Effect of increasing liver blood flow on nanodrug clearance by the liver for enhanced antitumor therapy

The clinical applications of particulate drug delivery systems have demonstrated limited treatment out- comes, which is largely attributable to the elimination of such systems by the immune system, especially in the liver. Inspired by the mechanism of nanomaterial clearance by the liver, we designed a new anti- cancer auxiliary delivery system by introducing norepinephrine loaded poly(acrylic acid) nanogels as angiotonics. The auxilliary system effectively decreased the liver uptake of nanodrugs by increasing the liver blood flow rate. With administration of the as-prepared norepinephrine-loaded poly(acrylic acid) nanogels, the blood perfusion amount increased significantly by 177.0% (i.e. 2.77 times) as observed directly by ultrasonic imaging, indicating an increased blood flow rate in the liver. Since the blood flow rate plays a key role in nanomaterial clearance in the liver, nanodrug clearance should be changed by modulation of the blood flow. Our in vivo experimental results clearly showed the enhancement of nano- drug efficiency with this two-step treatment, with a 52% improvement in plasma drug concentration, obvious drug accumulation in the tumor, and significant antitumor effects. These results indicate that a pre-conditioning strategy involving norepinephrine-loaded poly(acrylic acid) nanogels can serve as an ideal route for reducing nanodrug clearance by the liver.