Novel Hydrophilic Camptothecin Derivatives Conjugated to Branched Glycerol Trimer Suppress Tumor Growth without Causing Diarrhea in Murine Xenograft Models of Human Lung Cancer
Novel Hydrophilic Camptothecin Derivatives Conjugated to Branched Glycerol Trimer Suppress Tumor Growth without Causing Diarrhea in Murine Xenograft Models of Human Lung Cancer
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DOI：
10.1021/acs.molpharmaceut.9b00249
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发表时间：
2020-04-06
影响因子：
4.9
通讯作者：
Tsuchiya, Koichiro
中科院分区：
文献类型：
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作者：
Tsuchihashi, Yuki;Abe, Shinji;Tsuchiya, Koichiro
喜树碱对多种肿瘤具有广泛的抗肿瘤谱。尽管喜树碱具有显著的肿瘤抑制作用，但喜树碱太疏水，不能在水中溶解，因此目前尚未在临床应用。CPT-11（伊立替康）是喜树碱的亲水性类似物之一，被广泛使用。然而，它的水溶性仍然很低，而且会引起严重的腹泻。因此，我们将SN38与支链甘油三聚体（SN38- bgl）偶联，设计并合成了一种新型的高亲水性喜树碱衍生物，并将其作为一种独特的策略，赋予疏水分子更大的亲水性，使CPT-11的益处最大化，不良反应最小化。与CPT-11相比，SN38-BGLs在小鼠异种移植人肺癌模型中表现出相同或稍强的肿瘤抑制作用。然而，当给予SN38-BGL时，既没有观察到早发性腹泻，也没有观察到晚发性腹泻。空肠和回肠绒毛高度均大于CPT-11处理小鼠，说明SN38-BGL对小鼠的危害小于CPT-11。肝微粒体的体外消化没有产生SN38，但产生了一些其他分子，这与我们的预期相反，这表明除了SN38之外，还有其他活性代谢物的参与，这可能解释了这种差异。因此，SN38-BGLs可能是一种新的亲水喜树碱衍生物，不会引起严重的腹泻。
Camptothecin possesses broad antitumor spectra on various cancers. In spite of its marked tumor-suppressing potency, camptothecin is too hydrophobic to be solved in water and therefore not currently in clinical use. CPT-11 (irinotecan) is one of the hydrophilic analogues of camptothecin and widely prescribed. However, its water solubility is still low and furthermore evokes severe diarrhea. Therefore, we designed and synthesized novel highly hydrophilic camptothecin derivatives by conjugating SN38 with branched glycerol trimer (SN38-BGL), which we have been developing as a unique strategy to endow hydrophobic molecule with much hydrophilicity, to maximize the benefit of CPT-11 and minimize the adverse effects. The SN38-BGLs exhibited equivalent or slightly stronger tumorsuppressing effects in murine xenograft human lung cancer models compared to CPT-11. However, neither early- nor late-onset diarrhea was observed when SN38-BGL was administered. Heights of villi in jejunum and ileum were bigger than those from CPT-11treated mice, indicating that SN38-BGL is less harmful than CPT-11. Ex vivo digestion by liver microsome did not yield SN38 but a couple of other molecules against our expectations, which suggests the involvement of other active metabolites than SN38 and may explain the differences. Hence, SN38-BGLs can be a novel hydrophilic camptothecin derivative without causing severe diarrhea.