Historically, contamination due to radioactive materials has generally been limited to small numbers of radiation workers in controlled situations, with appropriate expertise available for diagnosis and treatment. Medical management of individuals with internal radiological contamination focuses on removing the radioactive material from the body, a process called radionuclide decorporation. Strategies for decorporation are fairly simple; for example, one method is binding the radionuclide so the body cannot absorb it and it can be passed out through the colon. In today’s world, a terrorist event such as a so-called “dirty bomb” could contaminate hundreds in a single incident. Effective decorporation agents would be needed quickly and in large quantities. These researchers are developing two agents that can bind plutonium so it is unavailable for absorption by the body. These agents are up to 30 times more active than any currently in use for this purpose.
Therapy for radioisotope contamination of a large population by a dirty bomb or other event will require a cocktail of decorporation agents because of the wide variety of possible radionuclides and their chemical/biological properties. Decorporation is the only way to reduce exposure of certain incorporated radioisotopes. Fission product lanthanides and the actinides are among the most intractable of these elements to decorporate. While diethylenetriaminepentaacetic acid (DTPA) has been the standard therapy for actinide/lanthanide decorporation since its development and use by the U.S. Atomic Energy Commission in the 1950s, it is limited in efficacy. A new family of sequestering agents has been developed using a biomimetic design based on the similar biochemical transport properties of plutonium(IV) and iron(III). These agents are more selective and have higher affinity for plutonium(IV) and a number of other actinide metal ions. Extensive toxicity and efficacy studies using a mouse model have been published, and limited tests have been done in dogs and baboons.
The results established that several of the new agents are up to 30 times more effective than DTPA and, unlike DTPA, can be orally active. Under a currently funded NIAID Bioshield project, we have conducted additional studies with two lead compounds, 3,4,3-LI-1,2-HOPO (an octadentate ligand) and 5-LIO-Me-3,2-HOPO (a tetradentate ligand), with the intention of moving these two ligands toward clinical use by scaling up the synthesis, establishing preparation methods suitable for good manufacturing practice (GMP), carrying out limited efficacy and toxicity studies for combinations of the two chelators in a mouse model, completing toxicity studies in human cell lines, and establishing preclinical safety of the candidate ligands under good laboratory practice (GLP) guidelines. This has been accomplished by an effective partnering of the Actinide Chemistry Group of Lawrence Berkeley National Laboratory (LBNL), which has expertise in ligand design, synthesis and laboratory testing, with SRI International, which has expertise in GLP testing and bringing pharmaceutical products to market.
The objective of this application is to enable the availability of multi-kilogram amounts of these two new decorporation agents so that test compound availability does not become a bottleneck in studies leading to clinical availability. This will be work in tandem with the NIAID Bioshield program to develop a pre–Investigational New Drug (IND) stage to obtain FDA input in our development plan, followed by additional pivotal testing necessary for the successful filing of a full IND application.
University of California, Berkeley
Kenneth N. Raymond, Ph.D.
Eleanor Blakely, Ph.D.
Polly Chang, Ph.D.
Patricia Durbin, Ph.D.
David Shuh, Ph.D.
Public Health Impact
Therapy for radioisotope contamination of a large population by a dirty bomb or other event will require a cocktail of decorporation agents because of the wide variety of possible radionuclides and their chemical/biological properties. The new family of sequestering agents produced in the Berkeley program are more selective and have higher affinity for plutonium(IV) and a number of other actinide metal ions than diethylenetriaminepentaacetic, which has been the standard therapy for actinide/lanthanide decorporation for the last 60 years.
Work on this project is complete. Additional preclinical development was supported by the National Institute of Allergy and Infectious Diseases’ Radiation and Nuclear Countermeasures Program. The investigator successfully filed an IND application using BrIDGs data and material.
- Synthesis of Good Manufacturing Practice (GMP) material