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Cited by 157Radiopharmaceutical Chemistry and ApplicationsRadioactivity and Radon MeasurementsChemical Reactions and Isotopes

The DOI matches its Crossref record; 266 of the 283 references it cites were found in a registry or an index.

Development of targeted alpha particle therapy for solid tumors.

Open access
Tafreshi, Narges K., Doligalski, Michael L., Tichacek, Christopher J., Pandya, Darpan N., Budzevich, Mikalai M., El-Haddad, Ghassan, Khushalani, Nikhil I., Moros, Eduardo G., McLaughlin, Mark L., Wadas, Thaddeus J., Morse, David L.·2019·Molecules
DOI 10.3390/molecules24234314PMC PMC6930656
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Abstract

Targeted alpha-particle therapy (TAT) aims to selectively deliver radionuclides emitting α-particles (cytotoxic payload) to tumors by chelation to monoclonal antibodies, peptides or small molecules that recognize tumor-associated antigens or cell-surface receptors. Because of the high linear energy transfer (LET) and short range of alpha (α) particles in tissue, cancer cells can be significantly damaged while causing minimal toxicity to surrounding healthy cells. Recent clinical studies have demonstrated the remarkable efficacy of TAT in the treatment of metastatic, castration-resistant prostate cancer. In this comprehensive review, we discuss the current consensus regarding the properties of the α-particle-emitting radionuclides that are potentially relevant for use in the clinic; the TAT-mediated mechanisms responsible for cell death; the different classes of targeting moieties and radiometal chelators available for TAT development; current approaches to calculating radiation dosimetry for TATs; and lead optimization via medicinal chemistry to improve the TAT radiopharmaceutical properties. We have also summarized the use of TATs in pre-clinical and clinical studies to date.

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Crossref · 10.3390/molecules24234314

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Figures

Figure 1 68Ga-PSMA-11 PET/CT images of a treatment-naïve patient with extensive bone metastasis at primary diagnosis. A complete remission was observed after three cycles of 225Ac-PSMA-617 with de-escalating activities of 8/7/6 MBq. The patient remained symptom-free with undetectable serum PSA and a negative 68Ga-PSMA-11 PET/CT at 11-month follow-up evaluation. This figure and legend were reproduced from Sathekge, et al. [6].
Figure 1 68Ga-PSMA-11 PET/CT images of a treatment-naïve patient with extensive bone metastasis at primary diagnosis. A complete remission was observed after three cycles of 225Ac-PSMA-617 with de-escalating activities of 8/7/6 MBq. The patient remained symptom-free with undetectable serum PSA and a negative 68Ga-PSMA-11 PET/CT at 11-month follow-up evaluation. This figure and legend were reproduced from Sathekge, et al. [6].CC BY · PubMed Central
Figure 2 (A) Linear energy transfer (LET) versus distance in water traveled by typical α-particles emitted by radionuclides in development for α-particle radioimmunotherapy: 225Ac (5.829 MeV)/213Bi (8.375 MeV), 211At (5.867 MeV), 212Bi (6.08 MeV)/212Po (8.78 MeV), 223Ra (5.716 MeV). The range of the α-particle and the position of the Bragg peaks are correlated with the initial energy of the α-particles. LET of α-particles in water was calculated using stopping-power and range tables (continuous slowing down approximation range) for electrons, protons and helium ions from the National Institute of Standards and Technology (NIST). (B) The deposition of heavy ion energy as a function of penetrating depth of (a) a pristine beam and (b) a modulated beam with widened stopping region (spread out Bragg peaks). This figure and legend were reproduced from [19].
Figure 2 (A) Linear energy transfer (LET) versus distance in water traveled by typical α-particles emitted by radionuclides in development for α-particle radioimmunotherapy: 225Ac (5.829 MeV)/213Bi (8.375 MeV), 211At (5.867 MeV), 212Bi (6.08 MeV)/212Po (8.78 MeV), 223Ra (5.716 MeV). The range of the α-particle and the position of the Bragg peaks are correlated with the initial energy of the α-particles. LET of α-particles in water was calculated using stopping-power and range tables (continuous slowing down approximation range) for electrons, protons and helium ions from the National Institute of Standards and Technology (NIST). (B) The deposition of heavy ion energy as a function of penetrating depth of (a) a pristine beam and (b) a modulated beam with widened stopping region (spread out Bragg peaks). This figure and legend were reproduced from [19].CC BY · PubMed Central
Figure 3 Survival of a human kidney T-cell culture irradiated with ionizing particles of different kinds: (1) particles with E = 2.5 MeV, LET = 165 keV/m; (2) particles with E = 27 MeV, LET = 25 keV/m; (3) deuterons with E = 3.0 MeV, LET = 20 keV/m; (4) X-rays with E = 20 keV and LET = 6 keV/m; (5) X-rays with E = 250 keV and LET = 2.5 keV/m; and (6) particles with E = 2.2 MeV, LET = 0.3 keV/m. This figure and legend were reproduced from [21].
Figure 3 Survival of a human kidney T-cell culture irradiated with ionizing particles of different kinds: (1) particles with E = 2.5 MeV, LET = 165 keV/m; (2) particles with E = 27 MeV, LET = 25 keV/m; (3) deuterons with E = 3.0 MeV, LET = 20 keV/m; (4) X-rays with E = 20 keV and LET = 6 keV/m; (5) X-rays with E = 250 keV and LET = 2.5 keV/m; and (6) particles with E = 2.2 MeV, LET = 0.3 keV/m. This figure and legend were reproduced from [21].CC BY · PubMed Central
Figure 4 The somatostatin mimetic octreotide and its DOTA-containing analogs. Octreotide: R1 = H, R2 = H and R3 = CH2OH; DOTATOC (endotreotide): R1 = DOTA, R2 = OH and R3 = CO2H; DOTATATE (Octreotate): R1 = DOTA, R2 = OH and R3 = CH2OH.
Figure 4 The somatostatin mimetic octreotide and its DOTA-containing analogs. Octreotide: R1 = H, R2 = H and R3 = CH2OH; DOTATOC (endotreotide): R1 = DOTA, R2 = OH and R3 = CO2H; DOTATATE (Octreotate): R1 = DOTA, R2 = OH and R3 = CH2OH.CC BY · PubMed Central
Figure 5 Common metal chelators and binders used to attach radionuclides to targeting ligands.
Figure 5 Common metal chelators and binders used to attach radionuclides to targeting ligands.CC BY · PubMed Central
Figure 6 Common conjugation chemistries used to functionalize biomolecules. Countless other schemes have been well characterized and the reader is directed to Bioconjugates Techniques for a review and protocols [117].
Figure 6 Common conjugation chemistries used to functionalize biomolecules. Countless other schemes have been well characterized and the reader is directed to Bioconjugates Techniques for a review and protocols [117].CC BY · PubMed Central

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Citations

Cites

Show all 283 references

Research works printed but not linked: 6

  1. Hall, E.J., and Giaccia, A.J. (2006). Radiobiology for the Radiologist, Lippincott Williams & Wilkins.
  2. Hermanson, G.T. (2013). Bioconjugate Techniques, Academic Press. [3rd ed.].
  3. Loevinger, R., Budinger, T.F., and Watson, E.E. (1991). MIRD Primer for Absorbed Dose Calculations, Revised Edition, The Society of Nuclear Medicine, Inc.
  4. Gil, A.V., Pérez, M.C., Aroche, L.T., Pacilio, M., Botta, F., and Cremonesi, M. (2012, January 3–7). MCID: A personalized dosimetric tool associating voxel-based models with MCNP5. Proceedings of the IAEA International Conference on Radiation Protection in Medicine, Setting the Scene for the Next Decade, Bonn, Germany.
  5. Liu, 2001, DOSIMG: A 3D voxel-based Monte Carlo program for absorbed dose calculations, J. Nucl. Med., 42, 243P
  6. Kratochwil, 2015, Ac-225-DOTATOCan empiric dose finding for alpha particle emitter based radionuclide therapy of neuroendocrine tumors, J. Nucl. Med., 56, 1232

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Metadata

Authors
Tafreshi, N. K., Doligalski, M. L., Tichacek, C. J., Pandya, D. N., Budzevich, M. M., El-Haddad, G., Khushalani, N. I., Moros, E. G., McLaughlin, M. L., Wadas, T. J., & Morse, D. L.
Affiliations
  • Moffitt Cancer Center (US)
  • Wake Forest University Health Sciences (US)
  • University of South Florida (US)
  • West Virginia University (US)
Corresponding author
Morse, David L.
ORCID
Venue
Molecules
Publisher
MDPI AG
Published
2019-11-26
Volume
24
Issue
23
Pages
4314
ISSN
1420-3049 (ISSN-L)
DOI
10.3390/molecules24234314
PMC
PMC6930656
OpenAlex
W2990493095
Cited by
157
References
283
Citations by year
2026: 21 · 2025: 25 · 2024: 24 · 2023: 26 · 2022: 23 · 2021: 30 · 2020: 7
FWCI
2.25
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • The Research Repository @ WVU (West Virginia University) (submittedVersion, cc-by)
Funders
  • Melanoma Research Alliance
  • National Institutes of Health
  • National Cancer Institute (P50CA168536)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
  • Physical Sciences › Physics and Astronomy › Radiation › Radioactivity and Radon Measurements
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Chemical Reactions and Isotopes
Keywords
alpha-emitting radionuclides, radiopharmaceuticals, linear energy transfer, tumor targeting, radiation dosimetry, castration-resistant prostate cancer, metastatic prostate cancer, cell death mechanisms, solid tumors
MeSH terms
Alpha Particles, Animals, Antibodies, Monoclonal, Humans, Neoplasms, Radioisotopes, Radiometry, Radiopharmaceuticals

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