3,4,3-LI(1,2-HOPO): In Vitro Formation of Highly Stable Lanthanide Complexes Translates into Efficacious In Vivo Europium Decorporation Page: 2 of 11
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3,4,3-LI(1,2-HOPO): In Vitro Formation of Highly Stable Lanthanide
Complexes Translates into Efficacious In Vivo Europium Decorporation
Manuel Sturzbecher-Hoehne," Clara Ng Pak Leung," Anthony D'Al6o," Birgitta Kullgren," Anne-Laure
Prigent," David K. Shuh," Kenneth N. Raymond"'b and Rebecca J. Abergel*"
The spermine-based hydroxypyridonate octadentate chelator 3,4,3-LI(1,2-HOPO) was investigated for its
ability to act as an antennae that sensitizes the emission of Sm"', Eul", and Tb"' in the Visible range (At0t
to = 0.2 - 7%) and the emission of Prl", Nd"', Sm"', and Yb"' in the Near Infra-Red range, with decay times
varying from 1.78 ps to 805 ps at room temperature. The particular luminescence spectroscopic properties
of these lanthanide complexes formed with 3,4,3-LI(1,2-HOPO) were used to characterize their respective
solution thermodynamic stabilities as well as those of the corresponding La"', Gd"', Dy"', Ho"', Er"',
Tm"I, and Lu"I complexes. The remarkably high affinity of 3,4,3-LI(1,2-HOPO) for lanthanide metal ions
1s and the resulting high complex stabilities (pM values ranging from 17.2 for La"I to 23.1 for Yb"')
constitute a necessary but not sufficient criteria to consider this octadentate ligand an optimal candidate
for in vivo metal decorporation. The in vivo lanthanide complex stability and decorporation capacity of
the ligand were assessed, using the radioactive isotope 152Eu as a tracer in a rodent model, which provided
a direct comparison with the in vitro thermodynamic results and demonstrated the great potential of 3,4,3-
20 LI(1,2-HOPO) as a therapeutic metal chelating agent.
Introduction
Siderophore-inspired multidentate hydroxypyridonate ligands can be used in a variety of applications such as magnetic resonance
imaging (MRI) contrast enhancement, lanthanide luminescence sensitization, and iron and actinide chelation.1-5 The octadentate ligand
3,4,3-LI(1,2-HOPO) (Fig. 1), composed of four 1-hydroxy-pyridin-2-one (1,2-HOPO) units linked to a spermine scaffold through amide
25 linkages, is currently considered the most efficient experimental decorporation agent for actinides. ''7 Studies have shown that this ligand
is orally active and is by far more efficacious than the commonly used diethylenetriamine-pentaacetic acid (DTPA, Fig. 1) at promoting
the in vivo decorporation of actinide metal ions, such as Uv, Npv, Puv, and Am"'.6-8 In addition, 3,4,3-LI(1,2-HOPO) is known to act as
an antenna that sensitizes the luminescence of Eu"', a feature that was used recently to determine the solution thermodynamic stability of
the corresponding [Eu"I(3,4,3-LI(1,2-HOPO))]- complex.9 In the work presented here, the photophysical properties of the complexes of
30 3,4,3-LI(1,2-HOPO) formed with metal ions from the whole lanthanide series were probed and characteristic emission sensitization was
observed in both the Visible and Near Infra-Red ranges, depending on the complexed metal ion. The use of the antenna effect as a
spectroscopic tool was extended to spectrofluorimetric competition titrations, to determine the formation constants of these lanthanide
complexes. While such thermodynamic parameters are essential to characterize 3,4,3-LI(1,2-HOPO) as a chelating agent and compare its
affinity to different metal ions, they are only indicative of the potential in vivo decorporation efficacy of the ligand. The in vivo Eul"
35 complex stability and EuI" decorporation capacity of 3,4,3-LI(1,2-HOPO) were therefore also assessed in mice, using the radioactive
isotope 152Eu as a contaminant, which provides a direct comparison with the in vitro thermodynamic results.
0
HON 0 0
O O H N HO0 HO3 O
N- N N N o N N N O
N OH N O O OH HO O OH
O N'H O
O
Fig. 1 Structures of the experimental octadentate ligand 3,4,3-LI(1,2,-HOPO) (left) and the approved decorporation agent DTPA (right).
40 Experimental
General considerations
All chemicals were obtained from commercial suppliers and used as received. The LnI salts utilized were of the highest purity available
(>99.9%). The ligand 3,4,3-LI(1,2-HOPO) was synthesized by Synthetech, Inc. (Albany, OR, USA), following previously reported
procedures, and used as received. A Millipore Milli-Q Advantage A10 Water System Production Unit was used to purify deionized
45 water.
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Sturzbecher-Hoehne, Manuel; Ng Pak Leung, Clara; Daleo, Anthony; Kullgren, Birgitta; Prigent, Anne-Laure; Shuh, David K. et al. 3,4,3-LI(1,2-HOPO): In Vitro Formation of Highly Stable Lanthanide Complexes Translates into Efficacious In Vivo Europium Decorporation, article, July 13, 2011; Berkeley, California. (https://digital.library.unt.edu/ark:/67531/metadc827667/m1/2/?rotate=270: accessed July 17, 2024), University of North Texas Libraries, UNT Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.