具有多重靶向及磁感应热疗功能的纳米载药体系研究

The non-uniform temperature field in tumor tissue is still the difficulty for magnetic-induction hyperthermia. In order to solve this problem, a novel magnetic mesoporous silicon carrier is presented here based on our preliminary studies on the preparation and drug loading technique for magnetic mesoporous silicon delivery system. This novel carrier combining function of magnetic-targeted drug delivery with magnetic-induction hyperthermia is consisting with self-target molecular, magnetic mesoporous silicon skeleton and peptide drug of Interleukin-2. Firstly, the carrier concentrates at target tissue, recognizes tumor cells and then releases Interleukin-2 under permanent magnetic field. Secondly, the heat is produced by the carrier’s magnetic cores and mesoporous shells through two different mechanisms under specific frequency alternating magnetic field. Such carrier that exhibits two different mechanisms of heat production can solve the problem of non-uniform temperature field in tumor tissue. Our research emphasis is about the synthesis of the carrier, the efficiency of heat production, the mechanisms of load and release of drug and the synthetical effect of hyperthermia combined with chemotherapy, as well as the correlation about heat production between the composition and the efficiency recognition of the carrier. Not only a novel method for the research of magnetic-induction hyperthermia carrier but also a positive exploration for synchronized therapy of hyperthermia, chemotherapy and targeted diagnosis.

针对磁感应热疗中存在的肿瘤组织温度场分布不均匀的难题,依据国内外相关研究最新进展和申请人在磁性介孔硅载体制备及载药技术方面的深入研究，我们提出磁靶向药物传递和磁感应热疗联合的研究思路，构建具有主动靶向、较大孔径的磁性介孔硅载体并载入大分子蛋白药物白介素-2。首先永磁场作用下该磁性载体在靶组织有效聚集并主动靶向到肿瘤细胞释放白介素-2；然后特定频率交变电场作用下靶向到细胞水平的磁性介孔载体其磁性核和介孔壳通过两种不同的机制联合产热。这种双组份双重加热模式对肿瘤细胞均匀有效加热，真正解决肿瘤组织温度场分布不均匀的难题。本研究重点围绕载体的组装、交变磁场产热效果评价、载药及释药行为和机理、热疗及化疗联合抑瘤效果评价等展开系统研究,探讨载体的组成、靶向识别效果和交变磁场产热效果的相关性。项目将为磁感应热疗载体研究提供新思路、新方法，同时将为肿瘤靶向诊断、热疗和化疗同步联合提供积极探索。

针对磁感应热疗中存在的肿瘤组织温度场分布不均匀的难题,构建了具有多重靶向及磁感应热疗/化疗的载药体系。首先永磁场作用下该磁性载体磁靶向有效聚集并主动靶向到肿瘤，然后交变电场作用下靶向到细胞水平的磁性介孔载体进一步在细胞核靶向释药。所构建载体MMSN-SS-FA多核单分散、尺寸均一，粒径100nm，孔径3.2nm。在交变磁场作用下（磁场频率200kHz、电流强度60.6A）溶液条件10mg/ml，15min内温度升温15℃。载体对HeLa细胞具有主动靶向性，pH5.0条件下，DOX的释放速率明显加快，累计释放量提高到70%。MMSN-SS-FA联合磁热性能、多重靶向性能，在交变磁场作用下（磁场频率200kHz、电流强度60.6A、20min）对HeLa细胞表现出热疗/化疗的协同增强性。对荷瘤鼠动物模型也表现出热疗/化疗抑瘤的协同增强性。对比不同温度下HeLa细胞摄取载体量的分析，揭示细胞靶向热疗的机理是受体介导的能量依赖所致载体摄入量的增加，这也是热疗/化疗双效协同增强抑瘤效果的机理所在。MMSN-SS-FA联合磁靶向性、叶酸靶向性的优势，实现了载体在肿瘤组织的精确分布，有效解决了肿瘤磁感应热疗研究中介质因素所导致的温度场分布不均的问题。MMSN-SS-FA联合磁靶向热疗、细胞核靶向释药的优势，实现了热疗/化疗的联合效用，具有双效协同增强抑瘤的效果，对肿瘤的治疗研究具有较大的科学意义。