微环境“自我门控”的二氧化锰给药系统用于骨质疏松性骨折治疗

Osteoporosis fracture greatly threats to the health and quality of life to the elderly. There is still some problems including long-term nonunion and secondary fracture in surgery and conservative therapy. It is suggested that some drugs that could promote bone fracture healing and orthopedic implants bone integration can be helpful for the healing of osteoporotic fracture. Especially the emerging drug therapies aim at eliminating senescent cells, which is different from the traditional antiosteoporosis drugs, has drawn great attention both in the foreign and domestic academia. One of them is senolytics composed by dasatinib and quercetin, is reported to improve age-related bone loss. Moreover, the senolytics will reduce senescent-cell burden, lead to the reduction of bone resorption and an increase (cortical bone) or maintenance (trabecular bone) in bone formation. Therefore, the senolytics could avoid the negative effects of reduced bone formation caused by traditional drugs.. This proposal suggests a microenvironment “self-gated” manganese dioxide (MnO2) drug delivery platform for the treatment of osteoporotic fracture. The MnO2 drug delivery platform loaded dasatinib and quercetin could degrade under acidic microenvironment of bone fracture, the locally released drugs easily reach to the fracture zone and eliminate senescent cells. Therefore, the age-related bone loss will be inhibited by reducing the bone resorption, that is benefit for the healing of osteoporosis fracture. In addition, the produced O2 from H2O2 by the catalyst of MnO2 and the manganese ions due to degradation of MnO2 also be helpful for bone formation. Expect the preparation and characterization of manganese dioxide (MnO2) drug delivery platform, this proposal will investigate the responses of osteoblast and osteoclast on it as well. The in vivo osteoporotic fracture healing results will also be evaluated by animal experiment. This study will provide different approaches and new ideas for the treatment of osteoporotic fractures.

骨质疏松性骨折是危害老年人生命健康和生活质量的一大威胁。目前手术和保守疗法仍然存在骨折长期不愈合和二次骨折的问题。为促进骨质疏松性骨折的愈合，需要借助促骨折愈合和骨内植入体骨整合的药物治疗。区别于传统骨质疏松药物，新兴的以衰老细胞为药物治疗靶点的研究逐渐得到关注。报道证实，由达沙替尼和槲皮素抗衰老药等在治疗年龄相关的骨量减少方面具有显著作用，其还可避免传统药物骨合成降低的负面效应。本项目拟通过微环境“自我门控”的二氧化锰局部给药系统实现对达沙替尼和槲皮素在骨折部位的直接给药，二氧化锰在骨折偏酸的微环境下可逐渐降解并释放药物，二氧化锰还可改善骨折乏氧的微环境，其降解产生的錳离子也有助于成骨。该项目将分别研究成骨细胞与破骨细胞在二氧化锰局部给药系统上的体外响应，并通过体内动物实验验证其治疗骨质疏松性骨折的效果。该项目研究成果将有助于为骨质疏松性骨折的治疗提供新方法和新思路。

本项目旨在以骨损伤微环境作为药物“门控开关”构建修复材料，实现骨损伤微环境响应性的药物可控释放、抑制细胞衰老和促进成骨，促进骨质疏松性骨损伤的修复。围绕这一目标，我们检测并发现多种动物模型中骨损伤后局部的过氧化氢升高。构建了基于骨损伤微酸环境响应性释放药物的含二氧化锰的复合水凝胶，并筛选出最优组成；构建了负载槲皮素和骨形态发生蛋白的水凝胶和其它骨修复材料。通过双氧水处理来模拟细胞衰老的实验中发现该材料能清除细胞内和骨损伤处的活性氧，从而保护细胞免受损伤和发生衰老，阐明含二氧化锰的材料具有较好的抗氧化性能。含二氧化锰的材料通过负载促成骨药物、抑制破骨药物、以及自身含有的二氧化锰能降低活性氧水平的作用三个方面发挥调控作用，最终达到促进干细胞成骨分化和抑制骨髓来源的巨噬细胞破骨分化的作用。最后，通过体内实验验证了含二氧化锰的材料能降低骨损伤处的过氧化氢水平，有效负载药物并促进骨损伤以及骨质疏松性骨损伤的修复。以上研究成果可望为骨损伤的修复提供理论基础和实践依据。. 项目执行期间，共发表标注项目批准号论文13篇，申请专利4项。项目负责人在学术会议上作口头报告5次，其中国际会议3次、国内会议2次。团队成员积极参与国内外学术交流，发表墙报2篇。