Structural Determination of the Nanocomplex of Borate with Styrene-Maleic Acid Copolymer-Conjugated Glucosamine Used as a Multifunctional Anticancer Drug.
Structural Determination of the Nanocomplex of Borate with Styrene-Maleic Acid Copolymer-Conjugated Glucosamine Used as a Multifunctional Anticancer Drug.
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DOI：
10.1021/acsabm.2c00883
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发表时间：
2022-12
影响因子：
4.7
通讯作者：
Waliul Islam;Hiroyasu Tsutsuki;K. Ono;A. Harada;K. Shinozaki;T. Niidome;Jun Fang;T. Sawa
中科院分区：
文献类型：
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作者：
Waliul Islam;Hiroyasu Tsutsuki;K. Ono;A. Harada;K. Shinozaki;T. Niidome;Jun Fang;T. Sawa
开发有效的抗癌药物对于特异性靶向癌症组织的化疗至关重要。我们最近合成了一种多功能的水溶性高分子抗癌药物，它由苯乙烯-马来酸共聚物（SMA）与氨基葡萄糖和硼酸（BA）的共轭物（SGB复合物）组成。由于增强的渗透性和保留效应，它表现出比正常组织中的蓄积高约10倍的肿瘤选择性蓄积，并且它通过糖酵解抑制、线粒体损伤和热中子照射抑制肿瘤生长。深入了解这种SGB复合物的抗癌作用需要确定其结构。因此，我们通过核磁共振，红外（IR）光谱和液相色谱-质谱研究了SGB复合物的化学结构。为了建立SGB复合物的化学结构，我们合成了一个简单的模型化合物─ ─马来酸-葡萄糖胺（MAG）共轭物─ ─通过使用马来酸酐（MA）单体单元代替SMA聚合物。MAG与BA反应后得到了两种分子量分别为325和343的MAG-BA配合物（MAGB）。我们证实，通过使用红外光谱，MAGB通过MA和葡萄糖胺之间的酰胺键形成稳定的复合物，BA通过二醇键与葡萄糖胺结合。作为通过MAGB分析鉴定的这种化学设计的结果，SGB复合物可以释放BA，并通过在模拟肿瘤微环境的轻度缺氧中抑制乳酸分泌来证明对癌细胞的毒性。对于SGB复合物的临床应用，我们证实该复合物在血清存在下是稳定的。这些发现证实了我们设计的SGB复合物在靶向实体癌和与中子照射组合时发挥治疗效果方面具有各种优势。
The development of effective anticancer drugs is essential for chemotherapy that specifically targets cancer tissues. We recently synthesized a multifunctional water-soluble anticancer polymer drug consisting of styrene-maleic acid copolymer (SMA) conjugated with glucosamine and boric acid (BA) (SGB complex). It demonstrated about 10 times higher tumor-selective accumulation compared with accumulation in normal tissues because of the enhanced permeability and retention effect, and it inhibited tumor growth via glycolysis inhibition, mitochondrial damage, and thermal neutron irradiation. Gaining insight into the anticancer effects of this SGB complex requires a determination of its structure. We therefore investigated the chemical structure of the SGB complex by means of nuclear magnetic resonance, infrared (IR) spectroscopy, and liquid chromatography-mass spectrometry. To establish the chemical structure of the SGB complex, we synthesized a simple model compound─maleic acid-glucosamine (MAG) conjugate─by using a maleic anhydride (MA) monomer unit instead of the SMA polymer. We obtained two MAG-BA complexes (MAGB) with molecular weights of 325 and 343 after the MAG reaction with BA. We confirmed, by using IR spectroscopy, that MAGB formed a stable complex via an amide bond between MA and glucosamine and that BA bound to glucosamine via a diol bond. As a result of this chemical design, identified via analysis of MAGB, the SGB complex can release BA and demonstrate toxicity to cancer cells through inhibition of lactate secretion in mild hypoxia that mimics the tumor microenvironment. For clinical application of the SGB complex, we confirmed that this complex is stable in the presence of serum. These findings confirm that our design of the SGB complex has various advantages in targeting solid cancers and exerting therapeutic effects when combined with neutron irradiation.