APPLICATIONS OF TECHNOLOGY:
- Ablation of target tissue
- Oncology imaging and treatment
- Targeted delivery of nuclides for better imaging
- Precise and effective treatment for certain cancers that preserves surrounding cells and tissues
Targeted alpha therapy is highly promising as a cancer treatment. It has the potential to deliver a highly cytotoxic dose to targeted cells while minimizing damage to surrounding healthy tissue. The metallic, short-lived, alpha-generating radioisotopes 225Ac and 227Th are among the most promising radionuclides for therapeutic use. In order to harness their benefits, adequate chelation and targeting is necessary.
Berkeley Lab scientists have developed a new cancer therapy delivery mechanism that harnesses the therapeutic potential of radioisotopes 225Ac and 227Th. It comprises (1) a therapeutic radionuclide, (2) a chelator for binding to the therapeutic radionuclide, (3) a protein, siderocalin wrapping around the chelator, and (4) antigen receptors on the siderocalin for targeting cancer cells.
The platform consists of a multidentate, high-affinity, oxygen-donating ligand, such as 3,4,3-Ll(CAM), bound to the mammalian protein siderocalin. This class of ligands is found to encompass some of the most powerful chelators for both trivalent and tetravalent metal ions at physiological pH. Moreover, the resulting metal complexes are also bound with extremely high affinity by siderocalin, as evidenced by X-ray structures of the protein.
Differences in biodistribution profiles between free and siderocalin-bound complexes confirm in vivo stability of the protein construct. Other examples of octadentate chelating ligands combine hydroxypyridinone (HOPO) and catecholamide (CAM) metal-binding groups, to form radionuclide delivery platforms when associated with siderocalin. The siderocalin assembly can therefore serve as a “lock” to consolidate binding to the therapeutic 225Ac and 227Th isotopes, or to diagnostic positron emitters such as 89Zr, 86Y, or 134Ce, independent of metal valence state. By incorporating the different metal-binding units on different positions of polyamine scaffolds, the respective affinities of the ligands for metal ions are tuned, as well as the recognition of the corresponding complexes by the protein.
FOR MORE INFORMATION:
Captain, Ilya, Gauthier J-P. Deblonde, Peter B. Rupert, Dahlia D. An, Marie-Claire Illy, Emeline Rostan, Corie Y. Ralston, Roland K. Strong, and Rebecca J. Abergel. “Engineered recognition of tetravalent zirconium and thorium by chelator–protein systems: toward flexible radiotherapy and imaging platforms.” Inorganic chemistry 55, no. 22 (2016): 11930-11936.
STATUS: Patent pending
OPPORTUNITIES: Available for licensing or collaborative research