Synthesis, Characterization, In Vitro Drug Release Of A Novel Anti-HBV Polymeric Prodrug: Glycoconjugated Chitosan-O-isopropyl-5’-O-3TC Monophosphate Conjugate As Hepatocyte-targeted Prodrug

In this study, a novel hepatocyte-targeted prodrug was synthesized andcharacterized. The prodrug is chitosan (CS) conjugated with lactobionic acids(LA) and Lamivudine (3TC) which have been used as a effective of hepatitisB virus antiviral drug was synthesized and characterized. The prodrug whichwas based on chitosan(CS) as the polymer carrier and anti-HBV drugLamivudine (3TC), an NRTI, as the model drug and LA which can be specificidentification by asialoglycoprotein receptor of the liver cell, was synthesizedand characterized by certain methods. There are three step to synthesyCS-3TC-LA. Firstly phosphoramidate linkage was used to connect3TC andCS, than we get CS-3TC, secondly LA was couple to CS-3TC using asuccinate linke. The structure Of CS-3TC-LA and CS-3TC were characterizedby NMR and the vitro release of the prodrug was research by Liquidchromatography in pH1.1and pH7.4at37.0±0.1°C. In the vitro release ofCS-3TC-LA, there are two kinds of small molecules,3TC and3TCmonophosphate derivative(3TC-P-OH) which release from the CS-3TC-LAthat can be detect by Liquid chromatography. The release of3TC-P-OH ismore significant than the release of3TC, because3TC-P-OH have thephosphoramidate linkage which make the3TC easyly skip the step of singlephosphorus acylation. So CS-3TC-LA can make the3TC better play efficacy. The results of the vitro release suggested that CS-3TC-LA may be used as asustained polymeric prodrug for improving therapy efficacy and the targettingof CS-3TC-LA may reduced side effects of other organs in Hepatitis Btreatment.The new conjugate were characterized by1H NMR, ICP-AES and XRD.Furthermore, we also prepared the nanosizing products of two conjugates bythe process of ionotropic gelation between TPP and chitosan-3TC conjugatesrespectively and studied the physicochemical characteristics by TEM, DLSand so on.The anti-HBV revealed that sulfating apparently decreased thecytotoxicity, and accordingly the side effects will be decreased. Finally, the SIfulfilled our former expectation and it was qualified for further study.