应用中空多孔磁性纳米颗粒靶向聚集及控制释放淫羊藿素以促进小鼠骨折愈合的研究

Delayed fracture healing and nonunion are major problem in the field of orthopedics, thus promoting fracture healing is of great significance. Existing drugs for promoting fracture healing such as BMPs and other growth factors are complex, expensive and low yield which are easily led to heterotopic ossification and other shortcomings, thus greatly limiting their clinical application. Icaritin has the ability to promote osteogenesis and angiogenesis. However, it is in poor targeting, rapid metabolic rate and low bioavailability after oral administration, which limits its clinical application. Porous hollow magnetic nanoparticles are of great advantages as their small particle size, drug loading and other characteristics, which can also be gathered and positioned in the static magnetic field and heating in alternating magnetic field. Importantly, it can also effectively reduce the network non-specific uptake of the endothelium-like system and prolongation of the circulation time in the body. Therefore, it has a good application prospect in many fields such as targeted drug delivery and drug controlled release. Therefore, our team firstly loaded icaritin into the synthesized hollow porous magnetic nanoparticle, which is injected into the mouse through the tail vein. After collected at the fracture site in the static magnetic field, the icaritin loaded porous magnetic nanoparticles are heating under the alternating magnetic field to promote the release of icaritin, thereby promoting fracture healing.

骨折的延迟愈合及骨不连是骨科领域面临的一大难题，因而促进骨折愈合具有重要的意义。现有的促进骨折愈合的药物如BMPs等生长因子提取过程复杂，成本昂贵，产率低下，且具有导致异位骨化等缺点，其临床应用受到了一定的局限。淫羊藿素作为淫羊藿在体内代谢的最小单体，具有较强的促进成骨过程及血管生成的能力。但淫羊藿素口服后在循环内靶向性差，代谢速度快，生物利用度不高，这限制了其临床应用。中空多孔磁性纳米颗粒除了具有粒径小、载药量大等特点，还具有超顺磁性和磁响应性，可以在静磁场下聚集和定位，在交变磁场下升温，同时能够有效的减少网状内皮系统的非特异性摄取和延长机体内的循环时间，因而在靶向给药、药物控释等多领域中有良好的应用前景。因此，我们团队通过将低分子量的淫羊藿素装载入合成的中空多孔磁性纳米颗粒内，经由尾静脉注射入小鼠体内，使之在静磁场下聚集于骨折部位，并在交变磁场下升温以控制淫羊藿素的释放，从而促进骨折愈

本项目主要研究内容是设计并构建多功能纳米材料，作为运送载体或成骨活性因子，为骨科疾病（骨质疏松、骨缺损）的治疗提供技术支持。在此项目的资助下，我们在基于纳米材料在骨质疏松、骨缺损治疗方面取得了一系列的进展，顺利完成了项目的预期目标。1. 我们基于高温热解和可控氧化的方法构建了中空多孔的磁性纳米颗粒，研究表明其可以和干细胞相互作用促进成骨分化，同时又可以作为中药单体淫羊藿素的高效运送载体，发挥协同促进成骨作用，并在促进骨折修复过程中发挥显著作用。2. 我们构建了基于磁性纳米药物的骨靶向纳米材料，外部偶联骨靶向药物阿伦磷酸钠，构建骨靶向磁性纳米药物递送系统。利用阿仑膦酸钠将纳米药物靶向到骨组织，并与之相互作用调控局部微环境达到治疗骨质疏松的目的。3. 我们设计并构建了一些列金纳米材料（金纳米球，金纳米棒，金纳米簇），并探究了不同因素（粒径大小、长径比、表面修饰）对其成骨分化的影响，筛选出最佳参数并探究其促进干细胞成骨分化中的作用。4. 基于上述具有成骨活性的纳米材料，我们构建了用于骨缺损修复的多功能复合材料，这些材料具有良好的生物相容性、机械性能及成骨活性，探索了其作为支架在骨修复中的作用。我们在具有成骨活性的纳米材料及复合骨修复支架方面取得了一些列进展，在Bioactive Materials，Materials & Design，IEEE Transactions on Biomedical Engineering，Colloids and Surfaces B: Biointerfaces 等高水平期刊发表论文9篇。