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

利用糖类细胞识别能力开发抗肿瘤药物选择性递送系统

• 批准号: 05680767
• 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: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05680767/
• 关键词: Saccharide; Cell-Recognition Ability; Macromolecular Prodrug; Carrier; Biodegradable-Absorbable Polymer; Antitumor Agent; Peptide Spacer; Lysosomal Enzyme; キャリヤー; リンソーム酵素

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.

聚（α-苹果酸）作为生物可降解和生物可吸附的聚（丙交酯）型药物载体是令人感兴趣的，其能够共价连接药物和靶向部分。抗肿瘤药物的高分子前体药物具有毒副作用小、靶向肿瘤细胞、抗肿瘤活性高等优点。研究了聚α-苹果酸/5-氟尿嘧啶（5 FU）/糖和聚α-苹果酸/阿霉素（ADR）/糖偶联物的设计。单糖如半乳糖胺、葡糖胺和甘露糖胺用作靶向部分。体外实验观察对多种肿瘤细胞的生长抑制作用，体内实验观察对荷瘤小鼠的生存效果。聚α-苹果酸/5-FU/半乳糖胺和聚α-苹果酸/ADR/半乳糖胺偶联物对人肝癌细胞的体外生长抑制作用强于聚α-苹果酸/5-FU和聚α-苹果酸/ADR偶联物。这些结果可以解释半乳糖受体介导的特异性摄取到肝细胞。此外，聚（α-苹果酸）与5 FU的缀合物通过腹膜内（ip）移植/ip注射在小鼠中对p388淋巴细胞白血病表现出显著的存活效果。所得偶联物在高剂量范围内未显示急性毒性。

项目成果

大内辰郎(分筆): "Biotechnology and Bioactive polymers" Plenum Press, 342 (1994)

Tatsuro Ouchi（作者）：“生物技术和生物活性聚合物”Plenum Press，342（1994）

Yuichi Ohya: "Synthesis of CM-Chitin Immobilizing Doxorubicins through Tetrapeptide Spacer Groups and Its Enzymatic Release Behavior of Doxorubicin in Vitro" Macromol. Chem. Phys.195. 2839-2853 (1994)

Yuichi Ohya：“通过四肽间隔基团合成CM-甲壳素固定阿霉素及其体外阿霉素的酶促释放行为”Macromol。

Tatsuro Ouchi: ACS Symposium Series 520. Am. Chem. Soc., 411 (1993)

大内达郎：ACS 研讨会系列 520。上午。

大内辰郎(分筆): "Am.Chem.Soc." ACS Symposium Series 545. 246 (1994)

Tatsuro Ouchi（作者）：“Am.Chem.Soc”。 ACS 研讨会系列 545. 246 (1994)

Yuichi Ohya: "Release Behavior of 5-Fluorouracil from Chitosan-Gel Microspheres Immobilizing 5-Fluorouracil Coated with Polysaccharides and Their Cell Specific Cytotoxicity" J.Macromol. Sci. -Pure Appl. Chem.A31. 629-642 (1994)

Yuichi Ohya：“从固定有多糖的 5-氟尿嘧啶的壳聚糖凝胶微球中释放 5-氟尿嘧啶的行为及其细胞特异性细胞毒性”J.Macromol。