光敏纳米复合材料的制备及在缺氧微环境中肿瘤光动力治疗研究

The photodynamic therapy (PDT) has been applied in the treatment of early stage tumor due to its high selectivity, low toxicity, and few side effects to the human tissues. However, because of its dependency on the excitation light and oxygen concentration in the tumor site, the higher therapeutic efficiency of the PDT is still expected. Until now, the NIR light can be utilized in the PDT by loading the photosensitizer agent on the upconversion nanoparticles (UCNPs) due to the absorption ability of the UCNPs and fluorescence resonance energy transfer (FRET) effect between them. Unfortunately, only a fraction of the excitation light can be absorbed by the UCNPs in the upconversion process, and the excessive absorption of excitation light by the body may lead to the hyperthermia to the human tissue. Besides, the hypoxic microenvironment of the tumor site can also affect the productivity of therapeutic reactive oxygen, whose concentration can be further decreased by the reduced glutathione, which is the fundamental cause of the relatively low therapeutic efficiency of the PDT. Accordingly, in this project, the UCNPs based multifunctional nanoplatform for the PDT will be fabricated. The components with oxygen release properties upon light irradiation can directly increase the concentration of the oxygen during the PDT process. Furthermore, the oxidation of glutathione by the functional component in the nanoplatform can also prevent the reactive oxygen from consumption. The improved ability of the absorption of the UCNPs to the NIR laser will be also conducted in this project for the enhancement of the therapeutic efficiency and decrease the side effect. The system delivery, tumor diagnosis, and therapeutic process will be detected by the imaging properties such as CT, MRI, fluorescence imaging, and photoacoustic imaging, which may further promote the fundamental research and practical application of the PDT. Finally, the basal pharmacology and toxicology of this kind of nanocomposite in vitro and in vivo will be thoroughly examined in this project.

光动力治疗是一种选择性好、毒性低、副作用小的新型肿瘤治疗手段，在几种癌症的早期治疗中已经实现了临床应用。然而，由于其治疗过程中对入射光及肿瘤所处环境中氧分子的含量存在较大的依赖性，光动力疗法在实际应用中的治疗效率依然有待提高。本项目提出以上转换纳米颗粒为基础构建光敏纳米复合材料治疗体系，通过材料分解释放氧及对恶性肿瘤细胞内还原性谷胱甘肽的消耗作用，实现光动力治疗过程中对肿瘤细胞微环境的改变，根本上提高治疗效率。同时，项目还将对提高上转换纳米颗粒对近红外光子吸收能力进行研究，实现入射光能量的高效利用，进一步提高治疗效率并且降低入射光对人体的副作用。此外，项目还将通过复合材料体系中功能组分的CT成像、MRI成像和荧光成像等，实现体系示踪、疾病诊断以及治疗过程的监控等功能，对光动力治疗在生物体内的作用机理研究以及优化治疗方案具有重要的推进作用。

光动力疗法作为一种微创治疗方式，且具有可控性高和毒副作用低等优点且已经被证明可以替代多种传统治疗肿瘤的方式，已发展成为一种可行的治疗人体表面肿瘤的选择。但在光动力疗法中存在一些问题，首先，应用于临床治疗的光敏剂需要通过可见光激发，而可见光在人体组织中穿透能力较低，并且在乏氧肿瘤的治疗中，基于分子氧光化学反应的光动力疗法的治疗效果会被严重制约，这限制了光动力疗法进一步的应用。另外，对于肿瘤的治疗现阶段，很多的治疗药物并不能够直接到达肿瘤部位，而且会对其他正常组织有不同程度的损伤。所以癌症的治疗关键是要把药物定向传送到癌症细胞或者只对肿瘤细胞效力，而又不会伤害到正常的细胞，这是开发高效肿瘤药物的关键。我们根据肿瘤微环境的特异性，如乏氧、过剩的过氧化氢及酸性环境等，开发一系列具有肿瘤微环境特异响应的智能纳米药物。肿瘤微环境响应的智能纳米药物制剂不仅可以大大提高对疾病的治疗效果，还能降低药物的毒副作用，从而在保证疗效的同时最大限度地减少对机体的损伤。本项目基于近红外光激发的UCNPs/Nd开发了一系列上转换纳米颗粒为基础的光敏纳米复合材料治疗体系，一方面在追求高量子效率和高荧光强度的基础上，根据其激发光的特点，增强了材料对入射光的吸收能力，获得的具有较高量子效率和入射光利用率的高质量稀土上转换纳米粒子，从光源方面增强光动力治疗在生物领域内的应用。另一方面，光敏剂组分针对肿瘤微环境缺氧的特点进行设计，改善光动力治疗乏氧环境下的治疗效率。最终获得了集化学治疗/光动力治疗/光热治疗等多模式治疗于一体的稀土基多功能光敏复合材料体系，，系统研究了生物成像技术与光动力治疗之间相关性，并利用UCL、MRI、CT和PA等多模式成像手段实现体系示踪、治疗过程实时监测以及肿瘤病灶发展情况跟踪等功能，评估并整理出一套完备的材料生物安全性数据。为此类材料在癌症诊疗领域的实际应用提供基础研究数据及理论指导。