包覆雄黄的高性能磁性纳米晶在肿瘤主动靶向热疗协同化疗中的应用

Magnetic ferrite nanostructure with high performance is of great scientific interest for researchers from a wide range of biomedicine applications, including clinical magnetic resonance imaging (MRI), cancer magnetic hyperthermia, triggered drug release, and catalysis. In these fields, magnetic nanoparticles (MNPs) as an efficient magnetic-induced heating agent have especially received enormous attention in clinical applications. However, it has rather challenging in MNPs-mediated active targeted magnetic hyperthermia (TMH) therapy by intravenously administration in vivo and their further enhanced therapy efficacy. The high performance and increased tumor-targeting accumulation of MNPs are the most important considerations in cancer TMH. To achieve these goals, we proposed a simple and safe magnetic lipid nanostructure with drug-loading in our project. In succession, to ensure a higher and long-lasting accumulation of MNPs within tumor tissue or tumor cells, some specific active targeted ligands and realgar will firmly attached to the surface of MNPs. In this regard, we hope to develop a sufficient intracellular hyperthermia based on our MNPs-mediated active targeting, promoting the magnetic-induced drug delivery, and finally suppressing the tumor growth. It will promote to the cancer magnetic-induced hyperthermia combining realgar-based chemotherapy, developing a cancer synergistic therapy, which should be received considerable attention in future clinical cancer therapy application.

高性能磁性纳米结构作为一类介入给药磁感应热疗制剂，已经在临床上获得应用。但是，如何实现经静脉给药，并经主动靶向发挥磁感应热疗是进一步提升肿瘤热疗效果的重大挑战。而磁性纳米材料的高磁热性能以及能够增加其在靶组织、靶细胞的累积量和富集时间是影响肿瘤主动靶向热疗的关键因素。为此，本项目通过优化反应条件，发展了一种简单、有效的的包覆载药脂质体的高性能磁性纳米核壳结构。通过在其偶联纳米雄黄和主动靶向分子，提高其在肿瘤组织或细胞的聚集，并期望由磁性材料介导的肿瘤组织热疗向肿瘤细胞内热疗发展，并在热疗的同时能够联合化疗，最终发展肿瘤的综合协同疗法，这将比单一的热疗或化疗更具有临床应用的前景。

高性能磁性纳米结构作为一类介入给药磁感应热疗制剂，已经在临床上获得应用。但是，如何实现经静脉给药，经主动运输发挥磁感应靶向热疗是进一步提升肿瘤热疗效果的重大挑战。为此，本项目研制出几类高性能纳米探针，包括荧光纳米雄黄量子点及团簇、协同磁感应热疗和化疗用(结合抗肿瘤药物紫杉醇、中药纳米雄黄、金簇或银簇等)的功能型的磁性纳米复合探针等，进一步在其表面偶联靶向配体或载体及生物分子（如修饰靶向配体叶酸（FA）、透明质酸（HA）、多肽（RGD）及红细胞膜等），并完成对这几类探针的理化性质以及体外释药性能的研究。在体外细胞层面上，该项目对功能磁性纳米探针的肿瘤细胞特异性靶向识别及体外细胞毒性及机制进行评价。在体内研究中，本项目结合适用于活体应用的交变磁场和成像系统，利用构建的小动物乳腺肿瘤（4T1）模型，在体内磁共振MRI（磁核）/荧光成像（如荧光金/银簇、纳米雄黄或其他荧光探针分子）引导下，通过静脉给药，对功能磁性纳米探针在肿瘤组织内进行特异性靶向，并对其主动靶向累积以及材料的代谢途径进行评价。在安全的给药剂量下，磁性纳米探针可显著提高材料在肿瘤组织内(特别是在肿瘤新生血管以及肿瘤细胞内)的富集量和富集时间，这为后续协同肿瘤治疗研究提供了前期基础。通过设计合理的试验方案(如治疗周期、有效剂量、给药次数、热疗频率等)，实现了在负载紫杉醇、中药纳米雄黄的磁性纳米核壳结构介导的细胞内靶向热疗以及协同化疗。协同治疗结果显示，肿瘤增长有明显的抑制作用，瘤体减小甚至消失这种肿瘤的综合协同疗法，将比单一的热疗或化疗更具有广阔的临床应用前景。