Carboxylate- and Phosphonate-Modified Polyethylenimine: Toward the Design of Actinide Decorporation Agents.

Plutonium (Pu) is an anthropogenic element involved in the nuclear industry cycle. Located at the bottom of the periodic table within the actinide family, it is a chemical toxic but also a radiological toxic, regardless of isotopy. After nearly 80 years of Pu industrialization, it has become clear that inhalation and wounds represent the two main ways a person may become contaminated after an accident. In order to reduce the deleterious health effects of Pu, it is crucial to limit chronic exposure by removing it or preventing its incorporation into the body. Diethylenetriaminepentaacetic acid (DTPA) has emerged as the gold standard for Pu decorporation, although it suffers from very short retention time in serum. Other molecules like the hydroxypyridonate family with high chemical affinity have also been considered. We have been considering alternative polymeric chelates and, in particular, polyethylenimine (PEI) analogues of DTPA (the carbonate or phosphonate version), which may present a real breakthrough in Pu decorporation not only because of their higher loading capacity but also because of their indirect vectorization properties correlated with a specific biodistribution into the lungs, bone, kidney, or liver. In the first part of this Forum Article, new data on the structural characterization of the complexation of PuIV with polyethylenimine methylphosphonate (PEI-MP) were obtained using the combination of extended X-ray absorption fine structure spectroscopy and ab initio molecular dynamics (AIMD) calculations. The use of thorium (Th) as a Pu chemical surrogate is also discussed because its unique oxidation state is IV+ in solution. In the second part of the paper, we put this new set of data on PEI-MP-Pu into perspective with use of the PEI platform to complex ThIV and PuIV. Uptake curves of ThIV witth polyethylenimine methylcarboxylate (PEI-MC) are compared with those of PEI-MP and DTPA, and the AIMD data are discussed.

Polyethyleneimine methylenecarboxylate: a macromolecular DTPA analogue to chelate plutonium(iv).

Up until now, molecular chelating agents, such as diethylenetriamine pentaacetic acid (DTPA), have been the standard method for actinide human decorporation. Mainly active in blood serum, their distribution within the body is thus limited. To treat a wider range of organs affected by plutonium contamination, a potential new class of macromolecular decorporation agents is being studied. Polyethyleneimine methylenecarboxylate (PEI-MC) is one such example. It is being considered here because of its capacity for targeting the liver and bones.

Towards the development of chitosan nanoparticles for plutonium pulmonary decorporation.

Since the 1940s, great amounts of Plutonium (Pu) have been produced for both military and civil purposes. Until now, the standard therapy for decorporation following inhalation has been the intravenous injection of diethylenetriaminepentaacetic acid ligand (Ca-DTPA form). This method offers a strong complexing constant for Pu(iv) but has poor chemical specificity, therefore its efficacy is limited to actinides present in the blood. Consequently, there is no decorporation treatment currently available which efficiently removes the intracellular Pu(iv) trapped in the pulmonary macrophages. Our research shows that a nanoparticle approach could be of particular interest due to large contact area and ability to target the retention compartments of the lungs. In this study, we have focused on the inhalation process involving forms of Pu(iv) with poor solubility. We explored the design of biocompatible nanoparticles able to target the macrophages in the lung alveoli and to chelate the forms of Pu(iv) with poor solubility. Nanoparticle formation was achieved through an ionic cross-linking concept using a polycationic polymer and an anionic chelate linker. We chose N-trimethyl chitosan, for its biocompatibility, as the polycationic polymer base of the nanoparticle and the phosphonic analogue of DTPA, diethylenetriamine-pentamethylenephosphonic acid (DTPMP) as the anionic chelating linker in forming NPs TMC-DTPMP. The synthesis and physico-chemical characterization of these NPs are presented. Secondly, the complexation mechanisms of TMC-DTPMP NPs with Thorium (Th(iv)) are discussed in terms of efficiency and structure. The Extended X-Ray Absorption Fine Structure (EXAFS) of the TMC-DTPMP complex with Th(iv) as well as Pu(iv) are defined and completed with DFT calculations to further delineate the plutonium coordination sphere after complexation. Finally, preliminary cytotoxicity tests onto macrophages were assayed.