Biomimetic actinide chelators: an update on the preclinical development of the orally active hydroxypyridonate decorporation agents 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO).

The threat of a dirty bomb or other major radiological contamination presents a danger of large-scale radiation exposure of the population. Because major components of such contamination are likely to be actinides, actinide decorporation treatments that will reduce radiation exposure must be a priority. Current therapies for the treatment of radionuclide contamination are limited and extensive efforts must be dedicated to the development of therapeutic, orally bioavailable, actinide chelators for emergency medical use. Using a biomimetic approach based on the similar biochemical properties of plutonium(IV) and iron(III), siderophore-inspired multidentate hydroxypyridonate ligands have been designed and are unrivaled in terms of actinide-affinity, selectivity, and efficiency. A perspective on the preclinical development of two hydroxypyridonate actinide decorporation agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), is presented. The chemical syntheses of both candidate compounds have been optimized for scale-up. Baseline preparation and analytical methods suitable for manufacturing large amounts have been established. Both ligands show much higher actinide-removal efficacy than the currently approved agent, diethylenetriaminepentaacetic acid (DTPA), with different selectivity for the tested isotopes of plutonium, americium, uranium and neptunium. No toxicity is observed in cells derived from three different human tissue sources treated in vitro up to ligand concentrations of 1 mM, and both ligands were well tolerated in rats when orally administered daily at high doses (>100 micromol kg d) over 28 d under good laboratory practice guidelines. Both compounds are on an accelerated development pathway towards clinical use.

Lauriston S. Taylor Lecture: the quest for therapeutic actinide chelators.

All of the actinides are radioactive. Taken into the body, they damage and induce cancer in bone and liver, and in the lungs if inhaled, and U(VI) is a chemical kidney poison. Containment of radionuclides is fundamental to radiation protection, but if it is breached accidentally or deliberately, decontamination of exposed persons is needed to reduce the consequences of radionuclide intake. The only known way to reduce the health risks of internally deposited actinides is to accelerate their excretion with chelating agents. Ethylendiaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) were introduced in the 1950's. DTPA is now clinically accepted, but its oral activity is low, it must be injected as a Ca(II) or Zn(II) chelate to avoid toxicity, and it is structurally unsuitable for chelating U(VI) or Np(V). Actinide penetration into the mammalian iron transport and storage systems suggested that actinide ions would form stable complexes with the Fe(III)-binding units found in potent selective natural iron chelators (siderophores). Testing of that biomimetic approach began in the late 1970's with the design, production, and assessment for in vivo Pu(IV) chelation of synthetic multidentate ligands based on the backbone structures and Fe(III)-binding groups of siderophores. New efficacious actinide chelators have emerged from that program, in particular, octadentate 3,4,3-LI(1,2-HOPO) and tetradentate 5-LIO(Me-3,2-HOPO) have potential for clinical acceptance. Both are much more effective than CaNa3-DTPA for decorporation of Pu(IV), Am(III), U(VI), and Np(IV,V), they are orally active, and toxicity is acceptably low at effective dosage.

The NCRP wound model: development and application.

The US National Council on Radiation Protection and Measurements, in collaboration with the International Commission on Radiological Protection, has been developing a biokinetic and dosimetric model for radionuclide-contaminated wounds. The finalised model is described briefly in this paper, together with the scientific basis and application. The multicompartment model uses first-order linear biokinetics to describe the retention and clearance of a radionuclide deposited in a wound site using seven default retention categories. Examples using plutonium nitrate in colloidal form and uranium in metal fragments show the behaviour of the less soluble forms of radionuclides in wounds, in which long-term retention is predicted. Using uranium as an example, the wound model is coupled to a uranium International Commission on Radiological Protection systemic model to predict urinary excretion patterns for different physicochemical forms of uranium. The latter application is needed for bioassay interpretation.

Synthesis and initial evaluation for in vivo chelation of Pu(IV) of a mixed octadentate spermine-based ligand containing 4-carbamoyl-3-hydroxy-1-methyl-2(1H)-pyridinone and 6-carbamoyl-1-hydroxy-2(1H)-pyridinone.

An improved synthesis for a series of 1-hydroxy-2(1H)-pyridinone-based octadentate ligands is reported. The mixed chelate, octadentate ligand, 3,4,3-LI(1,2-Me-3,2-HOPO), was designed, synthesized, and tested for in vivo chelation of Pu in a mouse model. This ligand incorporates both 1,2-HOPO and Me-3,2-HOPO metal chelating units; the latter has higher affinity toward actinide ions than does 1,2-HOPO at physiological pH. Injected or administered orally to fasted or normally fed mice at the standard clinical dose 30 micromol/kg, both 3,4,3-LI(1,2-HOPO) and 3,4,3-LI(1,2-Me-3,2-HOPO) remove significantly more Pu than injected CaNa(3)DTPA. Injected doses of 0.1 micromol/kg of these HOPO ligands are as effective as 30 micromol/kg of injected CaNa(3)DTPA. Ten daily injections of 30 micromol/kg of a HOPO ligand did not induce detectable acute toxicity in mice. The mixed HOPO ligand is somewhat more effective than 3,4,3-LI(1,2-HOPO) when given orally, and the enhanced reduction of liver Pu by the mixed ligand is statistically significant. Thus, both octadentate HOPO ligands meet the criterion of low toxicity at doses that are more effective than the standard dose of CaNa(3)DTPA. Their improved effectiveness at low dose along with great oral activity (despite low gastrointestinal absorption) implies that new treatment regimens can be developed using the HOPO ligands alone or as adjuncts to CaNa(3)DTPA therapy, which will greatly exceed the amount of Pu excretion that is achievable with CaNa(3)DTPA alone.