Synthesis and biological properties of antitumor-active conjugates of ADR with dextran

Abstract

Three kinds of polymeric adriamycin (ADR) conjugates of dextran were synthesized, namely a dextran–Gly-Leu-Gly-ADR (DGLGA) conjugate with a lysosomally degradable tripeptide spacer group, a dextran–Gly-Leu-Gly-ADR-galactosamine (DGLGA-Ga) conjugate with a targeting moiety of galactosamine on DGLGA, and a dextran–C₆H₁₀-ADR (DC₆A) conjugate with a hexamethylen spacer group. The content of the ADR moiety in the polymeric-drug conjugate was about 3 mol%. Enzyme hydrolysis of DGLGA and DC₆A was carried out by incubation with papain. The total amount of ADR released after 48 h was 43 mol% for DGLGA and less than 1 mol% for DC₆A. In an in vitro cytotoxicity experiment, the DGLGA-Ga conjugate has higher cytotoxic efficacy than the other conjugates for incubation with Hep-3B cells and consequently, the capability of targeting hepatoma cells of the galactosamine residue was determined. In contrast, for the incubation with SiHa cells of these conjugates, there was no significant cytotoxicity effect. The in vivo cytotoxic efficacy of each conjugate (20 mg ADR equiv./kg) against CT-26 mice colon cells implanted subcutaneously in Balb-C mice was studied. The DGLGA conjugate generated the best therapeutic effect with the presence of long-term survival (LTS) at day 50 (2/6).

Keywords:

• Dextran
• polymeric pro-drug
• antitumor activity
• adriamycin
• galactosamine.