scholarly journals A Novel Single-Step-Labeled 212Pb-CaCO3 Microparticle for Internal Alpha Therapy: Preparation, Stability, and Preclinical Data from Mice

Materials ◽  
2021 ◽  
Vol 14 (23) ◽  
pp. 7130
Author(s):  
Ruth Gong Li ◽  
Kim Lindland ◽  
Tina Bjørnlund Bønsdorff ◽  
Sara Westrøm ◽  
Roy Hartvig Larsen
Keyword(s):  
Cytotoxic Effect ◽  
Single Step ◽  
Stability Assessment ◽  
Promising Candidate ◽  
Targeted Alpha Therapy ◽  
Suitable Material ◽  
In Vitro Stability ◽  
Alpha Therapy ◽  
Carrier Vehicle

Lead-212 is recognized as a promising radionuclide for targeted alpha therapy for tumors. Many studies of 212Pb-labeling of various biomolecules through bifunctional chelators have been conducted. Another approach to exploiting the cytotoxic effect is coupling the radionuclide to a microparticle acting as a carrier vehicle, which could be used for treating disseminated cancers in body cavities. Calcium carbonate may represent a suitable material, as it is biocompatible, biodegradable, and easy to synthesize. In this work, we explored 212Pb-labeling of various CaCO3 microparticles and developed a protocol that can be straightforwardly implemented by clinicians. Vaterite microparticles stabilized by pamidronate were effective as 212Pb carriers; labeling yields of ≥98% were achieved, and 212Pb was strongly retained by the particles in an in vitro stability assessment. Moreover, the amounts of 212Pb reaching the kidneys, liver, spleen, and skeleton of mice following intraperitoneal (i.p.) administration were very low compared to i.p. injection of unbound 212Pb2+, indicating that CaCO3-bound 212Pb exhibited stability when administered intraperitoneally. Therapeutic efficacy was observed in a model of i.p. ovarian cancer for all the tested doses, ranging from 63 to 430 kBq per mouse. Lead-212-labeled CaCO3 microparticles represent a promising candidate for treating intracavitary cancers.

In vitro evaluation of 225 Ac-DOTA-substance P for targeted alpha therapy of glioblastoma multiforme

2018 ◽  
Vol 92 (1) ◽  
pp. 1344-1356 ◽  
Author(s):  
Agnieszka Majkowska-Pilip ◽  
Maria Rius ◽  
Frank Bruchertseifer ◽  
Christos Apostolidis ◽  
Mirjam Weis ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Substance P ◽  
Targeted Alpha Therapy ◽  
In Vitro Evaluation ◽  
Alpha Therapy

scholarly journals Towards elucidating the radiochemistry of astatine – Behavior in chloroform

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Emma Aneheim ◽  
Stig Palm ◽  
Holger Jensen ◽  
Christian Ekberg ◽  
Per Albertsson ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Solvent Extraction ◽  
Target Material ◽  
Promising Candidate ◽  
Experimental Conditions ◽  
Targeted Alpha Therapy ◽  
Radiolysis Products ◽  
Dry Distillation ◽  
Important Intermediate ◽  
Alpha Therapy

Abstract Targeted alpha therapy of disseminated cancer is an emerging technique where astatine-211 is one of the most promising candidate nuclides. Although astatine has been known for over 70 years, its chemistry is still largely unexplored, mainly due to the lack of stable or long-lived isotopes. However, substantial amounts of astatine-211 can be produced in cyclotrons by the bombardment of natural bismuth. The astatine can be recovered from the resulting irradiated target material through either wet extraction or dry-distillation. Chloroform has become an important intermediate solvent for the recovery of astatine after production, especially following dry distillation. In this work, the radiochemistry of astatine in chloroform was investigated using evaporation, solvent extraction, chromatographic methods and molecular modeling. The extraction of astatine in chloroform led to the formation of multiple astatine species, allowing for evaporation of the solvent to dryness without any loss of activity. Radiolysis products of chloroform were shown to play an important role in the speciation of astatine forming both reactive and kinetically stable compounds. It was hypothesized that reactions with chlorine, as well as trichloromethyl hydroperoxide, forming polar astatine compounds are important reactions under the current experimental conditions.

scholarly journals Radionuclide spatial distribution and dose deposition for in vitro assessments of 212 Pb‐αVCAM‐1 targeted alpha therapy

2020 ◽  
Vol 47 (3) ◽  
pp. 1317-1326
Author(s):  
Anne‐Marie Frelin‐Labalme ◽  
Thomas Roger ◽  
Nadia Falzone ◽  
Boon Quan Lee ◽  
Nicola R. Sibson ◽  
...  
Keyword(s):  
Spatial Distribution ◽  
Targeted Alpha Therapy ◽  
Dose Deposition ◽  
Alpha Therapy

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

Pharmaceutics ◽  
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.

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

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.

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

2020 ◽  
Vol 61 (5) ◽  
pp. 684-690
Author(s):  
Xudong Wang ◽  
Wenzong Ma ◽  
Weihao Liu ◽  
Huan Ma ◽  
Yuanyou Yang ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Tumor Therapy ◽  
Molecular Signature ◽  
Cell Counting ◽  
Targeted Alpha Therapy ◽  
Preclinical Evaluation ◽  
Antibody Conjugates ◽  
Alpha Therapy ◽  
Mesothelin Expression

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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