EPR-effect driven tumor delivery of multifunctional boron nanomedicine for neutron capture therapy

EPR效应驱动的多功能硼纳米药物的肿瘤递送用于中子捕获治疗

基本信息

批准号：
22KF0311
负责人：
新留琢郎
金额：
$ 1.41万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for JSPS Fellows
财政年份：
2023
资助国家：
日本
起止时间：
2023-03-08 至 2024-03-31
项目状态：
已结题

项目摘要

We synthesized a water-soluble micellar drug called styrene maleic acid (SMA) copolymer conjugated glucosamine and boric acid (SGB-complex). It showed tumor selective accumulation based on EPR effect and excellent tumoricidal activity in vitro as well as various mouse tumor models. However, the precise chemical structure of SGB-complex and the detailed mode of action of cytotoxicity without neutron irradiation was not understood.During FY2022 period, I focused on the determination of molecular structure of SGB-complex by UV-vis, IR, NMR spectroscopy and liquid chromatography mass spectroscopy. We confirmed that the SMA-polymer bound to the glucosamine via amide bond and the boric acid was attached to glucosamine by di-ol bond (This works we reported at ACS Applied Biomaterials journal). Next, we try to find out the possible mechanism of in vitro cytotoxicity of SGB-complex. We hypothesized that SGB-complex might induce ER or mitochondrial stress in mild-hypoxia state. To support our hypothesis, we measure the ER stress marker phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2), C/-EBP homologous protein (CHOP), and Caspase 3 and 7 expressions after treating of our drug. Interestingly, we found the SGB-complex significantly increased various ER stress markers that confirmed our drug induces ER stress in hypoxia adapted cancer cells. We also measured the mitochondrial membrane potential after treatment of our drug, and data showed very less changes occurred compare to non-treated group. TEM image will be able to confirm whether any mitochondrial damage occur or not.

我们合成了一种水溶性胶束药物，称为苯乙烯马来酸（SMA）共轭葡萄糖胺和硼酸共聚物（SGB-复合物）。它显示出基于EPR效应的肿瘤选择性积累和在体外以及各种小鼠肿瘤模型中优异的杀肿瘤活性。然而，SGB-复合物的精确化学结构以及无需中子照射的细胞毒性的详细作用模式尚不清楚。在FY2022期间，我重点研究了通过UV-vis、IR、NMR光谱测定SGB-复合物的分子结构和液相色谱质谱法。我们证实 SMA 聚合物通过酰胺键与葡萄糖胺结合，硼酸通过二醇键与葡萄糖胺结合（我们在 ACS Applied Biomaterials 杂志上报道了这项工作）。接下来，我们试图找出SGB-复合物体外细胞毒性的可能机制。我们假设 SGB 复合物可能在轻度缺氧状态下诱导 ER 或线粒体应激。为了支持我们的假设，我们在药物治疗后测量了 ER 应激标记物磷酸化真核起始因子 2 α (p-eIF2)、C/-EBP 同源蛋白 (CHOP) 以及 Caspase 3 和 7 的表达。有趣的是，我们发现 SGB 复合物显着增加了各种 ER 应激标记物，证实我们的药物在适应缺氧的癌细胞中诱导 ER 应激。我们还测量了药物治疗后的线粒体膜电位，数据显示与未治疗组相比，发生的变化非常少。 TEM 图像将能够确认是否发生线粒体损伤。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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DOI：
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影响因子：
0
作者：
通讯作者：

Development of potent antipseudomonal β‐lactams by means of polycarboxylation of aminopenicillins

通过氨基青霉素多羧化作用开发强效抗假单胞菌β-内酰胺类药物

DOI：
10.1111/1348-0421.12930
发表时间：
2021
期刊：
Microbiology and Immunology
影响因子：
2.6
作者：
Akter Shahinur;Migiyama Yohei;Tsutsuki Hiroyasu;Ono Katsuhiko;Hamasaki Chika;Zhang Tianli;Miyao Kenki;Toyomoto Touya;Yamamoto Keiichi;Islam Waliul;Sakagami Takuro;Matsui Hirotaka;Yamaguchi Yoshihiro;Sawa Tomohiro
通讯作者：
Sawa Tomohiro

A promising strategy for cancer treatment by using SMA-polymer encapsulated chlorophyll as a photodynamic therapy

使用 SMA 聚合物封装叶绿素作为光动力疗法治疗癌症的一种有前途的策略