Supramolecular Complex of Methyl-β-cyclodextrin with Adamantane-Grafted Hyaluronic Acid as a Novel Antitumor Agent
Supramolecular Complex of Methyl-β-cyclodextrin with Adamantane-Grafted Hyaluronic Acid as a Novel Antitumor Agent
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DOI：
10.1248/cpb.c17-00824
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发表时间：
2018-03-01
影响因子：
1.7
通讯作者：
Arima, Hidetoshi
中科院分区：
文献类型：
--
作者：
Elamin, Khaled Mohamed;Yamashita, Yuki;Arima, Hidetoshi
甲基-β-环糊精 (M-β-CyD) 具有细胞毒活性，并具有作为抗肿瘤剂的潜力。然而，M-β-CyD的肿瘤选择性较低，导致抗肿瘤活性低且副作用大。同时，透明质酸（HA）被认为是一种有前途的肿瘤靶向配体，因为各种癌细胞过度表达CD44（一种HA结合糖蛋白）。在本研究中，为了开发 M-β-CyD 的肿瘤选择性递送系统，我们设计了 M-β-CyD 与金刚烷接枝 HA 的超分子复合物（Ad-HA/M-β-CyD），并评估其作为肿瘤选择性抗肿瘤药物的作用。 M-β-CyD 与 Ad-HA 形成稳定的复合物 (K-c>10(4)m(-1))。此外，Ad-HA/M-β-CyD 形成了带有约 100% 轻微负电荷的纳米颗粒。粒径140nm，表明抗肿瘤药物具有良好的理化性质。 Ad-HA/M-beta-CyD 在人结肠癌细胞系 HCT116 细胞 (CD44(+)) 中通过 CD44 介导的内体途径表现出优异的细胞毒活性。此外，Ad-HA/M-β-CyD 的细胞毒活性是由细胞凋亡诱导的。这些结果表明Ad-HA/M-β-CyD具有作为肿瘤选择性超分子抗肿瘤剂的潜力。
Methyl-beta-cyclodextrin (M-beta-CyD) exhibits cytotoxic activity, and has the potentials as an antitumor agent. However, a tumor-selectivity of M-beta-CyD is low, leading to low antitumor activity and the adverse effects. Meanwhile, hyaluronic acid (HA) is known as a promising tumor targeting ligand, because various cancer cells overexpress CD44, a HA-binding glycoprotein. In the present study, to develop a tumor-selective delivery system for M-beta-CyD, we designed a supramolecular complex of M-beta-CyD with adamantane-grafted HA (Ad-HA/M-beta-CyD) and evaluated it as a tumor-selective antitumor agent. M-beta-CyD formed a stable complex with Ad-HA (K-c>10(4)m(-1)). In addition, Ad-HA/M-beta-CyD formed slightly a negative-charged nanoparticle with ca. 140nm of a particle size, indicating the favorable physicochemical properties for antitumor agents. Ad-HA/M-beta-CyD showed the superior cytotoxic activity via CD44-mediated endosomal pathways in HCT116 cells (CD44(+)), a human colon cancer cell line. In addition, cytotoxic activity of Ad-HA/M-beta-CyD was induced by apoptosis. These results suggest that Ad-HA/M-beta-CyD has the potentials as a tumor-selective supramolecular antitumor agent.