RIBAVIRIN CONJUGATED WITH LACTOSAMINATED POLY-L-LYSINE - SELECTIVE DELIVERY TO THE LIVER AND INCREASED ANTIVIRAL ACTIVITY IN MICE WITH VIRAL-HEPATITIS

Ribavirin (RIBV) is a useful drug in the treatment of chronic type C h epatitis but displays a toxicity for red blood cells (RBC), which limi ts its dosage and necessitates withdrawal in some patients. Selective concentration of RIBV in liver should improve therapeutic results. Liv er targeting can be achieved by coupling the drug to galactosyl-termin ating peptides, which specifically enter hepatocytes. In the present w ork, we conjugated RIBV to lactosaminated poly-L-lysine (L-Poly(Lys)), a hepatotropic carrier enabling intramuscular (IM) administration of conjugates. The L-Poly(Lys)-RIBV conjugate had a heavy drug load (312- 327 mu g of RIBV in 1 mg of conjugate) and was very soluble in 0.9% Na Cl (200 mg/mL). The conjugate was devoid of acute toxicity in mouse. W hen incubated with human or mouse blood, it did not release the drug. After IM administration to mice, the conjugate was selectively taken u p by the liver, where the drug was released in a pharmacologically act ive form. This was demonstrated using mice infected with a strain of m urine hepatitis Virus (MHV) sensitive to RIBV. Coupled RIBV, IM inject ed, inhibited MHV replication in liver at a daily dose two to three ti mes lower than that of the free drug. in mice IM injected with a conju gate tritiated in the RIBV moiety, the ratios between the levels of ra dioactivity in liver and RBC were two times higher than in animals inj ected with free tritiated RIBV. In conclusion, the present results sup port the possibility that the chemotherapeutic index of RIBV in chroni c type C hepatitis can be increased by conjugation with L-Poly(Lys). ( C) 1991 Elsevier Science Inc.