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

Nelson, Bryce; Andersson, Jan; Wuest, Frank

doi:10.3390/pharmaceutics13010049

Cited by 119 publications

(109 citation statements)

References 115 publications

(179 reference statements)

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“…The short-lived bismuth isotopes 212,213 Bi with halflives of 61 and 46 min respectively have already demonstrated their therapeutic perspective, however, the use of their parent radionuclides 212 Pb and 225 Ac seems to be more promising due to the longer half-life. [1] Radioisotope 212 Pb itself is a beta emitter and applied as a radiopharmaceutical acts as an in vivo generator of alpha emitting 212 Bi.…”

mentioning

confidence: 99%

Triacetate of Benzoazacrown Compound as a Chelator for Lead Cations Promising for Targeted Radiopharmaceuticals

Egorova¹,

Zamurueva²,

Zubenko³

et al. 2021

MHC

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Triacetate of 15-benzoazacrown-5 compound (H 3 BA3A) is a new ligand that has shown advantages towards chelation of some cations. In this paper H 3 BA3A was consequently studied for binding of lead cation. With respect to nuclear properties of 212 Pb radioisotope it can be used for therapy of various oncological diseases mainly due to alpha-emitting daughter radionuclide 212 Bi. Complexes of such radionuclides are considered as parts of targeted radiopharmaceuticals that can be conjugated with biomolecules to provide address delivery to cancerous tissues. Medical radionuclides are commonly short-lived and biomolecules are often heat-sensitive. That is why fast and stable complexation of trace amounts of lead cations in biologically relevant media without additional heating higher than 37 °C is important and challenging task. At the beginning we determined complexation constants in wide pH range including different protonated and hydrolyzed complex species via potentiometric titration technique. The obtained values are high enough for lead chelates logβ(BA3APb -) = 17.2 (1). Structural features of complex in aqueous solution were established due to 1 H and 13 C NMR spectroscopy. High resolution of obtained spectra and comparison with spectrum of deprotonated ligand shows presence of one rigid conformer of complexed form in the aqueous solution with C s symmetry. In order to study labelled compounds we used longer lived isotope of lead 210 Pb isolated from solution of 226 Ra. Using thin layer chromatography and gamma-spectrometry it was found that 100 μM of ligand is enough to completely chelate 210 Pb in the tracer concentration related to radiopharmaceutical concentration of 212 Pb. According to pH speciation obtained in complexation constant determination, pH 5.5-6 was selected for labelling experiments. Noteworthy, the labeled compound was obtained within 1-5 minutes at room temperature as well as upon heating at 90 o C. Macrocyclic H 3 BA3A demonstrates fast complexation apparently due to larger crown cavity compared to cyclen cavity in H 4 DOTA. This was indirectly shown in potentiometric titration where waiting time for curve's points was no longer than 5 minutes indicating that equilibrium was achieved within 5 minutes. In order to evaluate possible trans-chelation and transmetallation of complex in living organism we performed challenging experiments in static conditions: in presence of nine-fold excess of serum proteins, biologically relevant cations 5 mM Ca 2+ , 5 mM Mg 2+ , 0.1 mM Zn 2+ , 0.1 mM Cu 2+ , 0.1 mM Fe 3+ and isotonic solution of 0.15 M NaCl. It was shown that the 100 % intactness of complex can be kept for up to two days of incubation in competing media. Summarizing, the H 3 BA3A forms highly stable complex with lead cation not only in model solution, but also in presence of challenging agents. This stability is provided by high stability constants and rigid structure in solution.

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mentioning

confidence: 99%

Triacetate of Benzoazacrown Compound as a Chelator for Lead Cations Promising for Targeted Radiopharmaceuticals

Egorova¹,

Zamurueva²,

Zubenko³

et al. 2021

MHC

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“…The potential of Actinium-225 ( 225 Ac) for the treatment of advanced cancers has been proven in several clinical trials. It is produced from a Thorium-229 ( 229 Th) generator, however, there have been attempts of large-scale linear accelerator or cyclotron production by irradiation of Radium-226 ( 226 Ra) [101]. It is an alpha emitting particle with a relatively long half-life of 9.9 days which make 225 Ac a cytotoxic radionuclide.…”

Section: Actinium-225 Therapymentioning

confidence: 99%

“…It is an alpha emitting particle with a relatively long half-life of 9.9 days which make 225 Ac a cytotoxic radionuclide. 225 Ac is classified as a "nanogenerator" or "in-vivo generator" as the decay yields four alpha particles, three β − disintegrations and two gamma emissions [101][102][103]. There is a low abundance of gamma emissions which may be used for dosimetric calculations although their low abundance renders 225 Ac unsuitable for planar SPECT imaging.…”

Section: Actinium-225 Therapymentioning

confidence: 99%

PSMA Theranostics: Science and Practice

Mokoala

Lawal

Lengana³

et al. 2021

Cancers

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Prostate cancer (PCa) causes significant morbidity and mortality in men globally. While localized PCa may be managed with curative intent by surgery and/or radiation therapy, the management of advanced hormone resistant metastatic disease (mCRPC) is more challenging. Theranostics is a principle based on the ability to use an organ specific ligand and label it to both a diagnostic and a therapeutic agent. The overexpression of prostate specific membrane antigen (PSMA) on prostate cancer cells creates a unique opportunity for development of targeted radionuclide therapy. The use of both beta and alpha emitting particles has shown great success. Several clinical trials have been initiated assessing the efficacy and safety profile of these radionuclide agents. The results are encouraging with PSMA directed radioligand therapy performing well in patients who have exhausted all other standard treatment options. Future studies need to assess the timing of introduction of these radionuclide therapies in the management schema of mCRPC. Drugs or therapies are not without side effects and targeted radionuclide therapies presents a new set of toxicities including xerostomia and myelosuppression. New therapeutic strategies are being explored to improve outcomes while keeping toxicities to a minimum. This review aims to look at the various PSMA labelled tracers that form part of the theragnostic approach and subsequently delve into the progress made in the area of radionuclide therapy.

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“…Alpha-particleemitting atoms are used in targeted alpha (α) particle therapy (TAT), taking advantage of the short and highly ionizing path of α-particle emissions. Common α-emitters, including 225 Ac, 213 Bi, 224 Ra, 212 Pb, 227 Th, 223 Ra, 211 At, and 149 Tb, are in use [18]. TAT is part of the broader field of radiopharmaceutical therapy (RPT), which has expanded in recent years [19].…”

Section: Alpha Particle-based Radiotherapymentioning

confidence: 99%

The Potentiation of Anti-Tumor Immunity by Tumor Abolition with Alpha Particles, Protons, or Carbon Ion Radiation and Its Enforcement by Combination with Immunoadjuvants or Inhibitors of Immune Suppressor Cells and Checkpoint Molecules

Keisari

Kelson

2021

Cells

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The delivery of radiation therapy (RT) for cancer with intent to cure has been optimized and standardized over the last 80 years. Both preclinical and clinical work emphasized the observation that radiation destroys the tumor and exposes its components to the immune response in a mode that facilitates the induction of anti-tumor immunity or reinforces such a response. External beam photon radiation is the most prevalent in situ abolition treatment, and its use exposed the “abscopal effect”. Particle radiotherapy (PRT), which has been in various stages of research and development for 70 years, is today available for the treatment of patients in the form of alpha particles, proton, or carbon ion radiotherapy. Charged particle radiotherapy is based on the acceleration of charged species, such as protons or carbon-12, which deposit their energy in the treated tumor and have a higher relative biological effectiveness compared with photon radiation. In this review, we will bring evidence that alpha particles, proton, or carbon ion radiation can destroy tumors and activate specific anti-tumor immune responses. Radiation may also directly affect the distribution and function of immune cells such as T cells, regulatory T cells, and mononuclear phagocytes. Tumor abolition by radiation can trigger an immune response against the tumor. However, abolition alone rarely induces effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement abolition to reinforce the anti-tumor immunity to better eradicate residual local and metastatic tumor cells. Various methods and agents such as immunoadjuvants, suppressor cell inhibitors, or checkpoint inhibitors were used to manipulate the immune response in combination with radiation. This review deals with the manifestations of particle-mediated radiotherapy and its correlation with immunotherapy of cancer.

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

Cited by 119 publications

References 115 publications

Triacetate of Benzoazacrown Compound as a Chelator for Lead Cations Promising for Targeted Radiopharmaceuticals

Triacetate of Benzoazacrown Compound as a Chelator for Lead Cations Promising for Targeted Radiopharmaceuticals

PSMA Theranostics: Science and Practice

The Potentiation of Anti-Tumor Immunity by Tumor Abolition with Alpha Particles, Protons, or Carbon Ion Radiation and Its Enforcement by Combination with Immunoadjuvants or Inhibitors of Immune Suppressor Cells and Checkpoint Molecules

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