钛表面微环境自响应载药薄膜构建及其选择性生物学效应研究

Osteocarcinoma is a severe disease which threats to human life and health. Prosthesis replacement is the standard therapy to preserve the limb function of patients. Titanium is the most widely used commercial implant material at present, but it lacks anti-cancer and osteogenic effects and may induce surgery failure due to residual cancer cell invasion or poor bone integration. Therefore, developing prosthesis materials with both anti-cancer and osteogenesis abilities is of great importance to improve the life quality of the patients and extend their life spans. Considering the unique layered structures, excellent biocompatibilities and relatively high microenvironment sensitivities of Mg-Fe layered double hydroxides (Mg-Fe LDHs), in this project, a “microenvironment-response” drug-loading Mg-Fe LDHs film will be prepared on the surface of titanium. The film is designed to response to the change of in vivo environment and selectively kill cancer cells. Besides, the iron and magnesium ions released from Mg-Fe LDHs and their specific nano-structures can endow osteogenesis capacities to titanium, so the damaged bone can be repaired consequently. The selective cellular responsive of osteoblast and osteosarcoma to the drug-loading Mg-Fe LDHs films will be systemically investigated from the point of view of molecular biology. Their application potential in bone cancer therapy will be evaluated by in vivo experiments, which will provide referable insights into the design of prosthesis materials with both anti-cancer and osteogenesis promotion effects in the coming future.

骨肿瘤是威胁人类生命健康的重大疾病，人工假体置换是保留患者肢体功能的标准疗法。钛是目前市场上最主要的植入假体材料，但其缺乏抗癌、成骨作用，植入人体后由于残留肿瘤侵袭或骨整合差极易造成手术失败。因此，发展兼具抗癌和成骨功能的假体材料对提高患者生命质量延长其寿命有重要意义。本项目基于镁铁层状双氢氧化物（Mg-Fe LDHs）独特的层状结构、优良的生物相容性以及环境敏感性，提出在钛表面构建具有“微环境自响应能力”的载药Mg-Fe LDHs薄膜，使其能够响应体内微环境变化，选择性杀伤肿瘤细胞；同时利用Mg-Fe LDHs中所含镁、铁离子的释放及其独特的纳米形貌促进新骨形成，实现骨修复。从分子生物学层面系统研究载药Mg-Fe LDHs薄膜选择性调控成骨细胞和骨肉瘤细胞行为机制，并进一步通过体内实验评价其在骨癌治疗领域的应用潜力，为兼具抗癌和成骨功能的植入材料设计提供借鉴性研究思路和方法。

骨肿瘤是威胁人类生命健康的重大疾病，人工假体置换是保留患者肢体功能的标准疗法。钛是目前市场上最主要的植入假体材料，但其缺乏抗癌、成骨作用，植入人体后由于残留肿瘤侵袭或骨整合差极易造成手术失败。因此，发展兼具抗癌和成骨功能的假体材料对提高患者生命质量延长其寿命有重要意义。本项目基于层状双氢氧化物（LDHs）独特的层状结构、优良的生物相容性以及环境敏感性，提出在钛表面构建具有“微环境自响应能力”的载药LDHs薄膜。系统研究了钛基材料表面LDHs薄膜的可控构建工艺及LDHs薄膜药物装载和控释能力，同时研究了 LDHs 和药物对癌细胞和正常细胞影响的单独作用及协同作用规律和作用机制。研究结果显示，LDHs薄膜中所含功能离子的释放及其独特的纳米形貌促进新骨形成（相较于未改性样品，改性组ALP分泌量提升1.8倍），实现骨修复，但其响应体内环境变化，选择性杀伤肿瘤细胞能力较弱。通过热还原处理后，LDHs薄膜显示出较佳的光热效应，能够在近红外光刺激下发挥热化疗作用，实现对肿瘤的有效杀伤，动物实验结果显示其对肿瘤生长的抑制率超过75%。项目研究成果为同时赋予钛基材料“抗肿瘤”和“成骨”两个相互“矛盾”性能需求提供了新思路，为兼具抗癌和成骨功能的植入材料设计提供借鉴性研究思路和方法，对带动国内外新一代骨组织生物材料的研究及其产业化，提升我国在国际生物医学材料领域的研究地位和自主科技创新能力具有促进作用。