GLYCOSILATED MACROMOLECULAR CONJUGATES OF ANTIVIRAL DRUGS WITH A POLYASPARTAMIDE

Two new polymeric conjugates for specific liver targeting were prepared by conjugation of sugar moieties and antiviral drugs to alpha, beta-poly[N-2-(hydroxyethyl)-DL-aspartamide] (PHEA). PHEA-galactopyranosylphenylthiocarbamide-mono-O-succinylganciclovir (conjugate 7) and PHEA-mannopyranosylphenylthiocarbamide-O-succinylacyclovir (conjugate 8) were synthesized according to a multi-step procedure which allowed for obtaining high product yield and process standardization. Conjugate 7 contained 7.5 and 8.5% of galactose and ganciclovir (substituent/repeating unit, mol/mol), respectively, and conjugate 8 contained 14.2 and 10.8% of mannose and acyclovir, respectively. In vitro studies demonstrated that both acyclovir and ganciclovir are released from the polymeric adducts at a release rate, which depended on the incubation medium. Though a detailed study evidenced that the two bioconjugates undergo different hydrolysis pathways, in both cases high drug release rate was found in plasma, while the glycosidic moiety was not released. Pharmacokinetic studies carried out by intravenous administration of the bioconjugates to Balb/c mice demonstrated that the conjugation of glycosidic moieties promotes the disappearance of the polymer from the bloodstream. The two derivatives displayed a different pharmacokinetic profile. In particular, the mannosyl conjugation promoted the rapid disposition of the macromolecule in the kidneys and in the liver, while prevented the accumulation in the spleen. On the contrary, the galactosyl derivative was found to dispose in the liver at the same extent of the naked polymer. Few considerations on the different behavior of the conjugates were reported.