多功能夹芯型纳米复合物探针构建及其应用于原位监测药物可控释放和肿瘤光热化疗研究

There are some problems with current cancer therapies, such as low efficacy, poor targeting, drug premature release and degradation, and lack of low cost methods enabling noninvasive monitor drug release. The project focuses on the development of a new class of Au/phospholipid bilayer/Au sandwich-type nanostructure which consists of a gold core, a thin gold nanoshell, and a phospholipid bilayer as the middle layer. The phospholipid bilayers with high biocompatibility and biodegradability are used to deliver anti-cancer drug. While, the gold nanoshells are used as photoabsorbing agents which have tunable localized surface plasmon resonance (LSPR) peaks in the near-infrared region. Via utilization of near-infrared extinction properties and photo-thermal conversion capability of gold nanoshells, and drug loading capacity and sustained release characteristics of lipid bilayers, a new multifunctional probe for noninvasive monitoring of drug release and cancer targeted chemo-photothermal therapy will be developed. Moreover, an efficient, safe and intelligent method based on the developed sandwich-type nanostructure will be explored for near-infrared mediated chemo-photothermal therapy, which offers new insights into rational administration of drug and personalized medicine. Furthermore, on the basis of the large enhancement of electromagnetic field at the nanogap of the nanostructures, the development of novel SERS-based method for in-situ monitoring of near-infrared light-activatable drug release will also be explored, as compared with the conventional FRET methods，which is universal and expected to create a new technology platform for drug delivery and release studies.

针对目前肿瘤治疗存在的疗效低、靶向性差、药物过早释放与降解以及缺乏无毒、无创、低成本的药物释放监测手段等问题，本项目拟构建一种多功能夹芯型纳米复合物作为药物载体-内核为金纳米球，外层为LSPR可调的金纳米壳，中间层为具有良好生物相容性和可生物降解性的磷脂双分子层膜，被用来负载抗癌药物。在此基础上，综合利用金纳米壳的近红外消光特性、光热转化特性以及磷脂双分子层膜的载药功能和缓释作用，开发集热疗、化疗、靶向、缓释、监测于一体的新型多功能纳米探针，发展一种高效、安全和智能的近红外激发肿瘤热疗化疗联合治疗新手段，为未来的按需给药和个性化药物发展提供新的思路。利用金纳米壳与金纳米球夹缝局域电磁场极大增强的物理原理，结合药物分子自身的拉曼活性，提出一种基于SERS技术的原位监测近红外激发药物可控释放的新方法，方法对于药物分子具有普适性，可望形成药物传递与释放研究的新技术平台。

本项目合成了多种具有良好光、电性能的贵金属纳米团簇材料，探索了不同纳米团簇材料的表面生物分子（核酸、抗体等）固定化新技术，设计制备了多种灵敏特异的新型多功能纳米探针，系统研究了纳米探针的光电性能以及不同条件对性能的影响，构建了多种基于纳米团簇/等温酶信号放大的生物传感新原理，为新型生物传感技术研究提供新的思路和理论技术依据，发展了多种操作简单、高效且具有高灵敏度和高选择性的生物传感新技术并用于恶性肿瘤以及其它疾病相关的生物标志物检测，可望为癌症早期诊断建立新的技术平台。该项目自立项以来已取得一系列研究进展，发表了以国际著名刊物Biosensors & Bioelectronics, Analytica Chimica Acta为代表的通讯作者SCI论文8篇，授权国家发明专利7项，初步完成了项目预期的各项工作目标。