Mapping cardiac drug transport: In vitro assessment of cardiac P-glycoprotein function with [¹⁸F]MC225 by using...

P-glycoprotein (P-gp), an efflux transporter with diverse compound effects, is a vital part of cardiac function. To determine if the selective substrate tracer [¹⁸F]MC225 also functions in cardiac P-gp, micro-engineered heart tissues (µ-EHTs) utilizing human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes were used. This model offers advantages in potentially reducing animal experiments and allowing direct evaluation on human cells. However, its adoption in nuclear medicine remains very limited. This study aims to evaluate [¹⁸F]MC225 as a measurement method for cardiac P-gp function using a heart-on-chip model.

µ-EHTs were treated with the P-gp inhibitor Tariquidar (200 nM for 30 min) or the P-gp inducer Doxorubicin (1 µM for 24 h) and incubated with [¹⁸F]MC225 (1 MBq/mL for 30 min). First, we identified and confirmed the expression of P-gp in the µ-EHTs using immunofluorescent staining, which showed an increase of P-gp expression after Doxorubicin treatment. According to γ-counter measurements, Tariquidar-treated tissues exhibited a higher uptake (117.5 ± 33.67%, n = 24) (P = 0.035) than the control, compared to Doxorubicin-treated tissues which exhibited a lower uptake (63.97 ± 21.89%, n = 20) (P < 0.001) compared to its controls. Autoradiography visualized radioactive distribution in each µ-EHT and confirmed the γ-counter measurements.

[¹⁸F]MC225 effectively evaluates and measures cardiac P-gp function in µ-EHTs on the heart-on-chip platform. This research sets the stage for future studies using P-gp function to evaluate the efficacy and safety of novel cardiovascular drugs using µ-EHTs.