新型磁性荧光纳米药物的构建及其肿瘤精准高效光热治疗研究

As a new and safe method, photothermal therapy of tumor based on nanomaterials has attracted much attention. Aimed at solving the key problem of reducing of the curative effect in tumor photothermal therapy which induced by overexpression of heat shock protein HSP70 in tumor cells, this project will develop a new method for cancer therapy through the combination of expression silence of heat shock protein 70 (HSP70) and photothermal therapy. This project will focus on: (1) Designing and establishing a multifunctional nanomedicine with magnetic resonance imaging/photoacoustic imaging/fluorescence imaging (MRI/PAI/FLI) triple-modal imaging and pH-responsive properties based on Janus-structured magnetic fluorescent nanoparticles. (2) Study the drug targeting delivery of cancer using MRI/PAI/FLI technology through folate receptor targeting. Researching the controlled release of fluorescein-labeled siRNA by pH-responsive block copolymer, and monitoring the drug release accurately based on the fluorescence resonance energy transfer (FRET) between the siRNA and rare earth elements; (3) Then, detecting the expression of HSP and achieving the target of imaging-guided synergistic gene silence/photothermal therapy of cancer using a near-infrared laser. The successful implementation of the project is expected to significantly improve the therapeutic effect of cancer, which has important fundamental research significance and potential clinical application prospects.

基于纳米材料的肿瘤光热治疗作为一种新型、安全的治疗方法备受关注。针对光热治疗过程中热休克蛋白HSP70高表达引起肿瘤细胞产生热耐受，从而消减治疗效果的关键问题，本项目拟将HSP70去功能化与光热治疗相结合，开发一种肿瘤精准高效光热治疗新方法。本项目将重点研究：（1）以Janus结构磁性荧光纳米粒子为基础，设计构建具备磁共振/光声/荧光三模态成像功能的pH刺激响应性纳米药物；（2）运用多模态成像技术，研究肿瘤对纳米药物的摄取和转运过程，并根据荧光标记的siRNA与纳米药物载体之间的荧光共振能力转移强度变化对siRNA的释放过程进行实时监控，从而实现该纳米药物对肿瘤的siRNA可视化靶向递送；（3）在此基础上，检测肿瘤中HSP70的去功能化情况，结合磁性材料的光热性能，实现成像引导的肿瘤精准高效光热治疗。本项目的顺利实施，有望进一步提升肿瘤治疗的有效性和安全性，具有重要的基础研究价值。

光热治疗是肿瘤治疗的重要方法之一。针对肿瘤光热治疗过程中单一治疗方式疗效欠佳等关键问题，本项目将免疫疗法、肿瘤细胞铁死亡与激光诱导的光热治疗相结合，通过对纳米药物载体的设计，开发出肿瘤高效治疗新方法。主要研究内容有：（1）以磁性（铁基）纳米粒子为基础，结合表面化学等手段设计构建具备多种治疗功能的纳米药物，并对其性质进行研究；（2）在此基础上，分别从细胞、动物水平验证该纳米药物的肿瘤协同高效治疗效果。通过本项目的实施，成功构建了两种纳米药物：免疫-光热和铁死亡-光热纳米药物，实验证实这两种纳米药物都有着不俗的光热转换效率，在近红外激光诱导下可高效的将光能转换成热能，并具有良好的生物相容性。体内外肿瘤治疗实验证明，设计构建的纳米药物可分别用于肿瘤的免疫-光热协同治疗和铁死亡-光热协同治疗，并取得了优异的治疗效果。该研究，有望进一步提升肿瘤光热治疗的有效性和安全性，为肿瘤高效治疗提供了一种新思路，具有一定的基础研究价值。