Verification of Nanomaterial-Induced Size-Dependent Human Ether-à-Go-Go-Related Gene Potassium Channel Blockage Using Three-Dimensional Bioengineered Functional Cardiac Tissue Constructs

Abstract

Three-dimensional (3D) bioprinted functional cardiac tissue constructs are proposed for the first time as a screening platform to evaluate the nanomaterial-induced hERG potassium channel blockage based on the in situ measurement of K+ permeation and hERG protein immunofluorescence. Multifunctional anticancer spherical gold nanoparticles whose surface was bound with the ligand of thiol-terminated polyethylene glycol (PEG) conjugated to indomethacin (IMC-PEG-SH@AuNPs) were synthesized with mean diameters of 19, 33, and 64 nm. Triphenylphosphine-stabilized gold nanoparticles (F-108@TPP-AuNPs) were fabricated via temperature- and reaction time-controlled synthesis. Both IMC-PEG-SH@AuNPs and F-108@TPP-AuNPs showed a dose-dependent decrease in K+ permeation because of their binding to hERG proteins. The degree of the hERG potassium channel blockage was dependent on the surface ligand conjugated to the AuNPs. The size-dependent effect of the nanomaterials on the hERG K+ channel block was quantitatively evaluated using the three different sizes of IMC-PEG-SH@AuNPs. The effect of the K+ channel block was remarkably proportional to the size of IMC-PEG-SH@AuNPs. This is the first report demonstrating the size-dependent effect of an hERG K+ channel block induced by nanomaterials. In addition, small molecules showed a greater decrease in K+ permeation and hERG immunofluorescence compared with IMC-PEG-SH@AuNPs because of steric limitations in the binding of surface ligands to hERG proteins.