基于可控降解的磁性介孔纳米颗粒设计制备药物控释系统协同磁热疗研究

Recently, mesoporous composite nanoparticles as multifunctional platforms have been gained more and more attention due to their valuable applications in smart cancer diagnosis and therapy. Currently, many efforts have been made to design mesoporous composite nanoparticles for cancer therapy. It has been accepted that the synergetic therapies with controlled anticancer drug delivery and magnetic hyperthermia can enhance the therapuetic efficiency. However, it is still challenging to design and prepare magnetic mesoporous nanoparticles with controllable degradation as a multifunctional platform for controlled anticancer drug delivery and magnetic hyperthermia. .In this research proposal, magnetic mesoporous nanoparticles with core-shell structure and good magnetic heating capacity will be prepared using bis(triethoxysilyl-propyl)disulfide and tetraethoxysilane as silica sources and Fe3O4 nanoparticles as magnetic cores. The walls of magnetic mesoporous nanoparticles contain disulfide bonds, and the deoxidizer, such as glutathione, can induce the redox-driven disulfide cleavage, which result in the degradation of the disulfide-containing magnetic mesoporous nanoparticles. Magnetic mesoporous nanoparticles with core-shell structure could realize the high drug loading capacity without blocking effcet for drug transportation in mesoporous channels on the shells, magnetic targeted drug delivery, and hyperthermia effect under an alternating magnetic field. On the other hand, the use of a nucleic acid duplex as a heat labile and reversible system adds the additional feature of temperature tunability through changes in chain length and variations in G/C content. Herein, we design nucleic acid duplex as a temperature sensitive gatekeeping to cap the mesoporous channels of magnetic mesoporous nanoparticles for the construction of anticancer drug delivery system, which could be as a multifunctional platform for cancer therapy via the magnetothermal induced anticancer drug release and hyperthermia in cancer cells or organs under an alternating magnetic field. .We believe that this novel and original research proposal is highly scientific and feasible, and the research results would promote the development of mesoporous composite nanoparticles as multifunctional platforms for cancer therapy.

目前，介孔复合纳米颗粒在多功能的癌症诊断、治疗等方面的研究具有重要的应用前景。但是，基于可控降解的磁性介孔纳米颗粒为载体的抗癌药物控制释放系统协同磁热疗的研究还是一个新课题。本项目拟可控制备介孔骨架含有氧化还原特性的二硫键且具有好的磁热效应的磁性介孔纳米颗粒，以谷胱甘肽等还原剂控制降解。在此基础上，巧妙结合磁性介孔纳米颗粒的高药物储藏能力，磁控靶向输送功能，在交变磁场中的磁热效应以及核酸分子双螺旋结构的特定解链温度特性，精心设计核酸分子作为介孔孔道“开关”的磁性介孔纳米颗粒抗癌药物控释系统，以获得具有可控降解性能的抗癌药物输送系统在癌细胞或组织中的磁热诱导控制药物释放协同磁热疗功能，以期用于癌症治疗。本项目崭新的研究思路是介孔复合纳米颗粒应用于多功能的癌症治疗研究方面的新发展，具有创新性，对探索介孔复合纳米颗粒在癌症等疾病治疗方面具有重要的应用价值。

目前，在癌症治疗研究中，如何设计纳米颗粒载体成为提高癌症治疗效果的关键问题。本项目从磁性纳米颗粒和介孔纳米颗粒出发，设计新的方法以制备在生理环境中可控降解的纳米颗粒，实现抗癌药物控制释放协同磁热作用以提高癌症治疗效率，为基于介孔纳米颗粒载体的药物输送系统临床应用打下坚实基础。本项目完成研究计划并取得多项重要研究成果。.采用“选择性刻蚀”方法制备了粒径约50nm的含有二硫键的有机硅介孔纳米颗粒HMONs。细胞水平的降解实验结果显示，HMONs被4T1细胞吞噬7天后，只有非常少量的结构破坏纳米颗粒，表明HMONs具有生物降解性能。这是第一次直接证据证明介孔有机硅在细胞水平的降解能力。巧妙设计和制备了原卟啉锰(MnPpIX)功能化的HMONs纳米颗粒(HMONs-MnPpIX-PEG)用于MR成像引导下的肿瘤声动力学治疗。研究结果表明，HMONs-MnPpIX-PEG具有良好的生物安全性、生物相容性、生物降解性和良好的MRI成像效果，动物实验显示该方法对肿瘤的抑制率可达到75.4%。.采用以Fe3O4纳米颗粒为内核制备了颗粒粒径为100-200nm的Fe3O4/mSiO2磁性介孔纳米颗粒（MMSN）；以MMSN为载体设计制备了核酸分子（5’-COOH-(CH2)6-ACTCCTGGTATGTAGCGCTA）、氧化石墨烯量子点（GQDs）等为控释“开关”的温度响应型药物控释系统，可实现磁热诱导药物控释协同磁热疗的多模式癌症治疗，在癌症多功能协同治疗研究方面具有重要价值。.设计制备了GQDs修饰的介孔氧化硅纳米颗粒（MSN/GQDs），实现了pH响应药物控释联合光热治疗功能；提出一步法制备负载DOX的GQDs功能化金属有机框架纳米颗粒（DOX-ZIF-8/GQDs），DOX-ZIF-8/GQDs具有良好的光热效应、pH响应降解和药物释放性能，可同时实现药物化疗、光热疗和降解性于一体的多模式治疗作用，为癌症多功能协同治疗研究提供参考。.另外，本项目还拓展研究制备了树枝状介孔纳米颗粒用于pH响应的大分子药物输送系统，负载ICG和DOX的介孔纳米颗粒（DOX/MSN@ICG）结合聚乙烯吡络烷酮PVP制备透皮给药微针系统（PVP@DOX/MSN@ICG）用于表面实体瘤的化疗和光热联合治疗应用。.项目已发表学术论文15篇，其中SCI论文13篇，授权发明专利2项，申请发明专利4项。