金纳米锥药物载体靶向治疗乳腺癌的实时调控可视化研究

Precise therapy is recognized as the effective methods to improve treatment effect of breast cancer. The precise delivery and controllable release of drug are the potential methods to realize precise treatment. Based on function of targeting breast cancer of near infrared fluorescent dye IR-780 and the quenching properties of gold nanomaterials, our project will construct a unique drug carrier for chemotherapy with precise drug delivery and controllable release properties using gold nanobipyramids (GNBs), which the surface will be proportionally linked IR-780 and paclitaxel (PTX) by complementary DNA chains. When the carriers accumulates around the tumor, GNBs can be irradiated up to DNA melting temperature (Tm = 42 ℃), through real-time control of the near infrared laser intensity and time, then PTX and IR-780 with recovery fluorescent signal will proportionally release. By means of calculating the relationship between recovery signal and drug release dosage, we can realize the real-time visualization and quantitative tracing of drug release. And combining the signal intensity, drug release dosage with tumor treatment efficacy, the local drug concentration can be dynamically controlled by timely regulation to the laser intensity and time, in order to optimize chemotherapy and reduce drug toxicity. We hope such GNBs drug carrier could realize the precise drug delivery and controllable release that will offer a novel method for precise treatment for breast cancer.

精准治疗是提高乳腺癌疗效的有效方法。药物精准递送及可控释放是实现精准治疗的潜在手段。基于近红外荧光染料IR-780具有靶向乳腺癌的功能，及金纳米材料可猝灭近红外荧光染料信号的特性，本项目拟在金纳米锥表面通过DNA互补链成比例连接紫杉醇和IR-780，构建可用于化疗药物精准递送及可控释放的药物载体。当载体在乳腺癌局部富集后，通过实时调控近红外激光照射强度及时间，激发金纳米锥升温至DNA解链温度（Tm=42℃），在不灼伤组织的前提下成比例释放紫杉醇和IR-780，使猝灭的IR-780荧光信号成比例复燃。通过复燃信号强度与药物释放剂量的关系，对药物释放进行实时可视化定量示踪；并根据肿瘤信号强度、药物释放剂量及肿瘤治疗疗效综合比较，及时调控光照强度和时间，对局部药物浓度进行动态控制，优化疗效，降低药物毒性。预期该金纳米锥药物载体可实现化疗药物的精准递送及可控释放，为乳腺癌精准治疗提供新思路。

精准治疗是提高乳腺癌疗效的有效方法。药物精准递送及可控释放是实现精准治疗的潜在手段。本项目制备并表征了一系列近红外光响应特性的纳米载体，包括金纳米双锥、金纳米星、金三角片及可降解仿生材料黑色素纳米颗粒。为实现药物的精准递送，本项目在纳米药物载体表面交联具有主动靶向作用的透明质酸、靶向肿瘤微环境的穿膜肽或靶向肿瘤线粒体的IR-780，并定量了载体与药物的质量关系，进一步提高了药物在肿瘤的富集率，减少了药物的非特异释放，降低了药物的整体毒性；为实验药物的可控释放，本项目尝试将Tm=42℃的双链DNA作为连接金纳米载体和近红外荧光染料的桥梁，并进一步利用纳米载体或染料的特性，利用磁共振、CT、光学、光声成像等影像学技术手段实时、动态可视化示踪药物的体内分布及靶向能力，并根据信号强度评价药物释放剂量，及时指导或调整治疗方案；为实现精准治疗，在药物靶向递送和可视化监测基础上，本项目联合光热、光动力或化疗等治疗方式对肿瘤局部进行特异性治疗，显著提高了乳腺癌治疗疗效，并自主搭建了光学平台，首次提出辅助光热治疗对于防止保乳术后肿瘤复发的价值。本项目按照研究计划和研究内容顺利完成，为实现药物的精准递送、可控释放及乳腺癌精准治疗提供了新的思路。依托此项目发表SCI文章13篇，IF>10 的3篇，IF>5的6篇，授权国家发明专利 1项。项目负责人以第一作者发表SCI 论文3篇，其中IF>5的2篇。