纳米酶编码配位聚合物纳米粒子的构建及抗肿瘤研究

Hypoxia is one of the key roadblocks in photodynamic therapy of cancer. To enhance the efficiency of photodynamic therapy of hypoxia tumor, this project aims to develop a targeting nanoenzyme decorated coordination polymer nanoparticle (nanoenzyme-CPP) platform with near-infrared (NIR) absorption property for magnetic resonance imaging-guided enhanced photodynamic therapy. The coordination polymer nanoparticles (CPPs) with NIR absorption property will firstly be prepared based on the coordination self-assembly of Gd3+ and carboxylate iridium complexes bearing azadipyrromethenes/cyanines. The CPPs will then be decorated with nanoenzyme as the mimetics of catalase or/and peroxidase thus resulting in the nanoenzyme-CPP platform. A targeting property of the platform will additionally be achieved by the conjugation of the Her2 antibody on the surface of the nanoparticles. The formation mechanism of the nanoenzyme-CPP platform and the modulation principle of the activity of nanoenzyme will be investigated in detail. The relationship between the morphology/diameter and longitudinal relaxvity, the quantum efficiency of the singlet oxygen generation, and the activity of the catalase or/and peroxidase mimetics will also be evaluated. The enhanced targeted photodynamic therapy induced by nanoenzyme will be evaluated by magnetic resonance imaging on a xenografted breast cancer model. By providing a novel theranostic nanoplatform, this project would pave a new avenue for the targeted photodynamic therapy of hypoxic tumor in the field of oncology.

乏氧是制约肿瘤光动力学治疗效果的重要因素之一。本项目针对肿瘤的乏氧特征，以靶向纳米酶编码的配位聚合物纳米粒子为平台，开展磁共振成像指导下肿瘤的增敏光动力学治疗研究。以氮杂二氢吡咯或花菁为近红外吸收单元合成羧酸功能化的铱配合物，与Gd3+通过配位自组装构建配位聚合物纳米粒子，修饰具有过氧化物酶或/和过氧化氢酶活性的金属纳米酶，并评价纳米结构/粒径与纵向弛豫率、单线态氧量子产率、模拟过氧化物酶或/和过氧化氢酶活性及其近红外激光增强酶活性等之间的关系，阐述其形成机制与酶活性调控规律；通过在纳米粒子上修饰Her2抗体实现其靶向性，以乳腺癌细胞和小鼠为模型，利用磁共振成像动态评价纳米粒子的靶向性及其近红外光动力学治疗效果，阐述纳米酶对乏氧肿瘤（细胞）光动力学治疗效果的增敏及其分子机制。本项目的开展，将为乏氧肿瘤的靶向光动力学治疗技术在肿瘤医学领域中的应用提供新的思路。

本项目围绕具有纳米酶特性的金属配合物纳米粒子的合成及其在肿瘤诊疗中的应用，工作聚焦解决肿瘤的乏氧制约肿瘤治疗效果的问题。合成了具有近红外吸收的铱配合物纳米粒子，探索了其在近红外动力学治疗肿瘤中的应用；并利用纳米酶功能，探讨了材料在声动力学、放射增敏、免疫治疗及多手段中的应用，进一步通过理性设计，优化了活性氧产生的途径，突破肿瘤乏氧环境的限制，提高肿瘤治疗效果。并阐述了纳米酶对乏氧肿瘤（细胞）光动力学治疗效果的增敏及其分子机制。本课题的开展，为配合物纳米粒子在乏氧肿瘤的光动力学治疗技术中的应用提供了新思路。展现了配合物纳米粒子在肿瘤精准诊断与治疗中的应用前景，为实现其临床转化奠定基础。