Uranium(VI) (UO2(2+), uranyl) is nephrotoxic. Depending on isotopic composition and dosage, U(VI) is also chemically toxic and carcinogenic in bone. Several ligands containing two, three, or four bidentate catecholate or hydroxypyridinonate metal binding groups, developed for in vivo chelation of other actinides, were found, on evaluation in mice, to be effective for in vivo chelation of U(VI). The most promising ligands contained two bidentate groups per chelator molecule (tetradentate) attached to linear 4- or 5-carbon backbones (4-LI, butylene; 5-LI, pentylene; 5-LIO, diethyl ether). New ligands were then prepared to optimize ligand affinity for U(VI) in vivo and low acute toxicity. Five bidentate binding groups--sulfocatechol [CAM(S)], carboxycatechol [CAM(C)], methylterephthalamide (MeTAM), 1,2-hydroxypyridinone (1,2-HOPO), or 3,2-hydroxypyridinone (Me-3,2-HOPO)--were each attached to two linear backbones (4-LI and 5-LI or 5-LIO). Those ten tetradentate ligands and octadentate 3,4,3-LI(1,2-HOPO), an effective actinide chelator, were evaluated in mice for in vivo chelation of 233U(VI) (injection at 3 min, 1 h, or 24 h or oral administration at 3 min after intravenous injection of 233UO2Cl2) and for acute toxicity (100 micromol kg(-1) injected daily for 10 d). The combined efficacy and toxicity screening identified 5-LIO(Me-3,2-HOPO) and 5-LICAM(S) as the most effective low-toxicity agents. They chelate circulating U(VI) efficiently at ligand:uranium molar ratios > or = 20, remove useful amounts of newly deposited U(VI) from kidney and bone at molar ratios > or = 100, and reduce kidney U(VI) levels significantly when given orally at molar ratios > or = 100. 5-LIO(Me-3,2-HOPO) has greater affinity for kidney U(VI) while 5-LICAM(S) has greater affinity for bone U(VI), and a 1:1 mixture (total molar ratio = 91) reduced kidney and bone U(VI) to 15 and 58% of control, respectively--more than an equimolar amount of either ligand alone.

The threat of a dirty bomb or other major radiological contamination presents a danger of largescale 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 μmol kg −1 day −1 ) over 28 days under good laboratory practice (GLP) guidelines. Both compounds are on an accelerated development pathway towards clinical use.

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.

The interaction of human blood platelets with influenza virus (PR-8) was studied in vitro and in vivo. It was found that "live" influenza virus was rapidly adsorbed onto human blood platelets at 4 C. and completely eluted at 37 C. "Dead" virus was adsorbed at 4 C. but not eluted at 37 C. unless the platelets were treated with RDE (receptor destroying enzyme). Adorption of virus also occurred at tem peratures above 4 C. (from 20 to 37 C.). However, while adsorption was maintained throughout incubation at 4 C., slow elution occurred after 30 to 90 minutes incubation at 26 to 37 C. Storage of the platelets for lengthy intervals at 4 C. or coating of the platelets with macromolecules did not interfere with virus adsorption. After one cycle of adsorption-elution, blood platelets could not adsorb virus again. Treatment with RDE greatly reduced virus adsorption. During the process of virus adsorption, prominent platelet clumping occurred. During elution, clumping remained unchanged, and gross alterations in morphology of the platelets were observed. In the process of virus adsorption-elution, large numbers of platelets were lysed. Comparative experiments were performed simultaneously with human red blood cells (RBC) and identical results were obtained as with blood platelets. However, the extent of adsorption of live virus was equal for platelets and RBC only when the relationship between platelet number and RBC number in the preparations used was 6:1. This suggested a direct proportion between the surface area of both platelet and RBC and the number of available virus receptors. Virus suspensions infused into rabbits produced a sharp and sustained drop of the platelet count. Survival of radioactively labeled platelets treated with virus prior to infusion was markedly shortened with live virus and was only slightly reduced with dead virus. It is suggested from these experiments that blood platelets, as other blood cells, may serve as carriers of viruses in the circulation and that in this process the platelets are damaged and partially destroyed.