联合免疫检查点抑制剂及诊治一体的纳米靶向探针对小鼠胰腺癌治疗效果的研究

Pancreatic cancer is one of the highest malignant degree and most deadly cancers. We found that integrin αvβ6 is widely upregulated in pancreatic cancer, and prepared a near-infrared fluorescent probe targeting integrin αvβ6. It manifested remarkable antitumor effects through PDT in the mice bearing BxPC-3 tumor. However, the effects of inhibiting tumor growth is poorly durability. We optimize the probe based on the functionalization of graphene oxide nanoparticles to improve the uptake and tumor targeting for optical/magnetic resonance multimodal imaging and photodynamic therapy. We plan to implement a combination treatment through photodynamic therapy and immune checkpoint inhibition, and overcome hypoxia by the Fenton reaction. We plan to explore the immune responses in lymph nodes and tumors in the combination treatment. This work would be provide experimental basis for improve the level of the treatment of pancreatic cancer.

胰腺癌是一类恶性程度高、预后极差的肿瘤。我们前期研究发现整合素αvβ6高表达于胰腺癌中，将其作为靶点构建的光学探针介导的光动力学治疗能够一定程度地抑制小鼠皮下BxPC-3胰腺肿瘤的生长，但其抑制效果持久性不佳。因此，我们在此基础上优化光学探针，构建诊治一体的基于功能化氧化石墨烯纳米的多模态靶向探针，提高肿瘤摄取和靶向性；使得该探针能够应用于光学-磁共振多模态成像及光动力学治疗，并通过芬顿反应改善光动力学治疗过程中肿瘤微环境的乏氧状态；并联合免疫检查点抑制药物，增强肿瘤治疗效果；并探究联合治疗过程中淋巴结及肿瘤内发生的免疫反应；为提高胰腺癌的治疗水平提供实验依据。

胰腺癌是一类恶性程度高、预后极差的肿瘤，胰腺癌的早发现对于临床预后具有重要意义。本项目基于胰腺癌肿瘤高表达整合素αvβ6，构建了靶向整合素αvβ6的多模态分子探针MnFe2O4@GO(HPPH)-PEG-HK，该探针以氧化石墨烯纳米为载体，加载上靶向整合素αvβ6的多肽HK和光学信号分子HPPH、磁共振显像分子MnFe2O4。该探针不止在体外能够靶向摄取到肿瘤细胞，在裸鼠皮下动物模型的光学/磁共振显像实验中也能够实现靶向成像。增加探针注射剂量后，给予光动力学治疗联合PD-1抑制剂治疗肿瘤，治疗组肿瘤增长得到了抑制，对治疗组小鼠的肿瘤组织进行Ki67、GLUT-1免疫荧光染色，证实了肿瘤组织糖代谢水平降低。