包载姜黄素的多功能纳米诊疗剂用于假体周围骨溶解多模式早期诊断和光控靶向治疗的实验研究

Periprosthetic osteolysis is the leading complication that limits survivorship of joint arthroplasty. Despite the prevalence of this complication, few early detection and nonoperative treatment for periprosthetic osteolysis are available. Our previous study showed that curcumin may inhibit wear particle-induced inflammation. However, further study is necessary to determine the mechanism of action of curcumin and improve pharmacokinetics. The aim of this work is to investigate (1) the effects of curcumin on the production of inflammatory cytokines, reactive oxygen species, matrix metalloproteinase, and vascular endothelial growth factor in osteoclast precursor cells; (2) whether various signaling pathways were involved in the blockade of osteoclastogenesis during the process of periprosthetic osteolysis via the inhibition of NF-κB and MAPK using RNA interference;(3)the influence of curcumin on the process of apoptosis; (4) identification of curcumin target proteins by quantitative proteomics. The multifunctionalization of capsules may enable the development of multifunctional nanomedical platforms for simultaneous imaging diagnosis and therapy. We design a multifunctional mesoporous silica nanoparticles-based curumin delivery system for early detection (fluorescence, MRI and CT trimodal imaging) and targeted therapy (light-acivated) in a murine model of periprosthetic osteolysis.

假体周围骨溶解是影响人工关节使用寿命主要原因之一，临床上仍缺乏有效的早期诊断和治疗方法。我们前期研究表明姜黄素可以抑制磨损颗粒诱导的炎症反应，仍需进一步研究作用机制并且改善药物特性。本课题建立破骨细胞前体细胞培养模型，观察姜黄素对炎症因子、活性氧簇、金属基质蛋白酶和血管内皮生长因子的影响；采用RNA干扰技术阻断关键的信号通路NF-κB及MAPK，探讨姜黄素是否通过多条信号通路调节破骨细胞分化、成熟及凋亡，避免信号通路的交叉对话和负反馈机制；采取蛋白组学技术鉴定新的药物靶蛋白，进而揭示药物的作用机理；在提高药物包覆能力的基础上，赋予载体多功能的特性，将功能性纳米粒子引入到介孔氧化硅纳米粒子的空腔中，赋予其临床分子影像的功能。在小鼠植骨动物模型基础上，本课题组首次提出一种多功能化介孔空腔二氧化硅包载姜黄素的诊疗剂，多模式早期诊断(CT/MRI/荧光三模式成像)和靶向光控药物治疗假体周围骨溶解。

背景和目的：假体周围骨溶解是影响人工关节使用寿命主要原因之一，临床上仍缺乏有效的早期诊断和治疗方法。本研究表明姜黄素以及纳米姜黄素是否可以抑制磨损颗粒诱导的炎症骨溶解。方法：构建破骨细胞前体细胞培养和体内小鼠颅骨气囊模型，观察姜黄素和纳米姜黄素对炎症因子、活性氧簇、金属基质蛋白酶和血管内皮生长因子的影响；调节巨噬细胞和破骨细胞分化、成熟及凋亡作用；设计出一种PLGA纳米载体包载姜黄素，靶向药物治疗假体周围骨溶解。结果：姜黄素干预后能减轻.E颗粒刺激后气囊炎症介质的表达，减轻肉芽肿性组织的形成和颅骨的骨溶解，并且有剂量依赖性；姜黄素能诱导CD68阳性细胞的凋亡，使CD68阳性细胞的凋亡指数升高；姜黄素能抑制巨噬细胞Ti颗粒刺激引起的炎症反应，减少促炎细胞因子、趋化因子和炎症性酶的分泌，同时增加抗炎细胞因子的表达。制备包载姜黄素的纳米微球延长药物在体内的滞留，通过特定的靶向作用提高局部的药物浓度，从而增加治疗效果，减少毒性反应。结论：纳米姜黄素可能是一个有效的预防和治疗假体无菌性松动的药物。