Design of Macromolecular Prodrug Having Antitumor Activity

5-氟尿嘧啶(5FU)具有显著的抗肿瘤活性，但也伴随着不良反应。聚苹果酸、壳聚糖和聚半乳糖胺作为低或无毒、相容、可生物降解的大分子前药载体具有广阔的应用前景。为了提供一种副作用小、对肿瘤细胞具有亲和力、具有较强抗肿瘤活性的5FU大分子前药，将5FU共价连接到聚苹果酸/SA上。通过尿素或酯键通过疏水亚甲基间隔基对糖、甲壳氨基低聚糖和聚半乳糖胺进行反应，在体外37ﾟC条件下，所得到的偶联物可被水解物释放出游离的5FU。这些可生物降解的聚合物/5FU结合物通过体内注射(IP)转移/IP注射对小鼠p388淋巴细胞性白血病有很强的存活效应。此外，即使在高剂量范围内，这些结合物也没有表现出任何急性毒性。聚苹果酸/5FU/氨基半乳糖和聚半乳糖胺/5FU在体外对肝癌细胞有较强的生长抑制作用。这种含半乳糖残基的5FU/聚合物结合物对肝癌细胞的高度生长抑制现象可以用半乳糖受体介导的选择性摄取肝癌细胞来解释。

5-Fluorouracil (5FU) has a remarkable antitumor activity, which is accompanied, however, by undesirable side-effects. Poly (malic acid), chitosan and polygalactosamine are of interest for application as low or non-toxic, compatible and biodegradable carriers of macromolecular prodrug. In order to provide a macromolecular prodrug of 5FU reducing the side-effects, having affinity for tumor cells and exhibiting strong antitumor activity, the covalent attachment of 5FUs to poly (malic acid) /sa. ccharide, chitosamino-oligosaccharide and polygalactosam ine through hydrophobic methylene spacer groups via urea or ester bonds was carried out.The obtained conjugates were found to be hydrolyzed to release free 5FU itself at 37ﾟC in vitro. These biodegradable polymer/5FU conjugates exhibited strong survival effects against p388 lymphocytic leukemia in mice by intraperitoneal (ip) transiplantation / ip injection in vivo. Moreover, these conjugates did not display any acute toxicity even in the high dose ranges. Poly (malic acid) /5FU /galactosamine and polygalactosamine /5FU exhibited high growth-inhibitory effects against hepatoma cells in vitro th an the other conjugates obtained. Such an appearance of high growth-inhibitory for the conjugate of 5FU/polymer having galactosamine residues against hepatoma cells can be explained by galactose receptor-mediated selective uptake into the hepatoma cells.