细菌响应抗生素释放系统的建立及对骨感染病灶的靶向治疗作用研究

In the treatment of orthopedic infections such as posttraumatic infection, postoperative infection, and chronic osteomyelitis, problems exist, including the difficulty of systemic treatments to achieve local effective concentrations and bacterial endocytosis into osteoblasts to escape antibiotics. Our research group has developed zoledronic acid-modified mesoporous silica nanoparticles (MSNs) and confirmed that the material could enter the osteoblasts and target bone infection lesions in vivo. However, without the channel blocking the concentration produced at local sites and in cell is still too low for eliminating the bacteria．Accordingly, the project aims to develop a stimulus-responsive antibiotic release system specifically for bacteria and use the zoledronic acid, which has good binding ability with bone infection, to graft-modify MSNs. The bacteria-responsive drug release will be obtained by using liposomes (which can be damaged by bacteria-secreted fatty acids) to block the MSN pores. After the completion of the development and characterization of the material, in vitro bacteriological and cytological tests will be used to evaluate its bacteria-killing ability for the endocytosed bacteria in the osteoblasts and its impact on osteoblast differentiation. By using animal models of chronic osteomyelitis and intramedullary nail infection, we will evaluate the in vivo distribution, targeting efficiency, controlled release of antibiotics, and the clearance of infection. The results are expected to provide a new route of drug administration for the treatment of orthopedic infections, to reduce the incidence of recurrence of infections, and to greatly improve the therapeutic effect on orthopedic infectious diseases.

骨相关感染由于其极易复发且致残致畸率高，被认为是骨科最难治疾病之一。传统治疗无靶向性且难以杀灭胞内菌是导致骨感染复发的关键。为此，课题组已研制唑来膦酸修饰的介孔二氧化硅纳米颗粒 (MSN)，并证实该材料可在体内靶向骨感染病灶，并可进入成骨细胞内，但仍存在药物提前泄漏和无响应性释放等问题，常导致病灶和胞内药物浓度过低。针对上述问题，本项目研发细菌响应释放体系，利用脂质体(可被细菌分泌产物特异性破坏)对MSN孔道进行封堵同时实现药物不提前泄漏和细菌响应性释放。本项目拟通过细菌学和细胞学实验，评价其对成骨细胞内吞细菌的杀灭作用及其细胞生物相容性；通过慢性骨髓炎和髓内钉感染的动物模型，评价其在体内的分布情况、靶向效率、抗生素控释效应及对感染病灶的清除作用。预期结果将为骨相关感染的治疗提供新的方法和理论基础。

骨相关感染由于其极易复发且致残致畸率高，被认为是骨科最难治疾病之一。传统治疗无靶向性且难以杀灭胞内菌是导致骨感染复发的关键。为此，课题组已研制唑来膦酸修饰的介孔二氧化硅纳米颗粒 (MSN)，并证实该材料可在体内靶向骨感染病灶，并可进入成骨细胞内，但仍存在药物提前泄漏和无响应性释放等问题，常导致病灶和胞内药物浓度过低。针对上述问题，本项目研发细菌响应释放体系，利用脂质体(可被细菌分泌产物特异性破坏)对MSN孔道进行封堵同时实现药物不提前泄漏和细菌响应性释放。本项目拟通过细菌学和细胞学实验，评价其对成骨细胞内吞细菌的杀灭作用及其细胞生物相容性；通过慢性骨髓炎和髓内钉感染的动物模型，评价其在体内的分布情况、靶向效率、抗生素控释效应及对感染病灶的清除作用。预期结果将为骨相关感染的治疗提供新的方法和理论基础。

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