钙帮围攻肿瘤细胞!华东师大科学家团队发现抗癌新法

时间:2019-07-16 来源:www.idatingbd.com

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Professor Qi Wenbo from the School of Chemistry and Molecular Engineering of East China Normal University, Shanghai Key Laboratory of Green Chemistry and Chemical Process Greening, Professor Liu Xiaogang of the National University of Singapore, and Professor Yao Zhenwei of Huashan Hospital affiliated to Fudan University, inspired by clinical tumor calcification Ingeniously, the use of ultra-small calcium peroxide (CaO2) to activate tumor cells to produce a unique "calcium overload" biological effect, for the first time proposed a new type of tumor treatment strategy based on tumor cell "calcium death": ion interference therapy.

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Professor Bu Wenbo

Siege! Calcified tumor lesion area

It is well known that patients with cancer after a period of chemotherapy, radiotherapy and other series of treatment processes, patients with significant therapeutic effects, CT images of tumor lesions will appear calcification phenomenon.

This kind of phenomenon often causes a doubt to the clinician. Is there a necessary connection between the development of calcification in the tumor lesion area and the therapeutic effect?

From the perspective of cell biology, the development of tumor calcification may go through the following processes: radiotherapy in the tumor lesion area, chemotherapy - leading to oxidative stress in tumor cells - induced calcium overload in tumor cells - calcification in the lesion area - ultimately leading to tumor cell death.

From the perspective of materials science, the calcification point produced in the tumor lesion area is mainly composed of hydroxyapatite (Ca5(PO4)3(OH)). Therefore, combining this classic clinical medical phenomenon with materials science may stimulate a new class of advanced tumor treatment strategies.

xxRecently, Professor Qi Wenbo from the School of Chemistry and Molecular Engineering of East China Normal University, Shanghai Key Laboratory of Green Chemistry and Chemical Process Greening, and Professor Liu Xiaogang of the National University of Singapore and Professor Yao Zhenwei of Huashan Hospital affiliated to Fudan University were inspired by the above clinical practice. The phenomenon of tumor calcification, using the ultra-small calcium peroxide (CaO2) to activate tumor cells to produce a unique "calcium overload" biological effect, first proposed a new type of tumor treatment strategy based on tumor cell "calcium death": ion interference Therapy (Ion Interference Therapy, IIT). The international authoritative academic journal Cell, Chem, published the latest research results online on July 3, 2019 under the title "Calcium-Overload-Mediated Tumor Therapy by Calcium Peroxide Nanoparticles".

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Chem Magazine Map

Precision! Nanoparticles to help

Calcium ion (Ca2+), as the second messenger of intracellular signaling, plays a crucial role in regulating various physiological functions of the body, such as cell migration and proliferation, muscle contraction, and neuronal excitation.

Under normal physiological conditions, when cells are stimulated by external signals, they will cause continuous fluctuations in the cytoplasmic Ca2+ concentration at the spatial and temporal levels to achieve accurate signal transmission.

Many of the functions of cells depend on changes in the concentration of Ca2+ in the cytoplasm. Once this concentration change is uncontrolled, cell function is disturbed and even causes cell death.

xx例如,细胞质中Ca2 +的异常积累经常导致细胞钙超载,并且持续的钙超载进一步诱导细胞死亡。研究表明,在正常条件下,细胞对Ca2 +浓度具有极其严格的调节机制(ER/PR,钙泵,Ca2 +通道等),使细胞钙超载的异常状态一般难以继续;

然而,在氧化应激下,细胞调节Ca2 +的能力将逐渐降低,导致Ca2 +聚集并引发钙超载;在减少氧化应激后,细胞可以恢复正常状态。细胞的氧化应激和钙超载,这两种状态也具有相互促进和相互促进的协同作用,为基于钙超载的肿瘤的有效治疗提供理论支持。

基于以上考虑,合作研究团队采用简单的湿法化学方法巧妙地设计和合成了一类粒径小于5 nm的CaO2纳米粒子,并在表面涂了一层透明质酸钠,以获得超-Small SH。 -CaO2纳米颗粒。

在肿瘤病变区域,SH-CaO2表面的保护层被透明质酸酶分解,暴露的CaO2可加速肿瘤酸性微环境的分解,迅速产生过氧化氢和游离Ca2 +。

由于肿瘤细胞中过氧化氢酶表达的下调,CaO2分解产生的过氧化氢在肿瘤细胞中积累,在肿瘤细胞中诱导氧化应激,并且氧化应激进一步导致Ca相关离子通道的功能障碍。肿瘤细胞中的Ca2 +浓度不能正常调节,过氧化钙分解释放的Ca2 +长时间保留在肿瘤细胞中。这种异常的Ca2 +聚集行为将导致持续的细胞钙超载,其干扰或阻碍肿瘤细胞的代谢。和增殖过程,诱导肿瘤细胞代谢紊乱和功能紊乱,从而诱导细胞死亡;

同时,局部富集Ca2 +也可促进肿瘤病灶钙化的发展。由超小型过氧化钙纳米颗粒诱导的这种类型的肿瘤细胞死亡在该工作中被定义为“钙细胞凋亡”。

安全!临床研究和开发的巨大潜力

这些新型超小型过氧化钙纳米药物具有以下优点:首先,由于几乎所有肿瘤细胞都存在Ca2 +的特殊生物学效应,因此纳米药物用于肿瘤治疗在理论上是可行的。

其次,在正常细胞中,超小过氧化钙分解极慢,并且由缓慢分解产生的过氧化氢可通过过氧化氢酶迅速分解成氧和水,因此,不可能在正常细胞中诱导氧化应激。它缓解了细胞的“钙超载”应激反应,钙是人体必需的元素,具有良好的生物安全性;

最后,纳米药物的室温合成过程简单方便,适合批量制备。基于以上几点,随着“钙死亡”抑制肿瘤的分子机制和药代动力学基础研究的逐步完善,预计这种新型SH-CaO2纳米药物具有很大的临床转化潜力。

目前,各种无机纳米材料在肿瘤治疗研究方面取得了很大进展,但遗憾的是,无机纳米材料的生物相容性仍然是阻碍其临床应用的瓶颈。

基于钙离子在这项工作中的特殊生物效应,作者认为纳米材料(包括无机纳米材料)降解产生的功能性离子或离子簇的特殊生物效应会干扰或阻碍肿瘤细胞的代谢。增殖过程,或广义上,通过调节生物活性离子与肿瘤细胞的生理过程之间的相互作用来调节肿瘤细胞的代谢紊乱,从而抑制肿瘤生长和转移。

这种新型的癌症治疗策略定义为:离子干扰疗法(IIT),它将为无机纳米材料在临床癌症治疗中的应用开辟新的途径。

研究成果得到了国家自然科学基金,科技部,上海市科学技术委员会等相关基金项目和人才计划项目的大力支持。

来源|化学与分子工程学院

编辑|吴潇岚