells. There are several centers notably in Europe, the US and Australia that are actively involved in TAT clinical trials of different cancers using a variety of techniques, alpha emitters and MAbs. Observations from their cumulative experience suggest that TAT is safe and effectivebut needs further trials for practical acceptance. Especially critical is the issue of maximum tolerance dose (MTD) which needs to be established for maximum target kill. Bangladesh has the infrastructure to conduct aTAT clinical trial and can significantly add to the growing pool of data for advanced treatment of cancers through collaborative involvement in targeted alpha therapy research.Objective: The aim of the article is to present a general overview of targeted alpha therapy and to discuss the feasibility of a TAT clinical trial in Bangladesh in the context of current cancer management situation in the country.Method: Literature review of significant publications was done to obtain an update of the current status of targeted alpha therapy. Relevant issues of TAT are presented for a theoretical basis of the technology. Next, the methodology of a proposed clinical trial is discussed, together with the practicability of its introduction in Bangladesh.Conclusion: Implementation of TAT clinical trial will help to develop an advanced technology and build- up skilled manpower in Bangladesh.It will optimize the key parameters of targeted alpha therapy, i e stability and specific activity of the alpha-conjugate and establish the maximum tolerance dose for the AIC. If the clinical trial is successful, it can change the prognosis of many end-stage cancers. Patients in Bangladesh with advanced MUCI expressing tumors of the breast, ovary, pancreas and prostate can have some measure of hope with stability of the disease.Bangladesh J. Nuclear Med. 19(1): 43-50, January 2016

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Evaluation of Aminopolycarboxylate Chelators for Whole-Body Clearance of Free 225Ac: A Feasibility Study to Reduce Unexpected Radiation Exposure during Targeted Alpha Therapy

Pharmaceutics ◽

10.3390/pharmaceutics13101706 ◽

2021 ◽

Vol 13 (10) ◽

pp. 1706

Author(s):

Mitsuyoshi Yoshimoto ◽

Yukie Yoshii ◽

Hiroki Matsumoto ◽

Mitsuhiro Shinada ◽

Masashi Takahashi ◽

...

Keyword(s):

Radiation Exposure ◽

Feasibility Study ◽

The Body ◽

Whole Body ◽

Targeted Alpha Therapy ◽

Carboxylic Groups ◽

Alpha Therapy ◽

Body Clearance

Actinium-225 (225Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although 225Ac labeling of bifunctional chelating ligands is effective, previous in vivo studies reported that free 225Ac can be released from the drugs and that such free 225Ac is predominantly accumulated in the liver and could cause unexpected toxicity. To accelerate the clinical development of 225Ac TAT with a variety of drugs, preparing methods to deal with any unexpected toxicity would be valuable. The aim of this study was to evaluate the feasibility of various chelators for reducing and excreting free 225Ac and compare their chemical structures. Nine candidate chelators (D-penicillamine, dimercaprol, Ca-DTPA, Ca-EDTA, CyDTA, GEDTA TTHA, Ca-TTHA, and DO3A) were evaluated in vitro and in vivo. The biodistribution and dosimetry of free 225Ac were examined in mice before an in vivo chelating study. The liver exhibited pronounced 225Ac uptake, with an estimated human absorbed dose of 4.76 SvRBE5/MBq. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, significantly reduced 225Ac retention in the liver (22% and 30%, respectively). Significant 225Ac reductions were observed in the heart and remainder of the body with both Ca-DTPA and Ca-TTHA, and in the lung, kidney, and spleen with Ca-TTHA. In vitro interaction analysis supported the in vivo reduction ability of Ca-DTPA and Ca-TTHA. In conclusion, aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, were effective for whole-body clearance of free 225Ac. This feasibility study provides useful information for reducing undesirable radiation exposure from free 225Ac.

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Aminopolycarboxylate Chelators Are Effective for Whole-body Clearance of Free 225ac: A Method to Reduce Unexpected Radiation Exposure During Targeted Alpha Therapy

10.21203/rs.3.rs-815298/v1 ◽

2021 ◽

Author(s):

Mitsuyoshi Yoshimoto ◽

Yukie Yoshii ◽

Hiroki Matsumoto ◽

Mitsuhiro Shinada ◽

Masashi Takahashi ◽

...

Keyword(s):

Radiation Exposure ◽

The Body ◽

Whole Body ◽

Targeted Alpha Therapy ◽

Carboxylic Groups ◽

In Vitro Interaction ◽

Alpha Therapy ◽

Body Clearance

Abstract Purpose: Actinium-225 (225Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although 225Ac labelling of bifunctional chelating ligands is effective, previous in vivo studies have reported that free 225Ac can be released from the drugs. Notably, such free 225Ac predominantly accumulates in the liver and can cause unexpected toxicity. To accelerate the clinical development of 225Ac TAT, methods for addressing unexpected toxicity are therefore needed. In this study, we evaluated various chelators in vitro and in vivo with regard to reducing and excreting free 225Ac and compared their chemical structures. Methods: Nine candidate chelators (D-penicillamine, dimercaprol, Ca-DTPA, Ca-EDTA, CyDTA, GEDTA TTHA, Ca-TTHA, and DO3A) were tested. In vitro interaction of 225Ac and chelators was investigated. Biodistribution and dosimetry of free 225Ac were examined in mice prior to the in vivo chelating study. For in vivo chelation, nine candidate chelators were administered 1 h after free 225Ac injection, and biodistribution was compared 4 h after 225Ac injection in mice. Two favourable chelators were then investigated intensively for biodistribution 24 h after the 225Ac injection.Results: The liver exhibited pronounced 225Ac uptake corresponding to an estimated human absorbed dose of 4.76 SvRBE5/MBq. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, significantly reduced 225Ac retention in the liver (22% and 30%, respectively). Significant 225Ac reductions were observed in the heart and the remainder of the body with both Ca-DTPA and Ca-TTHA, and in the lung, kidney, and spleen for Ca-TTHA. In vitro interaction analysis supported the in vivo reduction ability of Ca-DTPA and Ca-TTHA.Conclusions. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, were effective for whole-body clearance of free 225Ac, with a significant reduction in the liver. This method could reduce undesirable radiation exposure from free 225Ac during 225Ac TAT.

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212Pb: Production Approaches and Targeted Therapy Applications

Pharmaceutics ◽

10.3390/pharmaceutics14010189 ◽

2022 ◽

Vol 14 (1) ◽

pp. 189

Author(s):

Konstantin V. Kokov ◽

Bayirta V. Egorova ◽

Marina N. German ◽

Ilya D. Klabukov ◽

Michael E. Krasheninnikov ◽

...

Keyword(s):

Clinical Trials ◽

Preclinical Studies ◽

Clinical Implementation ◽

Minimum Loss ◽

Targeted Alpha Therapy ◽

High Effectiveness ◽

Alpha Emitter ◽

Oncological Diseases ◽

Parent Radionuclide ◽

Alpha Therapy

Over the last decade, targeted alpha therapy has demonstrated its high effectiveness in treating various oncological diseases. Lead-212, with a convenient half-life of 10.64 h, and daughter alpha-emitter short-lived 212Bi (T1/2 = 1 h), provides the possibility for the synthesis and purification of complex radiopharmaceuticals with minimum loss of radioactivity during preparation. As a benefit for clinical implementation, it can be milked from a radionuclide generator in different ways. The main approaches applied for these purposes are considered and described in this review, including chromatographic, solution, and other techniques to isolate 212Pb from its parent radionuclide. Furthermore, molecules used for lead’s binding and radiochemical features of preparation and stability of compounds labeled with 212Pb are discussed. The results of preclinical studies with an estimation of therapeutic and tolerant doses as well as recently initiated clinical trials of targeted radiopharmaceuticals are presented.

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Advances in 211At production at Texas A&M University

EPJ Web of Conferences ◽

10.1051/epjconf/202125203002 ◽

2021 ◽

Vol 252 ◽

pp. 03002

Author(s):

S.J. Yennello ◽

L.A McIntosh ◽

J.D. Burns ◽

E.E. Tereshatov ◽

G. Tabacaru ◽

...

Keyword(s):

Half Life ◽

Targeted Alpha Therapy ◽

Short Half Life ◽

Alpha Emitter ◽

Alpha Therapy

Alpha emitting radionuclides with medically relevant half-lives are interesting for treatment of tumors and other diseases because they deposit large amounts of energy close to the location of the radioisotope. Researchers at the Cyclotron Institute at Texas A&M University are developing a program to produce 211At, an alpha emitter with a medically relevant half-life. The properties of 211At make it a great candidate for targeted alpha therapy for cancer due to its short half-life (7.2 h). Astatine-211 has now been produced multiple times and reliability of this process is being improved.

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Revisiting the Radiobiology of Targeted Alpha Therapy

Frontiers in Medicine ◽

10.3389/fmed.2021.692436 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jean-Pierre Pouget ◽

Julie Constanzo

Keyword(s):

Biological Effects ◽

Dna Lesions ◽

Alpha Particles ◽

Systemic Effects ◽

X Rays ◽

Castration Resistant Prostate Cancer ◽

Bystander Effects ◽

Targeted Alpha Therapy ◽

Alpha Emitter ◽

Alpha Therapy

Targeted alpha therapy (TAT) using alpha particle-emitting radionuclides is in the spotlight after the approval of 223RaCl2 for patients with metastatic castration-resistant prostate cancer and the development of several alpha emitter-based radiopharmaceuticals. It is acknowledged that alpha particles are highly cytotoxic because they produce complex DNA lesions. Hence, the nucleus is considered their critical target, and many studies did not report any effect in other subcellular compartments. Moreover, their physical features, including their range in tissues (<100 μm) and their linear energy transfer (50–230 keV/μm), are well-characterized. Theoretically, TAT is indicated for very small-volume, disseminated tumors (e.g., micrometastases, circulating tumor cells). Moreover, due to their high cytotoxicity, alpha particles should be preferred to beta particles and X-rays to overcome radiation resistance. However, clinical studies showed that TAT might be efficient also in quite large tumors, and biological effects have been observed also away from irradiated cells. These distant effects are called bystander effects when occurring at short distance (<1 mm), and systemic effects when occurring at much longer distance. Systemic effects implicate the immune system. These findings showed that cells can die without receiving any radiation dose, and that a more complex and integrated view of radiobiology is required. This includes the notion that the direct, bystander and systemic responses cannot be dissociated because DNA damage is intimately linked to bystander effects and immune response. Here, we provide a brief overview of the paradigms that need to be revisited.

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Nanoconstructs in Targeted Alpha-Therapy

Recent Patents on Nanomedicine ◽

10.2174/1877912305666150102000549 ◽

2015 ◽

Vol 4 (2) ◽

pp. 71-76 ◽

Cited By ~ 6

Author(s):

Jan Kozempel ◽

Martin Vlk

Keyword(s):

Targeted Alpha Therapy ◽

Alpha Therapy

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Internal dose assessment of 148Gd using isotope ratios of gamma-emitting 146Gd or 153Gd in accidently released spallation target particles

Scientific Reports ◽

10.1038/s41598-020-77718-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

C. Rääf ◽

V. Barkauskas ◽

K. Eriksson Stenström ◽

C. Bernhardsson ◽

H. B. L. Pettersson

Keyword(s):

Operation Time ◽

Isotope Ratios ◽

Dose Assessment ◽

Sensitive Indicator ◽

Whole Body ◽

Internal Dose ◽

Tungsten Target ◽

Alpha Emitter ◽

Spallation Source ◽

Effective Doses

AbstractThe pure alpha emitter 148Gd may have a significant radiological impact in terms of internal dose to exposed humans in case of accidental releases from a spallation source using a tungsten target, such as the one to be used in the European Spallation Source (ESS). In this work we aim to present an approach to indirectly estimate the whole-body burden of 148Gd and the associated committed effective dose in exposed humans, by means of high-resolution gamma spectrometry of the gamma-emitting radiogadolinium isotopes 146Gd and 153Gd that are accompanied by 148Gd generated from the operation of the tungsten target. Theoretical minimum detectable whole-body activity (MDA) and associated internal doses from 148Gd are calculated using a combination of existing biokinetic models and recent computer simulation studies on the generated isotope ratios of 146Gd/148Gd and 153Gd/148Gd in the ESS target. Of the two gamma-emitting gadolinium isotopes, 146Gd is initially the most sensitive indicator of the presence of 148Gd if whole-body counting is performed within a month after the release, using the twin photo peaks of 146Gd centered at 115.4 keV (MDA < 1 Bq for ingested 148Gd, and < 25 Bq for inhaled 148Gd). The corresponding minimum detectable committed effective doses will be less than 1 µSv for ingested 148Gd, but substantially higher for inhaled 148Gd (up to 0.3 mSv), depending on operation time of the target prior to the release. However, a few months after an atmospheric release, 153Gd becomes a much more sensitive indicator of body burdens of 148Gd, with a minimum detectable committed effective doses ranging from 18 to 77 µSv for chronic ingestion and between 0.65 to 2.7 mSv for acute inhalation in connection to the release. The main issue with this indirect method for 148Gd internal dose estimation, is whether the primary photon peaks from 146 and 153Gd can be detected undisturbed. Preliminary simulations show that nuclides such as 182Ta may potentially create perturbations that could impair this evaluation method, and which impact needs to be further studied in future safety assessments of accidental target releases.

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Manual on the proper use of sodium astatide ([211At]NaAt) injections in clinical trials for targeted alpha therapy (1st edition)

Annals of Nuclear Medicine ◽

10.1007/s12149-021-01619-2 ◽

2021 ◽

Author(s):

Tadashi Watabe ◽

Makoto Hosono ◽

Seigo Kinuya ◽

Takahiro Yamada ◽

Sachiko Yanagida ◽

...

Keyword(s):

Clinical Trials ◽

Japanese Society ◽

Radiation Safety ◽

Safety Management ◽

Evaluation Methodology ◽

Targeted Alpha Therapy ◽

Safety Issues ◽

Safety Standards ◽

And Training ◽

Alpha Therapy

AbstractWe present the guideline for use of [211At] sodium astatide (NaAt) for targeted alpha therapy in clinical trials on the basis of radiation safety issues in Japan. This guideline was prepared by a study supported by the Ministry of Health, Labour, and Welfare, and approved by the Japanese Society of Nuclear Medicine on 8th Feb, 2021. The study showed that patients receiving [211At]NaAt do not need to be admitted to a radiotherapy room and outpatient treatment is possible. The radiation exposure from the patient is within the safety standards of the ICRP and IAEA recommendations for the general public and caregivers. Precautions for patients and their families, safety management associated with the use of [211At]NaAt, education and training, and disposal of medical radioactive contaminants are also included in this guideline. Treatment using [211At]NaAt in Japan should be carried out according to this guideline. Although this guideline is applied in Japan, the issues for radiation protection and evaluation methodology shown here are considered internationally useful as well.

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