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Title: SU-C-204-03: DFT Calculations of the Stability of DOTA-Based-Radiopharmaceuticals

Abstract

Purpose: Application of the density function theory (DFT) to investigate the structural stability of complexes applied in cancer therapy consisting of the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelated to Ac225, Fr221, At217, Bi213, and Gd68 radio-nuclei. Methods: The possibility to deliver a toxic payload directly to tumor cells is a highly desirable aim in targeted alpha particle therapy. The estimation of bond stability between radioactive atoms and the DOTA chelating agent is the key element in understanding the foundations of this delivery process. Thus, we adapted the Vienna Ab-initio Simulation Package (VASP) with the projector-augmented wave method and a plane-wave basis set in order to study the stability and electronic properties of DOTA ligand chelated to radioactive isotopes. In order to count for the relativistic effect of radioactive isotopes we included Spin-Orbit Coupling (SOC) in the DFT calculations. Five DOTA complex structures were represented as unit cells, each containing 58 atoms. The energy optimization was performed for all structures prior to calculations of electronic properties. Binding energies, electron localization functions as well as bond lengths between atoms were estimated. Results: Calculated binding energies for DOTA-radioactive atom systems were −17.792, −5.784, −8.872, −13.305, −18.467 eV for Ac, Fr, At, Bi and Gd complexesmore » respectively. The displacements of isotopes in DOTA cages were estimated from the variations in bond lengths, which were within 2.32–3.75 angstroms. The detailed representation of chemical bonding in all complexes was obtained with the Electron Localization Function (ELF). Conclusion: DOTA-Gd, DOTA-Ac and DOTA-Bi were the most stable structures in the group. Inclusion of SOC had a significant role in the improvement of DFT calculation accuracy for heavy radioactive atoms. Our approach is found to be proper for the investigation of structures with DOTA-based-radiopharmaceuticals and will enhance our understanding of processes occurring at subatomic levels.« less

Authors:
;  [1]; ; ;  [2]; ;  [1];  [3]
  1. University of South Florida, Tampa, Florida (United States)
  2. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States)
  3. (United States)
Publication Date:
OSTI Identifier:
22624301
Resource Type:
Journal Article
Resource Relation:
Journal Name: Medical Physics; Journal Volume: 43; Journal Issue: 6; Other Information: (c) 2016 American Association of Physicists in Medicine; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; 60 APPLIED LIFE SCIENCES; 61 RADIATION PROTECTION AND DOSIMETRY; ACTINIUM 225; ASTATINE 217; BINDING ENERGY; BISMUTH 213; BOND LENGTHS; CHELATES; CHELATING AGENTS; CHEMICAL BONDS; FRANCIUM 221; GADOLINIUM COMPLEXES; NEOPLASMS; PARTICLE BEAMS; RADIOPHARMACEUTICALS; RADIOTHERAPY; RELATIVISTIC RANGE; TUMOR CELLS

Citation Formats

Khabibullin, A.R., Woods, L.M., Karolak, A., Budzevich, M.M., Martinez, M.V., McLaughlin, M.L., Morse, D.L., and H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. SU-C-204-03: DFT Calculations of the Stability of DOTA-Based-Radiopharmaceuticals. United States: N. p., 2016. Web. doi:10.1118/1.4955536.
Khabibullin, A.R., Woods, L.M., Karolak, A., Budzevich, M.M., Martinez, M.V., McLaughlin, M.L., Morse, D.L., & H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. SU-C-204-03: DFT Calculations of the Stability of DOTA-Based-Radiopharmaceuticals. United States. doi:10.1118/1.4955536.
Khabibullin, A.R., Woods, L.M., Karolak, A., Budzevich, M.M., Martinez, M.V., McLaughlin, M.L., Morse, D.L., and H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 2016. "SU-C-204-03: DFT Calculations of the Stability of DOTA-Based-Radiopharmaceuticals". United States. doi:10.1118/1.4955536.
@article{osti_22624301,
title = {SU-C-204-03: DFT Calculations of the Stability of DOTA-Based-Radiopharmaceuticals},
author = {Khabibullin, A.R. and Woods, L.M. and Karolak, A. and Budzevich, M.M. and Martinez, M.V. and McLaughlin, M.L. and Morse, D.L. and H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida},
abstractNote = {Purpose: Application of the density function theory (DFT) to investigate the structural stability of complexes applied in cancer therapy consisting of the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelated to Ac225, Fr221, At217, Bi213, and Gd68 radio-nuclei. Methods: The possibility to deliver a toxic payload directly to tumor cells is a highly desirable aim in targeted alpha particle therapy. The estimation of bond stability between radioactive atoms and the DOTA chelating agent is the key element in understanding the foundations of this delivery process. Thus, we adapted the Vienna Ab-initio Simulation Package (VASP) with the projector-augmented wave method and a plane-wave basis set in order to study the stability and electronic properties of DOTA ligand chelated to radioactive isotopes. In order to count for the relativistic effect of radioactive isotopes we included Spin-Orbit Coupling (SOC) in the DFT calculations. Five DOTA complex structures were represented as unit cells, each containing 58 atoms. The energy optimization was performed for all structures prior to calculations of electronic properties. Binding energies, electron localization functions as well as bond lengths between atoms were estimated. Results: Calculated binding energies for DOTA-radioactive atom systems were −17.792, −5.784, −8.872, −13.305, −18.467 eV for Ac, Fr, At, Bi and Gd complexes respectively. The displacements of isotopes in DOTA cages were estimated from the variations in bond lengths, which were within 2.32–3.75 angstroms. The detailed representation of chemical bonding in all complexes was obtained with the Electron Localization Function (ELF). Conclusion: DOTA-Gd, DOTA-Ac and DOTA-Bi were the most stable structures in the group. Inclusion of SOC had a significant role in the improvement of DFT calculation accuracy for heavy radioactive atoms. Our approach is found to be proper for the investigation of structures with DOTA-based-radiopharmaceuticals and will enhance our understanding of processes occurring at subatomic levels.},
doi = {10.1118/1.4955536},
journal = {Medical Physics},
number = 6,
volume = 43,
place = {United States},
year = 2016,
month = 6
}
  • Purpose: Commonly used radiopharmaceuticals were tested to define the most important dosimetric factors in preclinical studies. Dosimetric calculations were applied in two different whole-body mouse models, with varying organ size, so as to determine their impact on absorbed doses and S-values. Organ mass influence was evaluated with computational models and Monte Carlo(MC) simulations. Methods: MC simulations were executed on GATE to determine dose distribution in the 4D digital MOBY mouse phantom. Two mouse models, 28 and 34 g respectively, were constructed based on realistic preclinical exams to calculate the absorbed doses and S-values of five commonly used radionuclides in SPECT/PETmore » studies (18F, 68Ga, 177Lu, 111In and 99mTc).Radionuclide biodistributions were obtained from literature. Realistic statistics (uncertainty lower than 4.5%) were acquired using the standard physical model in Geant4. Comparisons of the dosimetric calculations on the two different phantoms for each radiopharmaceutical are presented. Results: Dose per organ in mGy was calculated for all radiopharmaceuticals. The two models introduced a difference of 0.69% in their brain masses, while the largest differences were observed in the marrow 18.98% and in the thyroid 18.65% masses.Furthermore, S-values of the most important target-organs were calculated for each isotope. Source-organ was selected to be the whole mouse body.Differences on the S-factors were observed in the 6.0–30.0% range. Tables with all the calculations as reference dosimetric data were developed. Conclusion: Accurate dose per organ and the most appropriate S-values are derived for specific preclinical studies. The impact of the mouse model size is rather high (up to 30% for a 17.65% difference in the total mass), and thus accurate definition of the organ mass is a crucial parameter for self-absorbed S values calculation.Our goal is to extent the study for accurate estimations in small animal imaging, whereas it is known that there is a large variety in the anatomy of the organs.« less
  • Highlights: • Development of improved tumor-targeting MRI contrast agents. • To increase the targeting ability of RGD, we developed cycloalkane-based RGD peptides. • Gd(DOTA) conjugates of cycloalkane-based RGD peptide show improved tumor signal enhancement in vivo MR images. - Abstract: Two new MRI contrast agents, Gd-DOTA-c(RGD-ACP-K) (1) and Gd-DOTA-c(RGD-ACH-K) (2), which were designed by incorporating aminocyclopentane (ACP)- or aminocyclohexane (ACH)-carboxylic acid into Gd-DOTA (gadolinium-tetraazacyclo dodecanetetraacetic acid) and cyclic RGDK peptides, were synthesized and evaluated for tumor-targeting ability in vitro and in vivo. Binding affinity studies showed that both 1 and 2 exhibited higher affinity for integrin receptors than cyclic RGDyKmore » peptides, which were used as a reference. These complexes showed high relaxivity and good stability in human serum and have the potential to improve target-specific signal enhancement in vivo MR images.« less