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Title: Automated cassette-based production of high specific activity [ 203/212Pb]peptide-based theranostic radiopharmaceuticals for image-guided radionuclide therapy for cancer

Abstract

A method for preparation of Pb-212 and Pb-203 labeled chelator-modified peptide-based radiopharmaceuticals for cancer imaging and radionuclide therapy has been developed and adapted for automated clinical production. Pre-concentration and isolation of radioactive Pb2+ from interfering metals in dilute hydrochloric acid was optimized using a commercially-available Pb-specific chromatography resin packed in disposable plastic columns. The pre-concentrated radioactive Pb2+ is eluted in NaOAc buffer directly to the reaction vessel containing chelator-modified peptides. Radiolabeling was found to proceed efficiently at 85 °C (45 min; pH 5.5). The specific activity of radiolabeled conjugates was optimized by separation of radiolabeled conjugates from unlabeled peptide via HPLC. Preservation of bioactivity was confirmed by in vivo biodistribution of Pb-203 and Pb-212 labeled peptides in melanoma-tumor-bearing mice. The approach has been found to be robustly adaptable to automation and a cassette-based fluid-handling system (Modular Lab Pharm Tracer) has been customized for clinical radiopharmaceutical production. Our findings demonstrate that the Pb-203/Pb-212 combination is a promising elementally-matched radionuclide pair for image-guided radionuclide therapy for melanoma, neuroendocrine tumors, and potentially other cancers.

Authors:
 [1];  [2];  [2];  [1];  [3];  [4];  [5];  [6];  [7];  [8]; ORCiD logo [9]; ORCiD logo [9];  [10];  [11]
  1. Univ. of Iowa, Iowa City, IA (United States). Interdisciplinary Graduate Program in Human Toxicology
  2. Univ. of Missouri, Columbia, MO (United States). Dept. of Biochemistry
  3. Univ. of Iowa, Iowa City, IA (United States). Stead Family Dept. of Pediatrics
  4. Eckert & Ziegler Radiopharma GmbH, Berlin (Germany)
  5. National Inst. of Standards and Technology (NIST), Gaithersburg, MD (United States)
  6. Eichrom Technologies, LLC, Lisle, IL (United States)
  7. Lantheus Medical Imaging North Billerica, MA (United States)
  8. Univ. of Iowa, Iowa City, IA (United States). Dept. of Radiology
  9. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  10. Viewpoint Molecular Targeting, LLC, Coralville, IA (United States); Univ. of Iowa, Iowa City, IA (United States). Carver College of Medicine, Dept. of Internal Medicine
  11. Univ. of Iowa, Iowa City, IA (United States). Interdisciplinary Graduate Program in Human Toxicology; Univ. of Iowa, Iowa City, IA (United States). Stead Family Dept. of Pediatrics; Univ. of Iowa, Iowa City, IA (United States). Dept. of Radiology; Viewpoint Molecular Targeting, LLC, Coralville, IA (United States); Univ. of Iowa, Iowa City, IA (United States). Carver College of Medicine, Dept. of Radiation Oncology; Univ. of Iowa, Iowa City, IA (United States). Dept. of Chemistry
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1491308
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Accepted Manuscript
Journal Name:
Applied Radiation and Isotopes
Additional Journal Information:
Journal Volume: 127; Journal Issue: C; Journal ID: ISSN 0969-8043
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Radionuclides; Pb-203; Pb-212; Alpha particle therapy; Peptides; Radiopharmaceuticals

Citation Formats

Li, Mengshi, Zhang, Xiuli, Quinn, Thomas P., Lee, Dongyoul, Liu, Dijie, Kunkel, Falk, Zimmerman, Brian E., McAlister, Daniel, Olewein, Keith, Menda, Yusuf, Mirzadeh, Saed, Copping, Roy, Johnson, Frances L., and Schultz, Michael K. Automated cassette-based production of high specific activity [203/212Pb]peptide-based theranostic radiopharmaceuticals for image-guided radionuclide therapy for cancer. United States: N. p., 2017. Web. doi:10.1016/j.apradiso.2017.05.006.
Li, Mengshi, Zhang, Xiuli, Quinn, Thomas P., Lee, Dongyoul, Liu, Dijie, Kunkel, Falk, Zimmerman, Brian E., McAlister, Daniel, Olewein, Keith, Menda, Yusuf, Mirzadeh, Saed, Copping, Roy, Johnson, Frances L., & Schultz, Michael K. Automated cassette-based production of high specific activity [203/212Pb]peptide-based theranostic radiopharmaceuticals for image-guided radionuclide therapy for cancer. United States. doi:10.1016/j.apradiso.2017.05.006.
Li, Mengshi, Zhang, Xiuli, Quinn, Thomas P., Lee, Dongyoul, Liu, Dijie, Kunkel, Falk, Zimmerman, Brian E., McAlister, Daniel, Olewein, Keith, Menda, Yusuf, Mirzadeh, Saed, Copping, Roy, Johnson, Frances L., and Schultz, Michael K. Wed . "Automated cassette-based production of high specific activity [203/212Pb]peptide-based theranostic radiopharmaceuticals for image-guided radionuclide therapy for cancer". United States. doi:10.1016/j.apradiso.2017.05.006. https://www.osti.gov/servlets/purl/1491308.
@article{osti_1491308,
title = {Automated cassette-based production of high specific activity [203/212Pb]peptide-based theranostic radiopharmaceuticals for image-guided radionuclide therapy for cancer},
author = {Li, Mengshi and Zhang, Xiuli and Quinn, Thomas P. and Lee, Dongyoul and Liu, Dijie and Kunkel, Falk and Zimmerman, Brian E. and McAlister, Daniel and Olewein, Keith and Menda, Yusuf and Mirzadeh, Saed and Copping, Roy and Johnson, Frances L. and Schultz, Michael K.},
abstractNote = {A method for preparation of Pb-212 and Pb-203 labeled chelator-modified peptide-based radiopharmaceuticals for cancer imaging and radionuclide therapy has been developed and adapted for automated clinical production. Pre-concentration and isolation of radioactive Pb2+ from interfering metals in dilute hydrochloric acid was optimized using a commercially-available Pb-specific chromatography resin packed in disposable plastic columns. The pre-concentrated radioactive Pb2+ is eluted in NaOAc buffer directly to the reaction vessel containing chelator-modified peptides. Radiolabeling was found to proceed efficiently at 85 °C (45 min; pH 5.5). The specific activity of radiolabeled conjugates was optimized by separation of radiolabeled conjugates from unlabeled peptide via HPLC. Preservation of bioactivity was confirmed by in vivo biodistribution of Pb-203 and Pb-212 labeled peptides in melanoma-tumor-bearing mice. The approach has been found to be robustly adaptable to automation and a cassette-based fluid-handling system (Modular Lab Pharm Tracer) has been customized for clinical radiopharmaceutical production. Our findings demonstrate that the Pb-203/Pb-212 combination is a promising elementally-matched radionuclide pair for image-guided radionuclide therapy for melanoma, neuroendocrine tumors, and potentially other cancers.},
doi = {10.1016/j.apradiso.2017.05.006},
journal = {Applied Radiation and Isotopes},
number = C,
volume = 127,
place = {United States},
year = {2017},
month = {5}
}

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Figures / Tables:

Fig. 1 Fig. 1: 224Ra/212Pb generator and decay scheme, including parent radionuclide 228Th. 212Pb is eluted periodically (approximately once every 24 h). The generator has a useful life that is governed by the 3.62 day half life of 224Ra.

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Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.