抗结核靶向释药复合体的破骨细胞内释药机制研究

Bone and joint tuberculosis always causes severely destruction of bone tissues. It is hard to remove residual mycobacterium tuberculosis (Mtb) completely via routine debridement, which results in easy relapse of infection and poor repair of bone tissues. Supported by National Natural Science Foundation (NSF) of 2010 and 2014, we previously investigated the releasing mechanism of anti-tuberculosis drugs as well as osteoinducing mechanism of nanoparticles, and developed an “anti-tuberculosis composite”. Based on the treatment principle of tuberculosis, multi-antibiotics and osteoinducing matrix could be gradually released by this composite, which can successfully improve the antimicrobial effect and osteogensis, and reduce systemic side-effects. However, it has been reported recently that a certain number of virulent Mtb could escape from normal administration of drugs by intracellularization of host osteoclasts via surface adhesion molecules after Mtb infection; the intracellular Mtb will re-enter the lesion and then cause relapse of infection. Based on our previous study of controlled drug delivery law of hexagonal mesoporous silica (HMS) drug-loaded particles, we plan to apply for the support of another NSF general program and carry out further researches to improve the targeting sterilization of this composite. Firstly, we will develop a novel HMS-based drug delivery particle, which could be inducing untaken by osteoclast. Secondly, the Intracellular or extracellular drug releasing mechanism of this novel HMS-based drug delivery particle to osteoclasts, as well as its biosafety to other related cells will be investigated. Finally, the eradication of intracellular Mtb in osteoclasts by this HMS-based drug delivery particle will be extensively observed via in vitro and in vivo studies. To carry out the above studies will contribute to the treatment of bone and joint tuberculosis by creating a safe and effective method.

骨关节结核对骨质破坏严重。外科手术难以彻底清除病灶致病菌：感染易复发，骨修复效果差。前期受两项国家自然科学基金资助，课题组在分别研究抗结核药物缓释机制和纳米颗粒诱导成骨机制的基础上，构建出 "抗结核释药复合体"。该复合体可根据抗结核原则在病灶内联合、梯度释放抗结核药物和促成骨基质，有效提高抗菌和成骨效果、降低全身毒副作用。然而，研究发现：结核菌感染后，少量细菌可通过粘附分子介导进入宿主破骨细胞，并以此躲避药物作用；待药物流逝后，细菌重新进入病灶，导致感染复发。为进一步提高复合体靶向杀菌作用，课题组拟在前期掌握介孔硅（HMS）颗粒药物控释规律的基础上，创新性①构建可诱导破骨细胞内化摄取的HMS载药颗粒；②研究 HMS 载药颗粒在破骨细胞内外的释药机制和对其他相关细胞的生物安全性；③通过细胞和动物实验研究HMS载药颗粒对破骨细胞内致病菌的杀灭作用。上述研究将为治疗骨结核提供安全、有效的新方法。

骨关节结核对骨质破坏严重。外科手术难以彻底清除病灶致病菌：感染易复发，骨修复效果差。课题组在分别研究抗结核药物缓释机制和纳米颗粒诱导成骨机制的基础上，构建出 "抗结核释药复合体"。该复合体可根据抗结核原则在病灶内联合、梯度释放抗结核药物和促成骨基质，有效提高抗菌和成骨效果、降低全身毒副作用。为进一步提高复合体靶向杀菌作用，课题组受国家自然科学基金面上项目资助，在前期掌握介孔硅（HMS）颗粒药物控释规律的基础上，先后构建出可诱导破骨细胞内化摄取的HMS载药颗粒，进而研究了 HMS 载药颗粒在破骨细胞内外的释药机制和对其他相关细胞的生物安全性，最后通过细胞和动物实验研究HMS载药颗粒对破骨细胞内致病菌的杀灭作用。研究期间课题组获得发明专利授权3项，实用新型专利授权1项；发表标注课题号SCI论文8篇，影响因子5以上4篇，培养博士研究生3名。课题相关成果参与获得2020年国家科技进步一等奖。课题组长还获批军队专项课题1项。上述研究为感染性骨缺损的治疗提供安全、有效的新方法。