基于光磁纳米粒子调控肿瘤组织缺氧及光动力疗法的研究

Molecular oxygen is indispensible to the efficacy of photodynamic therapy (PDT). However, tumor hypoxia restricts the supply of oxygen, and increases the proliferation and resistant of tumor cells as well. Therefore, it is necessary to increase the concentration of dissolved oxygen in tumor, so that to promote PDT treatment. Presently, oxygen self-supplement based on nanocarrier is very promising to circumvent hypoxia. As a matter of fact, however, the internalization of oxygen nanocarrier by tumor is rather small due to the heterogeneity and complexity of tumor microenvironment. In addition, the utilization of intra-tumor oxygen is also low. Based on our previous study on magnetic nanomaterials, fluorescent oxygen sensor and nanosensitizers, in this proposal we will utilize magnetic-optical multifunction nanoparticles to adjust O2 concentration in tumor microenvironment and optimize PDT treatment. Specifically, magnetic-optical multifunctional nanocarriers will be constructed to load oxygen-bearing materials, oxygen sensors, and photosensitizers respectively. Based on these nanocarriers, the internalization of NPs will be optimized by using magnetic targeting and EPR effect, controlled release of oxygen in nanocarrier will be studied under alternating magnetic field according to the concentration of dissolved oxygen monitored by fluorescent oxygen nanosenros, and oxygen-supplement PDT will be performed on tumor bearing mice. With the implement of this proposal, tumor hypoxia might be resolved, which would be of great help not only to PDT treatment but also to other nano-therapeutic modalities.

基于光诱导产生活性氧来进行疾病治疗的光动力疗法（PDT）逐渐成为肿瘤治疗一个重要的手段。然而，实体肿瘤的组织缺氧限制氧供给且产生抗药性，严重削弱了治疗效果。因此，提高肿瘤内溶氧水平对于增强PDT疗效具有重要的意义。目前基于纳米输运系统的自供氧有望克服组织缺氧，但是肿瘤微环境的异质性和复杂性导致对纳米粒子的摄取率极低，并且瘤内载氧利用效率不高。申请人基于在磁性纳米材料、荧光氧气传感以及肿瘤PDT方面的研究基础，在本项目中提出利用光磁纳米粒子来调控肿瘤内溶氧水平，并优化PDT治疗方案。具体而言，基于光磁复合纳米运载体系（载氧、光敏剂和荧光探针），通过外磁场的定向输运和肿瘤EPR效应提高对纳米粒子的摄取率；通过磁热效应释放携氧，同时基于荧光氧气传感监测溶氧以实现可控释放；开展自供氧PDT，及一定溶氧下的肿瘤预后。该项目不仅有助于解决组织缺氧问题，也为肿瘤PDT治疗及其他纳米医疗提供了有益的参考。

针对肿瘤乏氧对光动力疗法（PDT）的抑制，本项目构建了多种纳米体系，不仅为乏氧环境提供外源性氧气，而且对溶氧水平和单线态氧进行检测与成像，此外还协同化学动力疗法（CDT），以最终达到提高抗肿瘤的疗效。所取得的主要结果有：（1）制备了基于中空介孔SiO2纳米粒子的纳米载氧体系（直径70 nm），载氧能力为5.26 mg/g，且可通过808 nm近红外光来光热释放载氧；研究了乏氧下PDT，基于纳米载氧体系实现了乏氧诱导因子HIF-1α的下调，以及在PDT作用下损伤相关分子模式HSP70蛋白表达水平的提升。（2）构建了两类自供氧纳米光敏剂，利用PDT实现了乏氧条件下对肿瘤细胞有效杀伤。（3）构建了高质量的三维肿瘤多细胞球，制备了基于金属钌的超稳定荧光氧气纳米传感器（发射波长> 600 nm，水中荧光氧猝灭率高达74%），实现了肿瘤多细胞球中溶氧水平和纳米药物摄取情况的三维成像。（4）构建了两类荧光纳米探针，利用荧光成像实现了对PDT过程单线态氧产生的实时监测。（5）基于中空介孔SiO2纳米粒子来负载光敏剂、生长聚多巴胺壳层并螯合Fe2+离子，构建了808 nm/638 nm双波长敏化的多功能纳米粒子，不仅缓解了皮肤光毒性问题，而且利用PDT/CDT协同疗法实现了对小鼠肿瘤的有效治疗：100 μL给药量（200 μg mL-1）下，利用638 nm激光（100 mW cm-2）和808 nm激发（1 W cm-2）先后辐照20 min和5 min，对小鼠肿瘤的生长抑制率达到70.4%。本项目为PDT的临床应用提供了有益的探索，相关成果在多功能纳米载运体系的设计和合成方面具有一定的指导和借鉴意义。