Design of a temporally and spatially controlled drug delivery system for the treatment of liver diseases in mice

Strict regulation of the distribution and degradation kinetics is the ultim ate aim of drug delivery system. Regulation of drug delivery would increase the therapeutic efficacy and decrease the potential side effects. We encap sulated and used Z-Asp, a caspase inhibitor in poly-N-p-vinylbenzyl-D-lacto namide (PVLA) coated-poly (L-lactic acid) (PLA)-nanospheres in a mouse mode l of acute hepatitis. These nanospheres were internalized and accumulated i n hepatocytes both in vitro and in vivo. Encapsulation significantly extend ed the intracellular retention time of the content in hepatocytes, which in creased the bioavailability of the caspase inhibitor. In addition, the ther apeutic effect was temporally controllable in vivo by modifying the compone nt of the nanospheres. A cocktail of nanospheres with diverse degradation k inetics showed persistent therapeutic effects in acute hepatitis, and only nanospheres that targeted hepatocytes and controlled degradation rescued mi ce from lethal hepatic injury. This temporally and spatially controlled dru g delivery system could be used in various liver diseases.