Solution speciation and human serum protein binding of indium(III) complexes of 8-hydroxyquinoline, deferiprone and maltol

Orsolya Dömötör,Éva A Enyedy,Bernhard K Keppler

doi:10.1007/s00775-022-01935-6

Orsolya Dömötör, Éva A Enyedy + Show 1 more

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https://doi.org/10.1007/s00775-022-01935-6

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Abstract

Solution speciation and serum protein binding of selected In(III) complexes bearing O,O and O,N donor sets were studied to provide comparative data for In(III) and analogous Ga(III) complexes. Aqueous stability of the In(III) complexes of maltol, deferiprone, 8-hydroxyquinoline (HQ) and 8-hydroxyquinoline-5-sulfonate (HQS) was characterized by a combined pH-potentiometric and UV–visible spectrophotometric approach. Formation of mono, bis and tris-ligand complexes was observed. The tris-ligand complexes of HQ (InQ3) and deferiprone (InD3) are present in solution in ca. 90% at 10 µM concentration at pH = 7.4, while the tris-maltolato complex (InM3) displays insufficient stability under these conditions. Binding towards human serum albumin (HSA) and (apo)transferrin ((apo)Tf) of InQ3, InD3 and InM3 complexes and Ga(III) analogue of InQ3 (GaQ3) together with InCl3 was investigated by a panel of methods: steady-state and time-resolved spectrofluorometry, UV–visible spectrophotometry and membrane ultrafiltration. Moderate binding of InQ3 to HSA was found (log K′ = 5.0–5.1). InD3 binds to HSA to a much lower extent in comparison to InQ3. ApoTf is able to displace HQ, deferiprone and maltol effectively from their In(III) complexes. Protein binding of non-dissociated InQ3 was also observed at high complex-to-apoTf ratios. Studies conducted with the InQ3/GaQ3 – HSA – Tf ternary systems revealed the more pronounced Tf binding of In(III) via ligand release, while the original GaQ3 scaffold is preferably retained upon protein interactions and significant albumin binding occurs. Significant dissociation of InQ3 was detected in human blood serum as well.Graphical abstract

Highlights

Stability constants of deferiprone were determined by both methods in the present work to validate our experimental setup and data treatment, since the In(III) ‒ deferiprone system was already characterized by Orvig and collaborators [27]
Our results revealed the moderate binding of InQ3 to human serum albumin (HSA)
The fluorescence lifetimes of InQ3 and GaQ3 were determined and bi-exponential decays for the free and albumin-bound forms were found, respectively

Summary

Introduction

Numerous In(III) and Ga(III) complexes are applied as pharmaceutical agents in connection with their diagnostic and therapeutic properties. A number of In(III)-chelates have been tested for the selective delivery of 111In(III) to various tissues, the tris-ligand complex of 8-hydroxyquinoline (HQ) is the only indium containing product currently approved by the FDA for the detection and diagnosis of infections and inflammatory lesions [2, 4]. This HQ complex is not directly injected in the blood, extensive serum protein binding of In(III) necessitates standardized procedures where cellular elements of the blood (principally leukocytes) are separated and labelled with the complex outside the patient’s body and returned to the circulatory system [2, 5].

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