Preparation and Characterization of Targetable Dextran Polymer Prodrug

• Main Authors: Guu Jan An, 古振安
• Other Authors: Tzuoh-Min Juang
• Format: Others
• Language: zh-TW
• Published: 2002
• Online Access: http://ndltd.ncl.edu.tw/handle/87963151735681745071

博士 === 國立交通大學 === 應用化學系 === 90 === In this study preparation and characterization of an anticancer polymer prodrug have been discribed. The polymer prodrugs were obtained by utilizing dextran as the polymer carrier, which was conjugated with drugs, i.e., 5-fluorouracil (5-FU) and adriamycin (ADR) and with a targeting moiety, respectively. 5-FU was fixated to dextran through covalent bonds to provide a water-soluble macromolecular prodrug. A lysosomally digestable tripeptide chain of Gly-Leu-Gly was used as a spacer group between dextran and 5-FU. Moreover, 5-FU was attached to the spacer via amide bonding by the coupling agent, diethylphosphoric cyanide. The content of 5-FU moiety on the polymeric-drug conjugate was about 5mol%. Galactosamine, as a saccharide residue, was used for the targeting effect of the polymer-drug conjugate. Also investigated herein was the release behavior of 5-FU from the conjugate by papain. The total amount of 5-FU released after 48 hr was 20 mol% and about 50 mol% for a week for DGLG-5FU. The cytotoxicity of the conjugates against the hepatoma cells was determined by an MTT assay, in which the cell specific targeting of the conjugated to hepatoma cells by covalently bonding to a galactosamine group was observed. Three kinds of polymeric ADR conjugates of dextran was synthesized, including dextran-Gly-Leu-Gly-ADR (DGLGA) conjugate with lysosomally degradable tripeptide spacer group, dextran-Gly-Leu-Gly-ADR-galactosamine (DGLGA-Ga) conjugate with a targeting moiety of galactosamine on DGLGA, and dextran-C6H10-ADR (DC6A) conjugate with hexamethylene spacer group. The content of ADR moiety on the polymeric-drug conjugate was about 3mol%. The enzyme hydrolysis of DGLGA and DC6A was carried out by the incubation with papain. The total amount of ADR released after 48 hr was 43 mol% for DGLGA and less than 1 % for DC6A. For the in vitro cytotoxicity evaluation, DGLGA-Ga conjugate has higher cytotoxic efficacy than other conjugates for the incubation with Hep-3B cells, and the capability of targeting to hepatoma cell of galactosamine residue was observed consequently. In contrast, for the incubation with SiHa cells of these conjugates, there is no significant cytotoxicity observed. The in vivo cytotoxic efficacy of each conjugate (20 mg ADR-equiv./kg) against CT-26 mice colon cells implanted s.c. in Balb-C mice was studied. The DGLGA generated the best therapeutic effect with the presence of long term survival (LTS) at day 50 (2/6).