The prospects of hepatic drug delivery and gene therapy

Abstract

Liver targeted therapy is designed to deliver a substance preferentially to the organ in order to increase the accumulation, improve the therapeutic effect and reduce toxicity to other organs. The aim of selective targeting is to deliver a substance to a specific cell type in the liver. A variety of vehicles have been designed and further modified for selective targeting of therapeutics to the liver. The targeting properties and strategies of commonly used agents, such as liposomes, microspheres and recombinant chylomicrons, are discussed. Viral and non-viral vectors, such as cationic liposomes, reconstituted chylomicron remnants, adenoviruses, adeno-associated viruses, retroviruses, and SV-40, are currently being evaluated for the delivery of DNA to the liver. New developments in improving the targeting efficiency of the available vectors while avoiding their disadvantages have made their use in clinical trials of various genetic disorders possible. For viral hepatitis, antisense and ribozyme techniques are being employed with selective targeting approaches. A commonly employed current strategy for targeting hepatocellular carcinoma cells is to make the tumour cells convert non-toxic ‘prodrugs’ to toxic metabolites in situ, achieving a high concentration of the toxic product in the local milieu, while avoiding systemic toxicity. Although gene therapy itself is in its infancy, some encouraging results have been developed in studies of familial hypercholesterolaemia, haemophilia, α1-antitrypsin deficiency and Crigler-Najjar syndrome. The potential strengths as well as the problems with these studies are discussed.

• α1-antitrypsin deficiency
• adeno-associated virus
• adenovirus
• antisense
• asialofetuin
• asialoglycoprotein receptor
• chylomicron remnant
• Crigler-Najjar syndrome
• familial hypercholesterolaemia
• gene therapy
• haemophilia B
• hepatitis B virus
• hepatitis C virus
• hepatocellular carcinoma
• hepatocyte
• Kupffer cell
• liposome
• microsphere
• retrovirus
• ribozyme
• sinusiodal endothelial cell
• SV40
• targeting therapy
• viral hepatitis