基于可激活报告基因系统的白蛋白雷帕霉素纳米探针靶向治疗头颈癌的光学成像研究

Rapamycin (Rapa) is a novel carboxylic lactone-lactam macrolide and has been used as a potential antidrug in tumor therapy through inhibiting the activity of mTOR kinase. However, the application of rapamycin in tumor therapy is seriously impeded by rapamycin’s poor solubility in water, as well as by its low bioavailability and dose-limiting toxicity. Therefore, it is significant to improve the solubility in water and monitor the delivery and therapeutic effect in vivo. Herein, we plan to employ human serum albumin (HSA) nanoparticle as drug carrier to encapsulate rapamycin, and chemical crosslink the Cy5.5 fluorescence dye and EGF with the surface of nanoparticle, finally get the HSA-rapa targeted nanoparticle for human heck and neck cancer therapy. We employ fluorescence imaging to monitor the delivery of nanoparticle in vivo. To verify the result of fluorescence imaging, we then adopt split luciferase complementary technology to construct rapamycin induced activatable luciferase reporter gene system. So we can employ bioluminescence imaging to monitor the targeted delivery and therapeutic effect of nanoparticle in vivo. These two imaging information is then tested one another. Ultimately, this project can provide new visualized techniques and therapeutic tools for the application of rapamycin in tumor therapy.

雷帕霉素是一种新型的大环内酯类抗生素，通过抑制mTOR激酶的活性作为一种潜在的抗肿瘤药物用于多种肿瘤的治疗。然而，由于雷帕霉素水溶性差、生物药效率低及剂量限制的细胞毒性，从而大大限制了其在肿瘤治疗中的应用。因此，改善雷帕霉素的水溶性及体内输送问题，并监测其代谢途径和进行疗效评价，对于应用雷帕霉素于肿瘤治疗具有重要意义。本项目拟以人头颈癌为研究对象，采用人血清白蛋白纳米粒来装载雷帕霉素，并在纳米粒表面修饰Cy5.5荧光染料和表皮生长因子EGF，从而构建集靶向、示踪和治疗为一体的白蛋白-雷帕霉素纳米探针，并以荧光成像监测白蛋白纳米探针的在体靶向输送。为了进一步验证荧光成像信息，本项目还将采用分割荧光素酶互补技术，建立雷帕霉素介导的可激活荧光素酶报告基因系统，从而以生物发光成像监测雷帕霉素的靶向输送和在体疗效，两种成像信息相互验证，最终为雷帕霉素的精确靶向在体治疗提供新的监测手段和治疗工具。

雷帕霉素是一种新型的大环内酯类抗生素，通过抑制mTOR激酶的活性作为一种潜在的抗肿瘤药物用于多种肿瘤的治疗。然而，由于雷帕霉素水溶性差、生物药效率低及剂量限制的细胞毒性，从而大大限制了其在肿瘤治疗中的应用。因此，改善雷帕霉素的水溶性及体内输送问题，并监测其代谢途径和进行疗效评价，对于应用雷帕霉素于肿瘤治疗具有重要意义。本项目以人头颈癌为研究对象，采用人血清白蛋白纳米粒来装载雷帕霉素，并在纳米粒表面修饰Cy5.5荧光染料，从而构建了集示踪和治疗为一体的雷帕霉素-白蛋白纳米探针，并以荧光成像监测白蛋白纳米探针的在体靶向输送。为了进一步验证荧光成像信息，本项目还将采用了分割荧光素酶互补技术，建立了雷帕霉素介导的可激活荧光素酶报告基因系统，从而以生物发光成像监测雷帕霉素的靶向输送和在体疗效，两种成像信息相互验证，最终为雷帕霉素的靶向在体治疗提供新的监测手段和治疗工具。在该项目资助下，项目负责人以通讯作者或第一作者发表了15篇SCI论文，其中10分以上论文1篇，5分以上论文10篇，申请专利6项，授权1项，以第一完成人获得陕西省高等学校科学技术一等奖和陕西省科学技术三等奖各1项。