高性能磁性纳米药物的构建及其肿瘤诊疗一体化应用研究

Cancer diagnosis and therapy are one of the most important reseach topics in life science. The concept of theranostics opens new avenues in conquering cancers for human being. Starting with the design and synthesis of iron-oxide-based high-performance magntic resonance imaging (MRI) contrast agents, we propose in this project to construct the intelligent nanomedicines with controllable slow release, targeted ability, and high-sensitive MR imaging properties. Using these iron oxide nanostructures as drug carriers, we will design several types of intelligent nanomedicine systems, for example, porous silica-layer to encapulate novel anticancer drug Ni-As complex and MRI contrast agents, and nanoconjugates with doxirubicin or cisplatin prodrug through pH-labile linkers. We will modify the nanostructures with targeting motifs (e.g., RGD and Affibody) to form specific targeting nanomedicines. These unique nanomedicnices may significantly improve sensitivity of diagnosis and anticancer activity, which may provide a new way in combination of cancer therapy, diagnosis, on-time imaging, and prognose analysis. The aim of this proposal is to investigate the multifunctional smart nanomedicines and the relationships of their molecular-assembly, structure-activity, and in vivo behaviors with cancer diagnosis and therapy, which may provide theoretical basis and scientific proofs for design and exploitation of theranostic nanomedicines.

如何早期诊断并有效治疗癌症是当今科学研究的重大难题之一，诊疗一体化的理念为人类攻克癌症提供了新的思路。在青年科学基金项目资助下，我们开展了以氧化铁纳米颗粒为载体的靶向智能纳米药物的设计，也成功合成了钆掺杂氧化铁纳米材料等高性能磁共振造影剂。本项目拟以高性能磁性纳米材料为基础，构建多种具有靶向、缓慢释药和诊疗一体化的多功能智能纳米药物体系：包括多孔二氧化硅装载砷剂前体镍砷复合物和通过pH值敏感化学键连接阿霉素或顺铂药物前体；拟对纳米药物载体进行靶向功能化修饰，连接RGD、亲合体等靶向分子改善其体内行为性质；通过细胞和活体实验验证这类多功能智能纳米药物的诊疗效果。本项目旨在通过对一类新颖高性能磁性纳米药物的深入研究，探索其结构特性、分子组装和体内行为对肿瘤诊断和治疗的影响，有望同时实现肿瘤诊断，疗效分析、实时成像及预后评价，为研究与开发新型的诊疗一体化纳米药物提供理论基础和科学依据。

本项目主要研究内容是设计合成新型磁性纳米材料作为高性能磁共振造影剂，并以高性能磁性纳米材料为载体构建一类新颖的诊疗一体纳米药物。在此项目的资助下，我们在磁共振造影剂及智能纳米药物诊疗一体等方面取得了系列进展，顺利完成项目预期目标。①我们系统构建了用于磁共振成像的高性能造影剂，有力提高磁共振造影成像在疾病诊断分析的灵敏度、分辨率和准确性。②我们设计合成了一类具有pH响应的砷剂纳米药物。③该类砷剂纳米药物可用于实体瘤（如肝癌）的有效治疗，能够显著抑制肝癌细胞的侵袭与转移。④亚砷酸锰砷剂纳米药物是一类具有诊疗一体的纳米药物，可通过T1明场造影成像对药物的体内行为进行实时完整的示踪、成像和疗效分析。我们在磁共振造影剂设计合成方面取得了重要进展，首次从本质上提出了氧化铁纳米结构与磁共振造影性能的构效关系，具有重要科学意义。在ACS Nano、Chem. Mater.、Small、Chem. Commun.、Anal. Chem.、Nanoscale等高水平期刊已发表SCI论文25篇，中文核心论文1篇，申请中国发明专利6项，其中授权2项。