In vitro and preclinical studies of targeted alpha therapy (TAT) for colorectal cancer

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.

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Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The “Hopeful Eight”

Pharmaceutics ◽

10.3390/pharmaceutics13060906 ◽

2021 ◽

Vol 13 (6) ◽

pp. 906

Author(s):

Romain Eychenne ◽

Michel Chérel ◽

Férid Haddad ◽

François Guérard ◽

Jean-François Gestin

Keyword(s):

Production Process ◽

Clinical Studies ◽

Physical Characteristics ◽

Preclinical Studies ◽

Chemical Behavior ◽

Targeted Alpha Therapy ◽

Therapeutic Applications ◽

Radium 223 ◽

Chemical Design ◽

Alpha Therapy

Among all existing radionuclides, only a few are of interest for therapeutic applications and more specifically for targeted alpha therapy (TAT). From this selection, actinium-225, astatine-211, bismuth-212, bismuth-213, lead-212, radium-223, terbium-149 and thorium-227 are considered as the most suitable. Despite common general features, they all have their own physical characteristics that make them singular and so promising for TAT. These radionuclides were largely studied over the last two decades, leading to a better knowledge of their production process and chemical behavior, allowing for an increasing number of biological evaluations. The aim of this review is to summarize the main properties of these eight chosen radionuclides. An overview from their availability to the resulting clinical studies, by way of chemical design and preclinical studies is discussed.

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In vitro and preclinical targeted alpha therapy for melanoma, breast, prostate and colorectal cancers

Critical Reviews in Oncology/Hematology ◽

10.1016/s1040-8428(01)00113-5 ◽

2001 ◽

Vol 39 (1-2) ◽

pp. 139-146 ◽

Cited By ~ 19

Author(s):

B.J Allen ◽

S Rizvi ◽

Y Li ◽

Z Tian ◽

M Ranson

Keyword(s):

Colorectal Cancers ◽

Targeted Alpha Therapy ◽

Alpha Therapy

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In vitro and preclinical targeted alpha therapy of human prostate cancer with Bi-213 labeled J591 antibody against the prostate specific membrane antigen

Prostate Cancer and Prostatic Diseases ◽

10.1038/sj.pcan.4500543 ◽

2002 ◽

Vol 5 (1) ◽

pp. 36-46 ◽

Cited By ~ 46

Author(s):

Y Li ◽

Z Tian ◽

S M A Rizvi ◽

N H Bander ◽

B J Allen

Keyword(s):

Prostate Cancer ◽

Human Prostate ◽

Prostate Specific Membrane Antigen ◽

Human Prostate Cancer ◽

Targeted Alpha Therapy ◽

Specific Membrane ◽

Alpha Therapy ◽

J591 Antibody

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

Medical Physics ◽

10.1002/mp.13969 ◽

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

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

Journal of Radiation Research ◽

10.1093/jrr/rraa049 ◽

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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