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 ultimate aim of drug delivery system. Regulation of drug delivery would increase the therapeutic efficacy and decrease the potential side effects. We encapsulated and used Z-Asp, a caspase inhibitor in poly-N-p-vinylbenzyl-D-lactonamide (PVLA) coated-poly (L-lactic acid) (PLA)-nanospheres in a mouse model of acute hepatitis. These nanospheres were internalized and accumulated in hepatocytes both in vitro and in vivo. Encapsulation significantly extended the intracellular retention time of the content in hepatocytes, which increased the bioavailability of the caspase inhibitor. In addition, the therapeutic effect was temporally controllable in vivo by modifying the component of the nanospheres. A cocktail of nanospheres with diverse degradation kinetics showed persistent therapeutic effects in acute hepatitis, and only nanospheres that targeted hepatocytes and controlled degradation rescued mice from lethal hepatic injury. This temporally and spatially controlled drug delivery system could be used in various liver diseases.
Shibuya
I
I
Department of Biomolecular Engineering, Tokyo Institute of Technology, Yokohama, Japan.
Akaike
T
T
Watanabe
Y
Y
D000818:Animals; D001216:Asparagine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002214:Capsules; D061945:Caspase Inhibitors; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D007785:Lactose / Q000031:analogs & derivatives*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008863:Microspheres; D011137:Polystyrenes
D002214:Capsules; D061945:Caspase Inhibitors; D003692:Delayed-Action Preparations; D004791:Enzyme Inhibitors; D011137:Polystyrenes; C117865:benzyloxycarbonyl-asparagine; D001216:Asparagine; C074112:poly-N-4-vinylbenzyllactonamide; D007785:Lactose