Gd ³⁺ -doped carbon dots: modulation of mechanisms regulating gastrointestinal tract motility and the hepatobiliary system

Gadolinium-doped ultra-small organic particles are a promising material for theranostics, particularly as contrast agents for MRI. However, a number of unresolved issues remain regarding their potential effects on organs and tissues, especially due to possible toxic effects of gadolinium ions. The aim of this work was to conduct a comprehensive study of the functional state of the digestive system after an intravenous injection of a colloidal solution of gadolinium-doped carbon dot nanohybrids (GDNHs). The study was performed on Wistar rats. Spontaneous and agonist-induced contractions of the circular smooth muscle (SM) preparations from the gastric <i>antrum</i> and the <i>caecum</i> were measured in isometric mode. Lipid fractions and free amino acids in blood plasma were determined chromatographically. Molecular docking of GDNHs to the structure of the muscarinic acetylcholine receptor was performed using blind rigid docking with Smina osx.12. It was found that intravenous administration of GDNHs generally induced changes in spontaneous SM contractile activity, including increased contraction amplitude and altered frequency, modification of contraction-relaxation cycle durations and velocities, and enhanced efficiency indices. Under these conditions, mechanisms regulating and maintaining physiologically relevant differences in the mechanokinetic parameters of SM contractions across different digestive tract regions were also altered. Moreover, GDNHs modulated the mechanisms of adrenergic inhibition and cholinergic excitation in the <i>antrum</i> and <i>caecum</i>. The effects of GDNHs on carbacholine-induced contractions of the <i>antrum</i> SM were mainly attributed to their organic components, whereas in the <i>caecum</i>, they were predominantly mediated by Gd³⁺ ions complexed with nanohybrids. Molecular docking revealed characteristic binding interactions at the interfaces between the GDNHs and the muscarinic acetylcholine receptor in a potential competition with acetylcholine molecules. In addition, changes were observed in the concentrations of most lipid fractions and certain free amino acids in rat blood plasma. Overall, intravenous administration of GDNHs was accompanied by enhanced gastrointestinal SM motility (due to the activation of cholinergic excitation) and partial modulation of hepatic lipid and protein metabolism. However, these effects did not lead to pronounced dysfunction of the digestive system, indicating that GDNHs can be considered a promising basis for the development of MRI contrast agents.