Decorporation of aged americium deposits by oral administration of lipophilic polyamino carboxylic acids

Abstract

Several new powerful chelating agents, suitable for the removal of a variety of certain heavy-metal ions from the body by oral application, have been synthesized and tested. Structurally, these compounds are partially lipophilic polyamino carboxylic acids (PACA). They were synthesized in nonaqueous media from triethylenetetramine (TT) by monoalkylation of a primary amino group, followed by exhaustive carboxymethylation of the remaining amino groups using ethyl bromoacetate and subsequent alkaline hydrolysis of the ester. Compounds were characterized using IR, 1H NMR, 13C NMR, and mass spectrometry. Synthesis and testing of two of these compounds, C12- and C22-triethylenetetraminepentaacetic acid (CnTT), is described in detail. Gel permeation chromatography of a mixture of the PACA and actinide elements have shown these substances to be strong chelating agents similar to EDTA or DTPA. They were capable of removing plutonium from contaminated liver cytosol in vitro. In contrast to their nonlipophilic counterparts EDTA and DTPA, the model substances exhibited appreciable absorption from the intestine and, therefore, can be administered orally. With increasing length of the alkyl chain, the chelons can be directed primarily to the liver, one of the target organs for actinide contamination. In vivo, absorption from the ligated duodenum and jejunum of rats after 2 h was 27% of the amount introduced. Compared to untreated controls, daily feeding of 200 mumol of the chelons (C12TT or C22TT)/kg of body weight to rats for 10 days reduced the whole body Am by 29% and 44%, respectively. Am was eliminated most efficiently from the liver, with a reduction of 71% and 89% (p less than 0.001). However, the skeletal retention also was reduced by 17% and 32% from the femora (p less than 0.001) and 20% and 37% from the carcass for the C12TT and C22TT compounds, respectively. No weight loss or other obvious signs of blood, kidney, liver, or intestinal toxicity were observed after the 10-day treatment. These new chelators are promising as agents for oral chelation therapy to remove actinides and possibly other elements from body stores.

Age-associated Iron Accumulation in Bone: Implications for Postmenopausal Osteoporosis and a New Target for Prevention and Treatment by Chelation

“…The chelator used here (1-N-docosyltriethylenetetraminepentaacetic acid, Figure 1) has a high iron binding affinity and the ability to effectively deplete heavy metals such as plutonium from skeletal and soft tissues in experimental studies (Bruenger et al 1992;Miller et al 1993). Plutonium shares many properties with iron, including coordination chemistry, intracellular pathways and deposition patterns in skeletal tissues (White et al 1988).…”

“…The synthesis of 1-N-docosyl-triethylenetetraminepentaacetic acid was described previously (Bruenger et al 1992;Miller et al 1993). Briefly, excess triethylenetetramine reacted with 1-docosyl bromide in order to conjugate a single docosyl group to the triethylenetetramine through a primary amino group.…”

Therapeutic Effects of an Oral Chelator Targeting Skeletal Tissue Damage in Experimental Postmenopausal Osteoporosis in Rats

“…1-N-docosyl-triethylenetetraminepenaacetic acid, similar to triethylenetetraminehexaacetic acid, has high metal binding affinity and the ability to effectively deplete some metals such as iron, americium and plutonium from skeletal and soft tissues in experimental studies (12)(13)(14)21). The chelator also possesses oral bioavailability, even though it is highly charged with a molecular weight of 744.…”

“…The chelator also possesses oral bioavailability, even though it is highly charged with a molecular weight of 744. A possible explanation is that the chelator may form micelles due to its amphiphilic property, thus increasing intestinal absorption and bone marrow macrophage uptake (13). After chelation treatment, the iron and LLOFR contents of the bone were measured by EPR spectrometer.…”

“…The chelator 1-N-docosyl-triethylenetetraminepentaacetic acid (DoTTPA) (Figure 1) was synthesized as previously described (12)(13)(14). Its chemical structure and purity were characterized using 1 H-and 13 C-nuclear magnetic resonance spectroscopy, thin-layer chromatography and mass spectrometry.…”