A Combined Spectroscopic/Molecular Dynamic Study for Investigating a Methyl Carboxylated PEI as a Potential Uranium Decorporation Agent

Natural uranium has a very limited radioactive dose impact but its chemical toxicity due to chronic exposure is still a matter of debate. Once inside the human body, the soluble uranium, under its uranyl form (U(VI)), is quickly removed from the blood system, partially excreted from the body and partially retained in targeted organs, i.e. the kidneys and bone matrix essentially. It is then crucial to remove or prevent the incorporation of uranium in these organs in order to limit the long term chronic exposure. A lot of small chelating agents such as aminocarboxylate (PACA), catecholamide (CAM) and hydroxypyridonate (HOPO) have been developed so far. However they suffer from poor selectivity and targeting abilities.
Macromolecules and polymers are known to present a passive accumulation (size related), i.e. the so-called EPR (Enhanced Permeability and Retention) effect, towards the main organs, which can be used as indirect targeting. Very interestingly, the methyl carboxylated polyethyleneimine (PEI-MC) derivative, has been described as a potent sequestering agents for heavy metals. It would be therefore an interesting candidate to evaluate as a new class of decorporation agents with passive targeting capabilities matching uranium preferential sequestering sites. In the present work, we have explored the ability of a highly functionalized (89% rate) PEI-MC to uptake U(VI) close to physiological pH using a combination of analytical and spectroscopic techniques (ICP-OES, Inductively Coupled Plasma Optical Emission Spectrometry; EXAFS, Extended X-Ray Absorption Fine Structure; and FT-IR, Fourier transformed Infra-Red) together with molecular dynamics (MD) simulation. A maximum loading of 0.47 mg U(VI) per mg of PEI-MC has been determined by ICP-OES measurements. From FT-IR data, a majority of monodentate coordination of the carboxylate functions of the PEI-MC seems to occur. From EXAFS and MD, a mix of mono and bidentate coordination mode has been observed. Note that agreement between the EXAFS metrical parameters and MD radial distribution functions is remarkable. To the best of our knowledge, this is the first comprehensive structural study of a macromolecular PEI based agent considered for uranium decorporation purposes.