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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.

本文合成了一种水溶性胶束药物--苯乙烯马来酸共聚物-葡糖胺-硼酸（SGB-复合物）。在体外和多种小鼠肿瘤模型中显示出基于EPR效应的肿瘤选择性蓄积和优异的杀肿瘤活性。然而，在没有中子辐照的情况下，对SGB-复合物的精确化学结构和细胞毒性的详细作用模式尚不清楚，在FY 2022期间，我专注于通过UV-vis、IR、NMR光谱和液相色谱质谱法测定SGB-复合物的分子结构。我们证实SMA-聚合物通过酰胺键与葡糖胺结合，硼酸通过二醇键与葡糖胺连接（我们在ACS Applied Biomaterials杂志上报道了这一工作）。接下来，我们试图找出可能的机制，在体外细胞毒性的SGB-复合物。我们推测，在轻度缺氧状态下，SGB复合物可能诱导ER或线粒体应激。为了支持我们的假设，我们测量了我们的药物治疗后ER应激标志物磷酸化真核起始因子2 α（p-eIF 2），C/-EBP同源蛋白（CHOP）和Caspase 3和7的表达。有趣的是，我们发现SGB复合物显著增加了各种ER应激标志物，这证实了我们的药物在缺氧适应的癌细胞中诱导ER应激。我们还测量了我们的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了非常小的变化。TEM图像将能够确认是否有任何线粒体损伤发生。

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：
发表时间：
期刊：
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