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Abstract
Apart from using as radiopharmaceuticals, iminodiacetic acid derivatives, after complexation with gadolinium, have been also tested as MRI CAs (magnetic resonance imaging contrast agents) since they show high affinity to hepatocytes and therefore provide high-resolution MRI of the liver. The purpose of this study was to evaluate the biocompatibility of four gadolinium complexes with iminodiacetic acid (IDA) derivatives differing in substituent in aromatic ring by estimating their influence on plasma hemostasis, integrity of erythrocyte membrane, and toxicity towards human umbilical vein endothelial cells (HUVECs). The influence of gadolinium-based CAs on plasma hemostasis was evaluated by measuring PT (prothrombin time), APTT (activated partial tromboplastin time), and TT (thrombin time). The effects of tested compounds on RBCs (Red Blood Cells) were assessed using hemolysis assay and microscopy studies. The influence of gadolinium complexes on the barrier properties of HUVECs was assessed by means of real-time method based on the measurements of the impedance changes of the cells. Gadolinium complexes did not affect significantly PT and TT. APTT measurements revealed significant prolongation in the presence of all tested gadolinium complexes at the concentration higher than 0.5 μmol/mL. Hemolysis assay showed that compounds with alkyl substituents in benzene ring without halogen atom (1–3) do not exert unfavorable effect on the integrity of erythrocyte membrane over the entire concentration range. All gadolinium complexes at 1.0 μmol/mL contribute to the decrease in HUVEC viability and integrity. To conclude, the study describes biocompatibility studies of gadolinium-based CAs, provides additional insight into their potential toxicity associated with systemic administration, and underscores the necessity for further research.
Highlights
Contrast agents (CAs) are typically administered intravenously to human body which is related to instantaneous contact with blood tissue (red blood cells (RBCs), white blood cells (WBCs), platelets, and proteins)
In our previous paper [14], we evaluated the effects of all respective ligands for gadolinium complexation using CL test
We reported that gadolinium complexes apart from the highest concentration of compounds 1 and 2 did not affect the process of fibrin polymerization, which might suggest that the reaction of gadolinium complexation alters the profile of interaction with thrombin and does not contribute to the inhibition of amidolytic activity of the enzyme
Summary
Contrast agents (CAs) are typically administered intravenously to human body which is related to instantaneous contact with blood tissue (red blood cells (RBCs), white blood cells (WBCs), platelets, and proteins). A rapid sequence of events may occur. Many of these have not been fully elucidated and their potency to bind or interact with plasma proteins, blood cells, or endothelium may contribute to serious problems to blood functions [1, 2]. Coexistence with living tissues or organisms without being toxic, injurious, or physiologically reactive and not causing immunological response. One of the issues of biocompatibility constitutes blood compatibility, known as hemocompatibility [3]. Several interacting defense mechanisms or systems are activated upon the exposition of new compound to blood. The ideal tested compound should not release any toxic chemicals or fragment particles into the body; induce an excessive immune, inflammatory, thrombogenic, or fibrogenic response [4]. The development of novel hemocompatible drugs or devices is regarded as one of the most challenging problems of the contemporary pharmaceutical sciences
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