Development of a transmission alpha particle dosimetry technique using A549 cells and a Ra‐223 source for targeted alpha therapy

Darwish, R. Al; Staudacher, Alexander H.; Li, Y.; Brown, Michael P.; Bezak, Eva

doi:10.1118/1.4965805

Cited by 10 publications

(8 citation statements)

References 35 publications

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“…Cells with two α-hits were rarely seen (8/3000 cells) in our setup. This contrasts with widespread γ-H2AX formation in nuclei experiencing more traversing α-particles per cell corresponding to higher α-doses 24 , 40 .…”

Section: Resultsmentioning

confidence: 74%

“…They observed that multiple α-particle traversals of one cell induced a pan-nuclear γ-H2AX staining whose intensity depends on the number of tracks in the cell 24 . Extensively phosphorylated pan-γ-H2AX chromatin was also seen in cancer cells hit by multiple α-particles in the range of up to several Gy 40 . Unfortunately, the study of Horn et al .…”

Section: Discussionmentioning

confidence: 94%

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DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223

Schumann

Eberlein

Muhtadi

et al. 2018

Sci Rep

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Irradiation with high linear energy transfer α-emitters, like the clinically used Ra-223 dichloride, severely damages cells and induces complex DNA damage including closely spaced double-strand breaks (DSBs). As the hematopoietic system is an organ-at-risk for the treatment, knowledge about Ra-223-induced DNA damage in blood leukocytes is highly desirable. Therefore, 36 blood samples from six healthy volunteers were exposed ex-vivo (in solution) to different concentrations of Ra-223. Absorbed doses to the blood were calculated assuming local energy deposition of all α- and β-particles of the decay, ranging from 0 to 142 mGy. γ-H2AX + 53BP1 co-staining and analysis was performed in leukocytes isolated from the irradiated blood samples. For DNA damage quantification, leukocyte samples were screened for occurrence of α-induced DNA damage tracks and small γ-H2AX + 53BP1 DSB foci. This revealed a linear relationship between the frequency of α-induced γ-H2AX damage tracks and the absorbed dose to the blood, while the frequency of small γ-H2AX + 53BP1 DSB foci indicative of β-irradiation was similar to baseline values, being in agreement with a negligible β-contribution (3.7%) to the total absorbed dose to the blood. Our calibration curve will contribute to the biodosimetry of Ra-223-treated patients and early after incorporation of α-emitters.

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Section: Resultsmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 94%

DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223

Schumann

Eberlein

Muhtadi

et al. 2018

Sci Rep

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“…Various techniques were used for ex vivo evaluation of activity distribution in tissue samples. They include, e.g., an alpha camera [ 12 ] or a timepix detector [ 13 ] to assess the distribution in sub-organ or cellular levels. Also the possibility of the Cherenkov radiation luminescence imaging technique for α emitters employing the co-emitted β − radiations [ 14 ] was reported.…”

Section: Introductionmentioning

confidence: 99%

Progress in Targeted Alpha-Particle Therapy. What We Learned about Recoils Release from In Vivo Generators

2018

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This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha-particle emitters as well as in vivo alpha-particle generators. It discusses the production of radionuclides like 211At, 223Ra, 225Ac/213Bi, labelling and delivery employing various targeting vectors (small molecules, chelators for alpha-emitting nuclides and their biomolecular targets as well as nanocarriers), general radiopharmaceutical issues, preclinical studies, and clinical trials including the possibilities of therapy prognosis and follow-up imaging. Special attention is given to the nuclear recoil effect and its impacts on the possible use of alpha emitters for cancer treatment, proper dose estimation, and labelling chemistry. The most recent and important achievements in the development of alpha emitters carrying vectors for preclinical and clinical use are highlighted along with an outlook for future developments.

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“…[ 23 ] labeled a novel small molecule fusion peptide, VP2, with 211 At through a one-step method and the TAT conjugate had a high affinity for tumor cells expressing vasoactive intestinal peptide receptors (VIPRs); Charles Zhu et al . [ 30 ] presented a transmission dosimetry design for alpha particles using A549 lung carcinoma cells, an external alpha particle emitting source (radium 223; Ra-223) and a Timepix pixelated semiconductor detector. As for mesothelin, Urs B. Hagemann et al.…”

Section: Discussionmentioning

confidence: 99%

Construction and Preclinical Evaluation of 211At Labeled Anti-mesothelin Antibodies as Potential Targeted Alpha Therapy Drugs

Wang

Liu

et al. 2020

Journal of Radiation Research

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ABSTRACT Targeted alpha therapy (TAT) is a promising tumor therapy that can specifically transport α particle to the vicinity of tumor cells while the normal cells are only slightly irradiated. Mesothelin is a highly promising molecular signature for many types of solid tumors including malignant mesothelioma, pancreatic cancer, ovarian cancer and lung adenocarcinoma etc., while the expression in normal human tissues are limited, thus making mesothelin a promising antigen for TAT. Previously we developed a theoretical model that could predict and optimize in vitro screening of potential TAT drugs. The aim of the study is construction and preclinical evaluation of 211At labeled anti-mesothelin antibodies as potential TAT drugs. Mesothelin expression of two tumor cell lines were confirmed by flow cytometry, and their radiosensitivities were also evaluated. We used two kinds of anti-mesothelin antibodies, ET210–6 and ET210–28, to construct TAT drugs. Then, radiochemical purity, stability in vitro, affinity of the conjugates and mesothelin expression level were assessed. The specific killing of mesothelin-positive cancer cells treated by 211At-ET210–28 and 211At-ET210–6 were studied via Cell Counting Kit-8 assay and colony formation assay. 211At-ET210–28 and 211At-ET210–6 revealed excellent affinity and stability in both phosphate buffer saline and fetal bovine serum environment. Radiolabeled antibody conjugates bound specifically to mesothelin-positive cells in vitro. Both 211At-ET210–28 and 211At-ET210–6 could specifically kill mesothelin-positive cells with negligible damages to mesothelin-negative cells. Our findings provide initial proof-of-concept for the potential use of 211At labeled ET210–28/ET210–6 anti-mesothelin antibody in specific killings of mesothelin-positive tumor cells.

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Development of a transmission alpha particle dosimetry technique using A549 cells and a Ra‐223 source for targeted alpha therapy

Cited by 10 publications

References 35 publications

DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223

DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223

Progress in Targeted Alpha-Particle Therapy. What We Learned about Recoils Release from In Vivo Generators

Construction and Preclinical Evaluation of 211At Labeled Anti-mesothelin Antibodies as Potential Targeted Alpha Therapy Drugs

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