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.