Enhanced liver blood concentrations of adenine arabinoside accomplished by lactosaminated poly-l-lysine coupling: implications for regional chemotherapy of hepatic micrometastases

Conjugates of antiviral and antiblastic nucleoside analogs (NAs) with galactosyl terminating peptides selectively enter hepatocytes after binding of the carrier galactose residues to the asialoglycoprotein receptor. Since NAs, when set free from the carrier within hepatocytes, partly exit from these cells into the bloodstream, we considered the possibility that administration of galactosyl terminating conjugates of NAs could result in plasma concentrations of these drugs that would be higher in liver sinusoids than in capillaries of other organs. In the present study we demonstrated the validity of this hypothesis. We injected rats with a conjugate of adenine arabinoside (ara-A) with lactosaminated poly-l-lysine and found that the plasma concentrations of ara-A were >2-fold higher in blood of Liver than in systemic circulation. Liver blood was collected from the inferior vena cava after closing below and above the outflows of the hepatic veins. The present result suggests that conjugation with galactosyl terminating peptides might be a way to selectively increase the concentrations of NAs not only in hepatocytes, which have the asialoglycoprotein receptor, but also in cells infiltrating the liver, such as neoplastic cells of micrometastases nourished by hepatic sinusoids. (C) 1999 Elsevier Science Inc.