多功能纳米载药系统联合光动力与化疗靶向治疗口腔鳞状细胞癌的研究

Photodynamic therapy (PDT) is a novel cancer treatment method that stimulates photosensitizers by a light with special wavelength to produce reactive oxygen (ROS) that can kill tumors through multi mechanisms. PDT has many advantages for the clinical treatment of oral squamous carcinoma (OSCC), such as low toxicity, wide applicability, slight damage to connective tissue, which is favorable to preserving the structure and functions of oral cavity and to preventing the tumor metastasis and recurrence. However, it still has some limitations for cancer therapy, such as its poor targeting capability and relative low efficiency in killing tumor cells, etc. Thus, PDT is only used for the adjuvant treatment of OSCC currently. To enhance the effect of drugs and efficiently treat OSCC, this project designs a multi-functional nanotherapeutic system for the combination of PDT and chemotherapy. First, the nanomicelles with co-loading of the photosensitizer (haematoporphyrin) and the chemotherapy agent (doxorubicin) are prepared, and then HN-1 (OSCC-targeting peptide, TSPLNIHNGQKL) is conjugated to these nanomicelles, thus realize the integration of multi functions in single nanosystem. Moreover, the synergistic mechanism of this nanotherapeutic system is also investigated using in vitro and in vivo experiments in this project according to the following aspects, OSCC-targeted drug delivery, the killing effects on tumor cells, the inhibition of tumor neovascularization, the activation of the body immune responses, and the enhanced sensitivity and reduced toxicity of chemotherapy. In conclusion, the research of this project will provide a new strategy for the clinical treatment of OSCC.

光动力疗法（PDT）以其微创、低毒、保护器官组织结构等特性，用于治疗口腔鳞状细胞癌（OSCC）可有效避免手术造成的口颌面部外形受损与功能障碍，但其仍存在靶向性差，杀伤肿瘤细胞效率不足等局限，目前仅用于OSCC辅助治疗。为增强药物作用，达到高效治疗OSCC的目的，本项目拟采用纳米载药技术，制备共载光敏剂血卟啉与化疗药物阿霉素的纳米胶束，联合PDT与化疗治疗OSCC，以增强肿瘤对化疗药的敏感性，逆转肿瘤耐药，提高杀伤肿瘤效率；并通过载体表面偶联高度靶向OSCC的HN-1肽，构建多功能纳米载药体系，以期实现两种治疗剂的靶向递送、有效释放与协同作用的目标；并在此基础上系统研究—靶向OSCC的药物转运、对肿瘤细胞的杀伤机制、肿瘤新生血管的抑制、局部抗肿瘤免疫的激活等一系列活性和机理问题，探讨该多功能纳米体系的协同作用机制，为OSCC的治疗提供新的策略。

项目基本按照原定计划执行，主要针对目前口腔舌鳞状细胞癌（oral squamous cell, OSCC）临床治疗的难题，构建光敏剂血卟啉（HP）与化疗药物阿霉素（DOX）的共载纳米胶束，并通过纳米载体表面修饰靶向头颈部鳞状细胞癌的多肽HN-1获得体内靶向OSCC转运药物的能力，实现多种功能在纳米载体系统中的有效整合，以及对OSCC的联合治疗与协同作用；课题还从体内外靶向OSCC的药物转运、对肿瘤细胞的作用、对肿瘤新生血管的抑制、抗肿瘤免疫应答的激活以及对化疗药物的增敏与减毒作用等方面进行系统研究，初步阐明多功能纳米体系的协同作用机制。执行期间对一些研究内容稍作调整，尝试以能特异性识别肿瘤细胞表面整合素αvβ3的RGD肽为靶向修饰配基，构建了能够高效整合光动力与化疗的多功能纳米治疗体系，为OTSCC的靶向治疗提供了新策略。