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

Abstract

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, that is, the kidneys and bone matrix essentially. It is then crucial to remove or prevent the incorporation of uranium in these organs to limit the long-term chronic exposure. A lot of small chelating agents such as aminocarboxylates, catecholamides, and hydroxypyridonates 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), that is, the so-called enhanced permeability and retention effect, toward the main organs, which can be used as indirect targeting. Very interestingly, the methyl carboxylated polyethylenimine (PEI-MC) derivative has been described as a potent sequestering agent 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 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 (inductively coupled plasma optical emission spectrometry (ICP-OES); extended X-ray absorption fine structure (EXAFS); and Fourier transformed infrared (FT-IR)) together with molecular dynamics (MD) simulation. A maximum loading of 0.47 mg U(VI) per milligram of PEI-MC was 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 was 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.

Discovery and characterization of UipA, a uranium- and iron-binding PepSY protein involved in uranium tolerance by soil bacteria

“…2b), suggesting that the uranyl environment is very similar in all three proteins. Metrical parameters associated with the fit of the EXAFS data are summarized in Table S8 1 in the range of 2.9 -3.0 Å also support the presence of bidentate carboxylate functions (82,86). Therefore, we propose the presence of approximately 2 monodentate functions (Table S8) and complementary bidentate functions.…”

Interaction of Uranium(VI) with α-Amylase and Its Implication for Enzyme Activity

“…The shorter U–O eq distances (U–O eq 1 = 2.30 and 2.33 Å at pH 3.5 and 6.0, respectively) are comparable with the U–O distances observed for monodentately coordinating carboxylic groups in small organic molecules and peptides (2.25–2.32 Å). − The Asp and Glu groups in α-amylase, but also the carbonyl moieties (i.e., amide) of the peptide main chain or the side chains of Asn and Gln, and the phenolic units from Tyr can be considered for such shorter U–O distances. ,− On the other hand, the longer U–O eq distances (U–O eq 2 = 2.48 and 2.52 Å at pH = 3.5 and 6.0, respectively) are in good agreement with a typical U–O eq distance for bidentately coordinating carboxylate groups (2.45–2.49 Å). − , Additionally, the FT peaks appeared at around R + Δ = 2.2 Å in Figure , right can be interpreted as the single scattering from the C atoms of bidentately coordinating carboxylate groups. In fact, the calculated interatomic distances of 2.84 and 2.93 Å are in the range of the typical U–C distance for bidentately coordinating carboxylate ligands (2.88–2.93 Å). − , Given these facts, it is reasonable to conclude that the UO 2 2+ ions sorbed on α-amylase are primarily surrounded by 3–4 carboxyl/ate groups both in mono- and bidentate binding modes. However, possible coordination with carbonyl- or phenolate groups are also reported, ,− and its possibility cannot be completely excluded.…”

The toxicological mechanisms and detoxification of depleted uranium exposure

“…The biodistribution of macromolecules depends on their size, modulating their permeability and retention. In addition, macromolecules, especially highly soluble polymers, have been studied extensively and can easily be functionalized [ 78 ]. The functionalized methyl-carboxylated poly(ethylenimine) (PEI-MC) has been used as an effective scavenger of heavy metals from contaminated water [ 79 ].…”

“…The functionalized methyl-carboxylated poly(ethylenimine) (PEI-MC) has been used as an effective scavenger of heavy metals from contaminated water [ 79 ]. Lahrouch et al [ 78 ] assessed PEI-MC as a uranium decorporation agent under physiological pH conditions and found that the maximum load of uranium (VI) was 0.47 mg per milligram of PEI-MC, a far better load than those of sodium bicarbonate and Ca-DTPA.…”