title: Ribavirin conjugated with lactosaminated poly-L-lysine: selective delivery to the liver and increased antiviral activity in mice with viral hepatitis.
abstract: Ribavirin (RIBV) is a useful drug in the treatment of chronic type C hepatitis but displays a toxicity for red blood cells (RBC), which limits its dosage and necessitates withdrawal in some patients. Selective concentration of RIBV in liver should improve therapeutic results. Liver targeting can be achieved by coupling the drug to galactosyl-terminating peptides, which specifically enter hepatocytes. In the present work, 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 microg of RIBV in 1 mg of conjugate) and was very soluble in 0.9% NaCl (200 mg/mL). The conjugate was devoid of acute toxicity in mouse. When incubated with human or mouse blood, it did not release the drug. After IM administration to mice, the conjugate was selectively taken up by the liver, where the drug was released in a pharmacologically active form. This was demonstrated using mice infected with a strain of murine hepatitis virus (MHV) sensitive to RIBV. Coupled RIBV, IM injected, inhibited MHV replication in liver at a daily dose two to three times lower than that of the free drug. In mice IM injected with a conjugate tritiated in the RIBV moiety, the ratios between the levels of radioactivity in liver and RBC were two times higher than in animals injected with free tritiated RIBV. In conclusion, the present results support the possibility that the chemotherapeutic index of RIBV in chronic type C hepatitis can be increased by conjugation with L-Poly(Lys).
authors.affiliation: Dipartimento di Patologia Sperimentale, Università di Bologna, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Di Stefano
authors.forename: F P
authors.initials: FP
authors.lastname: Colonna
authors.forename: A
authors.initials: A
authors.lastname: Bongini
authors.forename: C
authors.initials: C
authors.lastname: Busi
authors.forename: A
authors.initials: A
authors.lastname: Mattioli
authors.forename: L
authors.initials: L
authors.lastname: Fiume
mesh_terms: D000606:Amino Sugars / Q000008:administration & dosage*; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000633:toxicity; D002478:Cells, Cultured; D004355:Drug Stability; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D006505:Hepatitis / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D007273:Injections, Intramuscular; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D011107:Polylysine / Q000008:administration & dosage*; D012254:Ribavirin / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D014316:Tritium
chemical_list: D000606:Amino Sugars; D000998:Antiviral Agents; D014316:Tritium; C032233:lactosamine; D011107:Polylysine; D012254:Ribavirin