基于层状铁氧体结构的磁性荧光粒子构建与细胞转运及光学示踪研究

The magnetic fluorescent particles using ferric oxide as the carrier are the focus of research in the field of targeted drug delivery and biological imaging. However, it is necessary to construct a core-shell structure to achieve targeted delivery, optical tracking and synchronous therapeutic functions, since Fe3O4 cannot directly combine with luminescent material and medicine molecules. The cellular barrier is the major cause of failure of most drugs and delivery systems, promoting cell transport performance requires improving the structure and shape of the carrier. Based on our previous work, the supermolecular assembly and pharmacy research of magnetic layered double hydroxide (MLDH), this project will utilize the layered architecture and nuclear targeted delivery characteristics of MLDH, to immobilize the therapeutic drugs in interlayer and bind quantum dots (QD) and biological targeted groups (TG) to the outer layer, thus the QD@MLDH(Drug)@TG layered magnetic fluorescent drug-loaded particles will be constructed. By using the physical and chemical characterization, optical imaging, pharmacodynamic and pharmacological experimental technologies, the interaction mechanism of the layered magnetic fluorescent drug-loaded particles with cancer cells and the in vivo therapeutic and tracer imaging effect will be studied. The affect of carrier structure on the cell transmission performance of targeted delivery systems will be revealed, and the cancer cell death mechanism caused by this layered delivery system will be elucidated. This project is expected to clarify the nuclear targeted transport and pharmacological mechanism of the MLDH delivery system, and obtain new magnetic fluorescent particles, which may provide a new way to resolve the contradictions in biological imaging, targeted transport and slow release chemotherapy functions, and also provide new theoretical basis for improving the transport performance of the drug delivery and imaging systems.

以氧化铁为载体的磁性荧光粒子是药物递释与成像领域的研究焦点，但氧化铁无法与发光材料及药物直接结合，需构筑核壳模型才能实现靶向转运、光学示踪及同步治疗功能；细胞屏障是众多药物和递药系统失效的主要原因，提升细胞转运性能需要改善载体结构与形状。本课题以磁性层状复合氢氧化物MLDH的超分子组装及制剂学研究为前期基础，拟利用MLDH的层状架构与细胞核靶向转运特性，在MLDH层内插载药物、层外结合量子点QD和生物配体TG，构建层状磁性荧光粒子QD@MLDH(Drug)@TG；通过理化表征、光学成像、药效及药理实验，研究系统的细胞作用机制及体内治疗、成像效果，揭示载体结构对靶向递药系统细胞转运性能的影响及层状递药系统引发癌细胞死亡的机制。预期阐明MLDH系统的细胞核靶向转运及药理作用机制，获得新的磁性荧光粒子，为化解生物成像、靶向递送及缓释化疗矛盾提供新的途径，为提升递药成像系统的转运性能提供理论依据。

项目以磁性层状复合氢氧化物MLDH的超分子组装及制剂学研究为前期基础，利用MLDH的层状架构与细胞核靶向转运特性，在MLDH层内插载药物、层外结合量子点QD，构建磁性层状QD@MLDH(Drug) 荧光粒子；通过理化表征、光学成像、药效及药理实验，研究系统的细胞作用机制及体内治疗、成像效果，揭示载体结构对靶向递药系统细胞转运性能的影响及层状递药系统引发癌细胞死亡的特殊机制。主要研究内容包括 QD@MLDH(Drug) 层状磁性荧光载药粒子的组装表征，QD@MLDH(Drug) 磁性荧光载药粒子的细胞作用及药理机制，QD@MLDH(Drug) 粒子体内治疗与光学成像效果等。.研究成果包括三个方面。（1）成功构建能攻击癌细胞核的QD@MLDH(Drug) 层状磁性荧光粒子，通过对其细胞转运规律、癌细胞死亡机制及体内同步治疗示踪效果的研究，揭示了载体结构对靶向递药系统细胞转运性能的影响及MLDH 递药系统引发癌细胞死亡的特殊表型；（2）以量子点及DMF纳米粒为基础，建立智能型新型给药系统，取得 “引发癌细胞核爆炸的磁性层状纳米装置” 等专利成果7项，其中授权国际专利2项；（3）研究了MLDH(Drug)纳米粒子引发癌细胞胀亡的细胞生物学表型及溶酶体相关的信号通路，在本专业主流杂志发表研究论文4 篇（SCI 论文4 篇）；培养研究生4人。.获得的关键数据及其科学意义，第一、克服现有磁性荧光多功能粒子中传统载体Fe3O4无法直接结合与控制药物释放的技术瓶颈，利用MLDH的细胞转运特性及生物量子点的荧光标记功能，解决DMF@CdHgTe系统制备的工艺问题，实现了对肿瘤细胞的成像与同步治疗。第二、构建一种能引发癌细胞核爆炸的层状磁性荧光纳米装置，借助活细胞成像技术揭示细胞胀亡过程的形态学变化；DMF@QD纳米系统具有诊疗一体化功能，在揭示细胞的胀亡机制和清除肿瘤病灶方面有特殊意义及良好的应用前景。第三、药理学研究结果显示，DMF@QD系统的细胞核靶向转运及药理作用可启动细胞的胀亡通路，引起癌细胞核爆炸和细胞解体。项目研究为诊疗一体化纳米装置的开发及应用提供了新的技术手段，丰富了人们对纳米药物药理作用以及多种细胞死亡形式的认识。