微波增敏消融联合化疗、PD-1阻断多功能纳米平台的构建及其骨肉瘤治疗机制研究

Osteosarcoma is one of the most common malignant bone tumors with poor prognosis and high mortality. As a new, safe, economical and effective hyperthermia therapy, microwave ablation provides a new idea for the treatment and limb-salvage reconstruction of osteosarcoma. However, there still exist severe postoperative complications and thermal damage to the surrounding tissue, as well as the recurrence risk in the process of microwave ablation. Security boundary identification of the tumor and temperature control of microwave are two key problems to be solved for clinical promotion. Based on the common scientific problems in our preliminary work and the CT enhancement effect of nano-ZrO2, this program attempts to utilize the unique hollow ZrO2 nanospheres as carriers to load anti-cancer drugs and microwave sensitization agent inside the hollow structure, and to cross-link active targeting molecule and immune checkpoint blockers coupling with tumor microenvironment sensitive mesoporous switch outside the surface. Then a composite nanostructure based on hollow ZrO2 nanospheres will be obtained, which owns the abilities of CT imaging, dual-mode active and passive targeting, microwave sensitization, drug controlled release and immunotherapy simultaneously. This will achieve the nano-visual tumor therapy, and provide novel materials and new techniques for targeted and multi-mode therapy-imaging of osteosarcoma.

骨肉瘤是最常见、预后极差且死亡率高的恶性骨肿瘤，微波消融作为一种新兴的安全、经济、有效的热疗手段，可为骨肉瘤治疗及保肢重建提供新的思路。然而，微波消融治疗骨肉瘤仍有较高的术后并发症、周围组织热损伤及复发风险等缺陷，其中肿瘤安全边界识别及温度控制是该技术临床推广亟待解决的两大关键问题。本项目是以骨肉瘤临床实践中发现的共性科学问题为切入点，以具有CT增强效应的纳米二氧化锆为研究载体，利用其独特的中空介孔结构，在空腔内装载化疗药物和微波增敏剂，表面修饰主动靶向分子及与肿瘤微环境敏感开关偶联的免疫检查点阻断剂。最终得到具有肿瘤影像增强功能、主动与被动靶向功能、微波增敏效应、化疗药物缓释控与免疫治疗的多功能二氧化锆纳米诊疗平台，为骨肉瘤的靶向多模式精准治疗-影像一体化提供新材料、新技术和新思路。

骨肉瘤是最常见、预后极差且死亡率高的恶性骨肿瘤，微波消融作为一种新兴的安全、经济、有效的热疗手段，可为骨肉瘤治疗及保肢重建提供新的思路。本项目针对微波消融治疗骨肉瘤中存在的较高术后并发症、周围组织热损伤及复发风险等缺陷，预期解决肿瘤安全边界识别及温度控制两大关键科学问题。以具有CT增强效应的纳米颗粒为研究载体，成功构建了具有良好的肿瘤影像增强功能、靶向功能、微波增敏效应及化疗药物缓释控的多功能二氧化锆纳米诊疗平台，为骨肉瘤的靶向多模式精准治疗提供了新材料和新技术。同时，微波消融骨肉瘤过程中可诱导抗原呈递细胞及细胞毒性T淋巴细胞的激活，即产生肿瘤特异性的免疫学反应，同时通过ERK信号途径干预肿瘤微环境中PD-L1/PD-1信号轴，基于此本项目提出了基于免疫检查点阻断的免疫疗法与微波消融协同降低微波术后骨肉瘤复发和转移的全新治疗策略。