Design of Macromolecular Prodrug Having Antitumor Activity

具有抗肿瘤活性的大分子前药的设计

• 批准号: 02650672
• 负责人: OUCHI Tatsuro
• 金额: $ 1.34万
• 依托单位: Kansai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1990
• 资助国家: 日本
• 起止时间: 1990 至 1991
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-02650672/
• 关键词: Macromolecular Prodrug; Poly (Malic Acid); Chitosan; Polygalactosamine; 5-Fluorouracil; Saccharide; Release Rate; Antitumor Activity; キチン; 生体内分解性高分子; PEG

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.

5-氟尿嘧啶（5FU）具有显著的抗肿瘤活性，但伴随有不良的副作用。聚苹果酸、壳聚糖和聚半乳糖胺作为低毒、无毒、相容、可生物降解的大分子前药载体具有广泛的应用前景。为了提供一种降低毒副作用、对肿瘤细胞有亲和力、具有较强抗肿瘤活性的5FU大分子前药，将5FU与聚苹果酸/sa共价结合。糖、壳寡糖和聚半乳糖胺通过疏水亚甲基间隔基团通过尿素或酯键进行分离。所得的缀合物在体外37℃的温度下被水解释放出游离的5FU。这些可生物降解的聚合物/5FU偶联物通过腹腔移植/腹腔注射对小鼠p388淋巴细胞白血病有很强的存活作用。此外，即使在高剂量范围内，这些缀合物也没有表现出任何急性毒性。聚苹果酸/5FU /半乳糖胺和聚半乳糖胺/5FU在体外对肝癌细胞具有较高的生长抑制作用。具有半乳糖胺残基的5FU/聚合物偶联物对肝癌细胞具有如此高的生长抑制作用，可以通过半乳糖受体介导的肝癌细胞选择性摄取来解释。

项目成果

TATSURO OUCHI: "Design of Poly (alpha-Malic)-5Fu Conjugate Exhibiting Antitumor Activity" Brit. Polym. J.23. 221-228 (1990)

TATSURO OUCHI：“具有抗肿瘤活性的聚（α-苹果酸）-5Fu 缀合物的设计”英国。

TATSURO OUCHI: "Design of Polysachharide-5-Fluoro-Uracil Conjugate Exhibiting Antitumor Activities" Acs Symposium Series. 469. 71-83 (1991)

TATSURO OUCHI：“展示抗肿瘤活性的多糖-5-氟-尿嘧啶缀合物的设计”Acs 研讨会系列。

大内 辰郎: "Antitumor Activity of Chitasan and Chitin Immobilized 5ーFluorouracils through Hexamethylene Spacers via Corbamoyl Bonds" J.Bioact.Compat.Polymer. 4. 363-371 (1989)

Tatsuo Ouchi：“壳聚糖和甲壳素通过 Corbamoyl 键通过六亚甲基间隔基固定的 5-氟尿嘧啶的抗肿瘤活性”J.Bioact.Compat.Polymer。 4. 363-371 (1989)

大矢 裕一: "Synthesis of Antitumor Activity of αー1,4ーPolygalactosamine and NーAcetylーαー1,4ーpolygalactos amine Immobilized 5ーFluorouracils through Hexamethylene Spacer Groups via Urea,Urea Bonds" J.Control.Rel.17. 259-266 (1991)

Yuichi Oya：“通过尿素、尿素键通过六亚甲基间隔基团固定化 5-氟尿嘧啶的 α-1,4-聚半乳糖胺和 N-乙酰基-α-1,4-聚半乳糖胺的抗肿瘤活性” J.Control.Rel.17 .259-266 (1991)

TATSURO OUCHI: "Synthesis and Antitumor Activity of Conjugates of Poly (alpha-Malic Acid) and 5-Fluorouracils Bound Via Ester, Amide or Carbamoyl Bonds." J. Control. Rel.12. 143-153 (1990)

TATSURO OUCHI：“通过酯、酰胺或氨基甲酰键结合的聚（α-苹果酸）和 5-氟尿嘧啶缀合物的合成和抗肿瘤活性。”