介孔颗粒原位触发肿瘤内药物反应用于抗肿瘤安全化疗

Traditional chemotherapeutics has been criticized for its strong toxic and side effects. "New use of old drugs" provides a new opportunity for biosafe chemotherapy. The antitumor activity of disulfiram (DSF) has been affirmed and reported to be Cu2+-dependent in the journal Nature in 2017. How to improve the concentration of copper ions in tumor tissues effectively? How to enhance the anti-tumor therapeutic effect of DSF tumor-selectively? How to avoid the possible side effects? Concerning these issues, herein, a new strategy of nanoparticle-triggered in-situ Cu-DSF reaction for safe chemotherapy is proposed based on a well-designed nanosystem which can release copper ions and DSF in a tumor-specific way. The novel bio-safe nanosystem will be subtly established by integrating DSF molecules into the mesoporous microstructure of the Cu2+ self-supplying nanoparticles. The fast release of Cu2+ ions sensitive to mild acidic tumoral microenvironment resulted in the fast biodegradation of the nanoparticles and accelerated DSF release in tumor site, followed by the in-situ reaction of released Cu2+ ions and DSF to achieve Cu-enhanced DSF chemotherapy. The item is aimed to regulate the key components and structural parameters of the novel nanodrug, then study its anti-tumor efficiency, molecular biology mechanism and biological effects systematically. Furthermore, a feasible approach is expected to be provided for exploring anti-tumor nanosystems with high-efficiency and low-cost based on inorganic nanomaterials.

传统抗癌药物因其强毒副作用备受诟病，“旧药新用”为安全化疗提供了新契机。Nature期刊2017年报道确认了戒酒药双硫仑（DSF）的抗癌作用，且其抗癌效率与铜离子浓度正相关。为了靶向提高肿瘤内铜离子浓度，特异性增强DSF对肿瘤组织的细胞毒性，避免全身性毒副作用，切实推进DSF临床转化应用，本项目提出一种基于介孔纳米颗粒降解触发的肿瘤内药物反应策略，拟设计构建一种铜离子自供给型介孔纳米颗粒，利用介孔孔道负载DSF构建安全无毒的纳米药物体系。在肿瘤微环境刺激下，载体骨架中的Cu2+迅速析出，触发纳米颗粒降解释放DSF，肿瘤原位发生Cu-DSF反应，产生毒性物质，针对性杀死肿瘤细胞。本项目拟系统调控该纳米药物的关键组成和结构参数，考察其抗癌疗效、生物学机制和化疗安全性，以介孔纳米材料的构筑为基础，探索安全、高效的治疗体系，期望为新型高效、廉价的抗癌药物体系研发提供新的研究思路。

双硫仑（DSF）是一种临床使用的廉价戒酒药，其细胞毒性可在螯合铜离子后显著增强，可有效杀死肿瘤细胞。但机体内较低的铜离子浓度无法满足这一需求，而全身性的铜离子供应往往会引起严重的重金属中毒问题，极大阻碍了DSF在癌症治疗中的临床转化。为此，我们设计了一种铜离子自供给型的纳米药物DSF@PEG/Cu-HMSNs，该纳米药物经静脉注射后可在肿瘤部位有效富集，并在肿瘤微环境响应下，原位释放负载的DSF药物和掺杂的铜离子，二者在肿瘤原位可发生Cu-DSF螯合反应，生成高细胞毒性的CuET。同时螯合反应中产生的Cu（I）能够在瘤内触发类芬顿反应，产生羟基自由基与CuET协同杀死肿瘤细胞，从而实现DSF的高效、低毒化疗。本项目研究结果为DSF在肿瘤原位发生“无毒-有毒”转化提供了新思路，为肿瘤原位触发化学反应用于肿瘤治疗提供了一个范例。