The BioActinide Chemistry Group is a part of Lawrence Berkeley National Laboratory's Chemical Sciences Division. We are located in Berkeley, California, USA.
The multidisciplinary research undergone in the group is at the interface of coordination chemistry, analytical chemistry, photophysics, biological chemistry, health physics, pharmacology, and molecular and cellular biology. We study the effects of heavy element exposure and contamination on different biological systems in addition to the coordination chemistry and metabolic properties of lanthanide and actinide complexes formed with synthetic and biological ligands. Our goals are to gain a better understanding of the biological coordination chemistry and toxicity mechanisms of the f-elements and to develop specific strategies for decontamination, remediation, and separation. Other applications include the development of new antimicrobial strategies that target metalacquisition systems and the design of advanced alpha-immuno therapeutic and diagnostic agents.
Actinide Decorporation Program
Exposure to radionuclides in the context of a nuclear accident or attack may have disastrous consequences. The only practical therapy for internal actinide contamination is treatment with sequestering agents that can form excretable low-molecular-weight complexes. This project aims to mitigate the toxic effects of human contamination with radioactive heavy metals such as plutonium or uranium, using biomimetic synthetic chelators that exhibit extremely high affinity and specificity for targeted radionuclides. The pre-clinical development program for two lead compounds led to an IND filing for the actinide decorporation agent, 3,4,3-LI(1,2-HOPO), which is formulated as an oral therapeutic. The approval to proceed to first-in-human clinical studies for this compound was received in August 2014 and initiated the next development phase that will ultimately bring this new pharmaceutical to a licensure stage. Approval of such an orally available pharmaceutical would address the urgent international need in nuclear safety and public health posed by the increasing global use of nuclear energy and the sustained threat of nuclear incidents.
Toxicity Pathways and Transport Mechanisms
Actinides and lanthanide fission products, as well as other radionuclides from the nuclear fuel process, are a severe health risk as contaminants due to both radiological and chemical toxicity. The toxicity of these ions is governed by uptake mechanisms, oxidation state and speciation, intracellular distribution, and interactions with various macromolecules, and depends on their physiochemical properties and ligand preferences. Little is known about the toxicity mechanisms of actinides and lanthanides at the molecular level, the impact of radiation induced damage versus chemically induced damage, and how metal sensing translates into appropriate cellular responses. We are applying modern biochemical methodologies to study actinide and lanthanide speciation, biochemistry, and resulting toxicity in biological samples. We are systematically investigating the consequences of exposure to radioactive and non-radioactive f-block metals using a combined functional genomic, biochemical, and spectroscopic approach on different rodent tissue samples and the powerful eukaryote model, S. cerevisiae. Functional genomic analyses include: (i) characterization of gene expression through RNA microarrays and functional gene arrays to capture alterations in genetic regulation, and (ii) characterization of protein regulation and identification of metal-protein complexes using mass spectrometry, fluorescence spectroscopy, radio-detection, liquid chromatography, and gel electrophoresis.
Ligand Design for Actinide Sensitization and f-Orbital Bonding Characterization
The need to (i) resolve the role of f-electrons in lanthanide and actinide bonding and (ii) understand and design new molecular systems that control the chemical selectivity of f-elements constitutes two scientific challenges in the development of improved materials and processes for nuclear applications in energy and medicine. To address these needs, our research aims to enable the selective tuning of spectroscopic and thermodynamic properties of specific lanthanide and actinide complexes through precision ligand design and molecular recognition. Systematic and iterative characterization of the designed species are used to harness the influence of f-orbital bonding on differences in lanthanide and actinide complex energetic and coordination features, including kinetic, thermodynamic, and optical properties. We are exploring the lanthanide and actinide sensitization efficiency of selective ligands through the antenna effect in order to develop thermodynamically stable complex systems that display characteristic optical features. These features will be essential to the development of new therapeutic strategies, environmental decontamination platforms, and diagnostic probes in nuclear medicine. Corresponding energetic and optical data also provide critical benchmarks for the development of theoretical models that may accurately describe and predict f-orbital bonding.
Our work has been funded by the programs of Federal Agencies, private foundations, and corporate entities:
- AbbVie StemCentrx LLC (2016- )
- Bayer AS (2016- )
- DOE Nuclear Physics Isotope Production Program (2016- )
- DOE Basic Energy Science Heavy Element Chemistry Program (2014- )
- DOE Early Career Program (2014- )
- LBNL LDRD Programs (2011-2012) (2015-2016)
- NIH/NIAID Medical Countermeasures Against Radiological Threats (MCART) Consortium (2012-2015)
- BARDA 1PIAA12OS99609 (2012-2014)
- NIH/NIAID GO Grant RAI087604Z (2009-2012)
- Cooley's Anemia Foundation Junior Faculty Research Fellowship (2009-2011)