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Cancer Biotherapy & Radiopharmaceuticals Nov 2013Due to its ability to target both known and occult lesions, radioimmunotherapy (RIT) is an attractive therapeutic modality for solid tumors. Poor tumor uptake and... (Review)
Review
Due to its ability to target both known and occult lesions, radioimmunotherapy (RIT) is an attractive therapeutic modality for solid tumors. Poor tumor uptake and undesirable pharmacokinetics, however, have precluded the administration of radioimmunoconjugates at therapeutically relevant doses thereby limiting the clinical utility of RIT. In solid tumors, efficacy of RIT is further compromised by heterogeneities in blood flow, tumor stroma, expression of target antigens and radioresistance. As a result significant efforts have been invested toward developing strategies to overcome these impediments. Further, there is an emerging interest in exploiting short-range, high energy α-particle emitting radionuclides for the eradication of minimal residual and micrometastatic disease. As a result several modalities for localized therapy and models of minimal disease have been developed for preclinical evaluation. This review provides a brief update on the recent efforts toward improving the efficacy of RIT for solid tumors, and development of RIT strategies for minimal disease associated with solid tumors. Further, some of promising approaches to improve tumor targeting, which showed promise in the past, but have now been ignored are also discussed.
Topics: Alpha Particles; Animals; Antibodies, Monoclonal; Disease Models, Animal; Humans; Immunoconjugates; Neoplasm, Residual; Neoplasms; Peritoneum; Radioimmunotherapy; Radioisotopes; Radiopharmaceuticals
PubMed: 23844555
DOI: 10.1089/cbr.2013.1523 -
Journal of Nuclear Medicine : Official... Sep 2023Auger electron (AE) radiopharmaceutical therapy (RPT) may have the same therapeutic efficacy as α-particles for oncologic small disease, with lower risks of... (Review)
Review
Auger electron (AE) radiopharmaceutical therapy (RPT) may have the same therapeutic efficacy as α-particles for oncologic small disease, with lower risks of normal-tissue toxicity. The seeds of using AE emitters for RPT were planted several decades ago. Much knowledge has been gathered about the potency of the biologic effects caused by the intense shower of these low-energy AEs. Given their short range, AEs deposit much of their energy in the immediate vicinity of their site of decay. However, the promise of AE RPT has not yet been realized, with few agents evaluated in clinical trials and none becoming part of routine treatment so far. Instigated by the 2022 "Technical Meeting on Auger Electron Emitters for Radiopharmaceutical Developments" at the International Atomic Energy Agency, this review presents the current status of AE RPT based on the discussions by experts in the field. A scoring system was applied to illustrate hurdles in the development of AE RPT, and we present a selected list of well-studied and emerging AE-emitting radionuclides. Based on the number of AEs and other emissions, physical half-life, radionuclide production, radiochemical approaches, dosimetry, and vector availability, recommendations are put forward to enhance and impact future efforts in AE RPT research.
Topics: Radiopharmaceuticals; Electrons; Alpha Particles; Half-Life; International Agencies
PubMed: 37591544
DOI: 10.2967/jnumed.122.265039 -
International Journal of Environmental... Nov 2020Alpha-emitting radioisotopes are the most toxic among all radionuclides. In particular, medium to long-lived isotopes of the heavier metals are of the greatest concern... (Review)
Review
Alpha-emitting radioisotopes are the most toxic among all radionuclides. In particular, medium to long-lived isotopes of the heavier metals are of the greatest concern to human health and radiological safety. This review focuses on the most common alpha-emitting radionuclides of natural and anthropogenic origin in wild mushrooms from around the world. Mushrooms bio-accumulate a range of mineral ionic constituents and radioactive elements to different extents, and are therefore considered as suitable bio-indicators of environmental pollution. The available literature indicates that the natural radionuclide Po is accumulated at the highest levels (up to 22 kBq/kg dry weight (dw) in wild mushrooms from Finland), while among synthetic nuclides, the highest levels of up to 53.8 Bq/kg dw of Pu were reported in Ukrainian mushrooms. The capacity to retain the activity of individual nuclides varies between mushrooms, which is of particular interest for edible species that are consumed either locally or, in some cases, also traded on an international scale. The effective radiation dose from the ingestion of this food can reportedly range from 0.033 µSv/kg dw to 26.8 mSv/kg and varies depending on the country. Following pollution events, such consumption may expose consumers to highly radiotoxic decay particles produced by alpha emitters.
Topics: Adult; Agaricales; Alpha Particles; Humans; Radiation Monitoring; Radioisotopes; Soil Pollutants, Radioactive
PubMed: 33172165
DOI: 10.3390/ijerph17218220 -
Biomacromolecules Jul 2019Glycogen, a randomly branched glucose polymer, provides energy storage in organisms. It forms small β particles which in animals bind to form composite α particles,...
Glycogen, a randomly branched glucose polymer, provides energy storage in organisms. It forms small β particles which in animals bind to form composite α particles, which give better glucose release. Simulations imply β particle size is controlled only by activities and sizes of glycogen biosynthetic enzymes and sizes of polymer chains. Thus, storing more glucose requires forming more β particles, which are expected to sometimes form α particles. No α particles have been reported in bacteria, but the extraction techniques might have caused degradation. Using milder glycogen extraction techniques on Escherichia coli, transmission electron microscopy and size-exclusion chromatography showed α particles, consistent with this hypothesis for α-particle formation. Molecular density and size distributions show similarities with animal glycogen, despite very different metabolic processes. These general polymer constraints are such that any organism which needs to store and then release glucose will have similar α and β particle structures: a type of convergent evolution.
Topics: Alpha Particles; Beta Particles; Energy Metabolism; Escherichia coli; Glucose; Glycogen; Microscopy, Electron, Transmission; Polymers
PubMed: 31244022
DOI: 10.1021/acs.biomac.9b00586 -
Pharmaceuticals (Basel, Switzerland) Jun 2015This review presents an overview of the successes and challenges currently faced in alpha radionuclide therapy. Alpha particles have an advantage in killing tumour cells... (Review)
Review
This review presents an overview of the successes and challenges currently faced in alpha radionuclide therapy. Alpha particles have an advantage in killing tumour cells as compared to beta or gamma radiation due to their short penetration depth and high linear energy transfer (LET). Touching briefly on the clinical successes of radionuclides emitting only one alpha particle, the main focus of this article lies on those alpha-emitting radionuclides with multiple alpha-emitting daughters in their decay chain. While having the advantage of longer half-lives, the recoiled daughters of radionuclides like 224Ra (radium), 223Ra, and 225Ac (actinium) can do significant damage to healthy tissue when not retained at the tumour site. Three different approaches to deal with this problem are discussed: encapsulation in a nano-carrier, fast uptake of the alpha emitting radionuclides in tumour cells, and local administration. Each approach has been shown to have its advantages and disadvantages, but when larger activities need to be used clinically, nano-carriers appear to be the most promising solution for reducing toxic effects, provided there is no accumulation in healthy tissue.
PubMed: 26066613
DOI: 10.3390/ph8020321 -
Cancer Research Feb 2020Preclinical studies, , and studies, in combination with mathematical modeling can help optimize and guide the design of clinical trials. The design and optimization of...
Preclinical studies, , and studies, in combination with mathematical modeling can help optimize and guide the design of clinical trials. The design and optimization of alpha-particle emitter radiopharmaceutical therapy (αRPT) is especially important as αRPT has the potential for high efficacy but also high toxicity. We have developed a mathematical model that may be used to identify trial design parameters that will have the greatest impact on outcome. The model combines Gompertzian tumor growth with antibody-mediated pharmacokinetics and radiation-induced cell killing. It was validated using preclinical experimental data of antibody-mediated Bi and Ac delivery in a metastatic transgenic breast cancer model. In modeling simulations, tumor cell doubling time, administered antibody, antibody specific-activity, and antigen-site density most impacted median survival. The model was also used to investigate treatment fractionation. Depending upon the time-interval between injections, increasing the number of injections increased survival time. For example, two administrations of 200 nCi, Ac-labeled antibody, separated by 30 days, resulted in a simulated 31% increase in median survival over a single 400 nCi administration. If the time interval was 7 days or less, however, there was no improvement in survival; a one-day interval between injections led to a 10% reduction in median survival. Further model development and validation including the incorporation of normal tissue toxicity is necessary to properly balance efficacy with toxicity. The current model is, however, useful in helping understand preclinical results and in guiding preclinical and clinical trial design towards approaches that have the greatest likelihood of success. SIGNIFICANCE: Modeling is used to optimize αRPT.
Topics: Actinium; Alpha Particles; Animals; Antibodies, Monoclonal; Bismuth; Breast Neoplasms; Cell Line, Tumor; Diffusion Magnetic Resonance Imaging; Disease Management; Dose Fractionation, Radiation; Drug Administration Schedule; Female; Humans; Image Processing, Computer-Assisted; Mice; Mice, Transgenic; Models, Biological; Positron-Emission Tomography; Radioimmunotherapy; Radioisotopes; Radiopharmaceuticals; Receptor, ErbB-2; Single Photon Emission Computed Tomography Computed Tomography
PubMed: 31772036
DOI: 10.1158/0008-5472.CAN-19-2553 -
The Quarterly Journal of Nuclear... Jun 2015Beta-emitting radionuclides are not able to kill isolated tumor cells disseminated in the body, even if a high density of radiolabeled molecules can be targeted at the... (Review)
Review
Beta-emitting radionuclides are not able to kill isolated tumor cells disseminated in the body, even if a high density of radiolabeled molecules can be targeted at the surface of these cells because the vast majority of emitted electrons deliver their energy outside the targeted cells. Alpha-particle emitting radionuclides may overcome this limitation. It is thus of primary importance to test and validate the radionuclide of choice, the most appropriate carrier molecule and the most promising clinical indication. Four α-particle emitting radionuclides have been or are clinically tested in phase I studies namely 213Bi, 225Ac, 212Pb and 211At. Clinical safety has been documented and encouraging efficacy has been shown for some of them (213Bi and 211At). 211At has been the most studied and could be the most promising radionuclide but 225Ac and 212Pb are also of potential great interest. Any carrier molecule that has been labeled with β-emitting radionuclides could be labeled with alpha particle-emitting radionuclide using, for some of them, the same chelating agents. However, the physical half-life of the radionuclide should match the biological half-life of the radioconjugate or its catabolites. Finally everybody agrees, based on the quite short range of alpha particles, on the fact that the clinical indications for alpha-immunotherapy should be limited to the situation of disseminated minimal residual diseases made of small clusters of malignant cells or isolated tumor cells.
Topics: Alpha Particles; Drug Carriers; Evidence-Based Medicine; Humans; Immunotherapy; Isotope Labeling; Neoplasms; Radioisotopes
PubMed: 25752501
DOI: No ID Found -
Journal of Experimental & Clinical... Mar 2023We recently identified CD46 as a novel prostate cancer cell surface antigen that shows lineage independent expression in both adenocarcinoma and small cell...
We recently identified CD46 as a novel prostate cancer cell surface antigen that shows lineage independent expression in both adenocarcinoma and small cell neuroendocrine subtypes of metastatic castration resistant prostate cancer (mCRPC), discovered an internalizing human monoclonal antibody YS5 that binds to a tumor selective CD46 epitope, and developed a microtubule inhibitor-based antibody drug conjugate that is in a multi-center phase I trial for mCRPC (NCT03575819). Here we report the development of a novel CD46-targeted alpha therapy based on YS5. We conjugated Pb, an in vivo generator of alpha-emitting Bi and Po, to YS5 through the chelator TCMC to create the radioimmunoconjugate, Pb-TCMC-YS5. We characterized Pb-TCMC-YS5 in vitro and established a safe dose in vivo. We next studied therapeutic efficacy of a single dose of Pb-TCMC-YS5 using three prostate cancer small animal models: a subcutaneous mCRPC cell line-derived xenograft (CDX) model (subcu-CDX), an orthotopically grafted mCRPC CDX model (ortho-CDX), and a prostate cancer patient-derived xenograft model (PDX). In all three models, a single dose of 0.74 MBq (20 µCi) Pb-TCMC-YS5 was well tolerated and caused potent and sustained inhibition of established tumors, with significant increases of survival in treated animals. A lower dose (0.37 MBq or 10 µCi Pb-TCMC-YS5) was also studied on the PDX model, which also showed a significant effect on tumor growth inhibition and prolongation of animal survival. These results demonstrate that Pb-TCMC-YS5 has an excellent therapeutic window in preclinical models including PDXs, opening a direct path for clinical translation of this novel CD46-targeted alpha radioimmunotherapy for mCRPC treatment.
Topics: Male; Animals; Humans; Radioimmunotherapy; Lead; Alpha Particles; Prostatic Neoplasms, Castration-Resistant; Lead Radioisotopes; Membrane Cofactor Protein
PubMed: 36906664
DOI: 10.1186/s13046-023-02636-x -
American Society of Clinical Oncology... 2014Because alpha-particles have a shorter range and a higher linear energy transfer (LET) compared with beta-particles, targeted alpha-particle immunotherapy offers the... (Review)
Review
Because alpha-particles have a shorter range and a higher linear energy transfer (LET) compared with beta-particles, targeted alpha-particle immunotherapy offers the potential for more efficient tumor cell killing while sparing surrounding normal cells. To date, clinical studies of alpha-particle immunotherapy for acute myeloid leukemia (AML) have focused on the myeloid cell surface antigen CD33 as a target using the humanized monoclonal antibody lintuzumab. An initial phase I study demonstrated the safety, feasibility, and antileukemic effects of bismuth-213 ((213)Bi)-labeled lintuzumab. In a subsequent study, (213)Bi-lintuzumab produced remissions in some patients with AML after partial cytoreduction with cytarabine, suggesting the utility of targeted alpha-particle therapy for small-volume disease. The widespread use of (213)Bi, however, is limited by its short half-life. Therefore, a second-generation construct containing actinium-225 ((225)Ac), a radiometal that generates four alpha-particle emissions, was developed. A phase I trial demonstrated that (225)Ac-lintuzumab is safe at doses of 3 μCi/kg or less and has antileukemic activity across all dose levels studied. Fractionated-dose (225)Ac-lintuzumab in combination with low-dose cytarabine (LDAC) is now under investigation for the management of older patients with untreated AML in a multicenter trial. Preclinical studies using (213)Bi- and astatine-211 ((211)At)-labeled anti-CD45 antibodies have shown that alpha-particle immunotherapy may be useful as part conditioning before hematopoietic cell transplantation. The use of novel pretargeting strategies may further improve target-to-normal organ dose ratios.
Topics: Alpha Particles; Animals; Antibodies, Monoclonal, Humanized; Bismuth; Clinical Trials as Topic; Humans; Immunoconjugates; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Radioimmunotherapy; Radioisotopes
PubMed: 24857092
DOI: 10.14694/EdBook_AM.2014.34.e126 -
Sensors (Basel, Switzerland) Mar 2018The United Kingdom (UK) has a significant legacy of nuclear installations to be decommissioned over the next 100 years and a thorough characterisation is required prior... (Review)
Review
Alpha Particle Detection Using Alpha-Induced Air Radioluminescence: A Review and Future Prospects for Preliminary Radiological Characterisation for Nuclear Facilities Decommissioning.
The United Kingdom (UK) has a significant legacy of nuclear installations to be decommissioned over the next 100 years and a thorough characterisation is required prior to the development of a detailed decommissioning plan. Alpha radiation detection is notoriously time consuming and difficult to carry out due to the short range of alpha particles in air. Long-range detection of alpha particles is therefore highly desirable and this has been attempted through the detection of secondary effects from alpha radiation, most notably the air-radioluminescence caused by ionisation. This paper evaluates alpha induced air radioluminescence detectors developed to date and looks at their potential to develop a stand-off, alpha radiation detector which can be used in the nuclear decommissioning field in daylight conditions to detect alpha contaminated materials.
PubMed: 29597340
DOI: 10.3390/s18041015