Antitumor Activity of Novel Bone-seeking, α-emitting 224Ra-solution in a Breast Cancer Skeletal Metastases Model

Juzeniene, Asta; Bernoulli, Jenni; Suominen, Mari I.; Halleen, Jussi M.; Larsen, Roy H.

doi:10.21873/anticanres.12432

Cited by 18 publications

(33 citation statements)

References 24 publications

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“…Samarium lexidronam ( 153 Sm-EDTMP) is approved worldwide for the pain relief of osteoblastic metastatic bone lesions. While radium itself is inherently a bone-seeker, EDTMP has been used to increase the proportion of daughter nuclides 212 Pb and 212 Bi delivered to the bone in mouse models [ 19 , 20 ]. However, if the goal is to ensure radionuclide accumulation at other target sites, the complexation and bone-seeking properties may be problematic.…”

Section: Introductionmentioning

confidence: 99%

Improved Formulation of 224Ra-Labeled Calcium Carbonate Microparticles by Surface Layer Encapsulation and Addition of EDTMP

Lindland

Tonstad

et al. 2021

Pharmaceutics

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Radium-224-labeled CaCO3 microparticles have been developed to treat peritoneal carcinomatosis. The microparticles function as carriers of 224Ra, facilitating intraperitoneal retention of the alpha-emitting radionuclide. It was necessary to control the size of microparticles in suspension over time and introduce a sterilization process for the clinical use of the radiopharmaceutical. Ethylenediamine tetra(methylene phosphonic acid) (EDTMP) was investigated as a stabilizing additive. The possibility of encapsulating the radiolabeled microparticles with an outer surface layer of CaCO3 for the improved retention of radioactivity by the carrier was studied. This work evaluated these steps of optimization and their effect on radiochemical purity, the biodistribution of radionuclides, and therapeutic efficacy. An EDTMP concentration of >1% (w/w) relative to CaCO3 stabilized the particle size for at least one week. Without EDTMP, the median particle size increased from ~5 µm to ~25 µm immediately after sterilization by autoclaving, and the larger microparticles sedimented rapidly in suspension. The percentage of adsorbed 224Ra progeny 212Pb increased from 56% to 94% at 2.4–2.5% (w/w) EDTMP when the 224Ra-labeled microparticles were layer-encapsulated. The improved formulation also resulted in a suitable biodistribution of radionuclides in mice, as well as a survival benefit for mice with intraperitoneal ovarian or colorectal tumors.

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Section: Introductionmentioning

confidence: 99%

Improved Formulation of 224Ra-Labeled Calcium Carbonate Microparticles by Surface Layer Encapsulation and Addition of EDTMP

Lindland

Tonstad

et al. 2021

Pharmaceutics

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“…Most recently, Westrom et al investigated the use of Ra-224-coated microparticles for localized internal α-therapy in mice [ 4 , 5 ]. Furthermore, Juzeniene et al showed in a mouse model that Ra-224 is a promising candidate for the treatment of bone metastases related to breast cancer [ 6 ]. These publications highlight the renewed interest in using Ra-224 for clinical applications.…”

Section: Introductionmentioning

confidence: 99%

Correlation of the absorbed dose to the blood and DNA damage in leukocytes after internal ex-vivo irradiation of blood samples with Ra-224

et al. 2018

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BackgroundIrradiation with α-particles creates densely packed damage tracks along particle trajectories in exposed cells, including complex DNA damage and closely spaced double-strand breaks (DSBs) in hit nuclei. Here, we investigated the correlation of the absorbed dose to the blood and the number of α-induced DNA damage tracks elicited in human blood leukocytes after ex-vivo in-solution exposure with Ra-224. The aim was to compare the data to previously published data on Ra-223 and to investigate differences in DNA damage induction between the two radium isotopes.ResultsBlood samples from three healthy volunteers were exposed ex-vivo to six different concentrations of Ra-224 dichloride. Absorbed doses to the blood were calculated assuming local energy deposition of all α- and β-particles of the Ra-224 decay chain, ranging from 0 to 127 mGy. γ-H2AX + 53BP1 DNA damage co-staining and analysis was performed on ethanol-fixed leukocytes isolated from the irradiated blood samples. For damage quantification, α-induced DNA damage tracks and small γ-H2AX + 53BP1 DSB foci were enumerated in the exposed leukocytes. 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.ConclusionsOur data provide a first estimation of the DNA damage induced by Ra-224 in peripheral blood mononuclear cells. A comparison with our previously published Ra-223 data suggests that there is no difference in the induction of radiation-induced DNA damage between the two radium isotopes due to their similar decay properties.

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“…One study demonstrated high labelling efficiencies of 224 Ra on the surface of calcium carbonate microparticles with high retention of both 224 Ra and its 212 Pb daughter, and the radioactivity remained primarily localized in the peritoneal cavity [89]. 224 Ra has also been investigated for osteolytic bone metastasis of MDA-MB-231(SA)-GFP-bearing nude mice, decreasing the number and area of tumor foci and prolonging survival [99]. Preclinical diffusing alpha emitters therapy (DaRT) using 224 Ra-loaded wires was tested on mice bearing prostate (PC-3), glioblastoma (GBM, U87-MG), colon (HCT15), squamous cell carcinoma (FaDu), and melanoma (C32) cancer cell tumors.…”

Section: Ramentioning

confidence: 99%

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

2020

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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.

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Antitumor Activity of Novel Bone-seeking, α-emitting 224Ra-solution in a Breast Cancer Skeletal Metastases Model

Abstract: Abstract. Background

Cited by 18 publications

References 24 publications

Improved Formulation of 224Ra-Labeled Calcium Carbonate Microparticles by Surface Layer Encapsulation and Addition of EDTMP

Improved Formulation of 224Ra-Labeled Calcium Carbonate Microparticles by Surface Layer Encapsulation and Addition of EDTMP

Correlation of the absorbed dose to the blood and DNA damage in leukocytes after internal ex-vivo irradiation of blood samples with Ra-224

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

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