A hyaluronic acid-taxol antitumor bioconjugate targeted to cancer cells
A hyaluronic acid-taxol antitumor bioconjugate targeted to cancer cells
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DOI：
10.1021/bm000283n
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发表时间：
2000-06-01
影响因子：
6.2
通讯作者：
Prestwich, GD
中科院分区：
文献类型：
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作者：
Luo, Y;Ziebell, MR;Prestwich, GD
对由紫杉醇和化学修饰的透明质酸（HA）制备的细胞靶向聚合物前药进行了体外评价。在此，我们报告了四个结果，支持HA-紫杉醇前药的选择性摄取和靶向毒性。首先，合成荧光标记的HA-紫杉醇（FITC-HA-Taxol），并使用流式细胞术和共聚焦显微镜来证明细胞特异性结合和摄取。其次，FITC-HA-Taxol的选择性细胞毒性允许摄取与选择性细胞毒性直接相关。第三，HA-泰素生物缀合物的快速摄取和选择性细胞毒性可以被过量的HA或抗-CD 44抗体阻断，但不能被硫酸软骨素（CS）阻断。最后，在人血浆或细胞培养基中从HA-泰素释放游离泰素揭示游离药物通过不稳定的2'酯键的裂解从生物缀合物水解释放。总之，这些数据支持HA-泰素生物缀合物的靶向细胞毒性需要受体介导的细胞摄取生物缀合物，然后水解释放游离泰素的观点。
A cell-targeted polymeric prodrug prepared from Taxol and chemically modified hyaluronic acid (HA) was evaluated in vitro. Herein we report four results in support of the selective uptake and targeted toxicity of the HA-Taxol prodrug. First, a fluorescently labeled HA-Taxol (FITC-HA-Taxol) was synthesized and used to demonstrate cell-specific binding and uptake using flow cytometry and confocal microscopy. Second, the selective cytotoxicity of FITC-HA-Taxol allowed direct correlation of uptake with selective cytotoxicity. Third, the rapid uptake and selective cytotoxicity of HA-Taxol bioconjugates could be blocked by either excess HA or by an anti-CD44 antibody, but not by chondroitin sulfate (CS), Finally, the release of free Taxol From HA-Taxol in human plasma or in cell culture media revealed that the free drug was hydrolytically released from the bioconjugate by cleavage of the labile 2' ester linkage. Taken together, these data support the notion that the targeted cytotoxicity of HA-Taxol bioconjugates requires receptor-mediated cellular uptake of the bioconjugate followed by hydrolytic release of free Taxol.