Development on Selective Delivery System of Antitumor Agents by Utilizing Cell-Recognition Ability of Saccharides

聚(α-苹果酸)是一种可生物降解和可生物吸附的聚丙交酯类药物载体，它能够共价结合药物和靶向部分。抗肿瘤药物的大分子前药具有毒副作用小、靶向肿瘤细胞能力强、抗肿瘤活性高等优点。研究了聚(α-苹果酸)/5-氟尿嘧啶(5FU)/糖和聚(α-苹果酸)/阿霉素(ADR)/糖结合物的设计。以氨基半乳糖、氨基葡萄糖、甘露糖等单糖作为靶向基团。体外对多种肿瘤细胞的生长抑制作用和对荷瘤小鼠的存活作用。聚α-苹果酸/5FU/半乳糖胺和聚α-苹果酸/ADR/半乳糖胺结合物在体外对人肝癌细胞的生长抑制作用明显强于聚α-苹果酸/5FU和聚α-苹果酸/ADR结合物。这些结果可以通过半乳糖受体介导的肝细胞特异性摄取来解释。此外，聚α-苹果酸与5-氟尿嘧啶的偶联物对小鼠p388淋巴细胞性白血病有明显的存活作用。所得结合物在高剂量范围内未表现出急性毒性。

Poly (alpha-malic acid) is of interest as a biodegradable and bioadsorbable poly (lactide) type drug carrier, which is able to covalently attach both drug and targeting moiety. The macromolecular prodrug of antitumor drug will reduce the side-effects, have the ability to target tumor cells and exhibit high antitumor activity. The design of poly (alpha-malic acid) /5-fluorouracil (5FU) /saccharide and poly (alpha-malic acid) /adriamycin (ADR) /saccharide conjugates were investigated. Monosaccharides such as galactosamine, glucosamine and mannosamine were used as targeting moieties. Growth inhibition against various tumor cells in vitro and the survival effect against mice bearing tumor cells in vivo were tested. Poly (alpha-malic acid) /5FU/galactosamine and poly (alpha-malic acid) /ADR/galactosamine conjugates showed stronger growth-inhibitory effects than poly (alpha-malic acid) /5FU and poly (alpha-malic acid) /ADR conjugates against human hepatoma cells in vitro. These results could be explained by galactose receptor-mediated specific uptake into hepatocyte cells. Moreover, the conjugates of poly (alpha-malic acid) with 5FU exhibited significant survival effects against p388 lymphocytic leukemia in mice by intraperitoneal (ip) transplantation/ip injection. The obtained conjugates did not display an acute toxicity in the high dose ranges.