胰腺癌是目前预后最差的实体肿瘤，5年生存率低于5%。在胰腺癌的治疗中，85%的病例确诊时已丧失手术切除机会，因此化疗已成为胰腺癌综合治疗的最常用且有效的手段之一。但目前临床上传统的化疗药物载运系统低效高毒，对于胰腺癌的治疗并无太大的帮助。本项目针对纳米药物载体在肿瘤组织的渗透和滞留，及药物的智能控释的关键科学问题，将肿瘤组织微酸环境诱导聚集和近红外光控药物释放相结合，把化疗药物通过光敏感的化学键共价缔合到上转换纳米粒子表面，设计肿瘤微环境响应的小尺寸纳米药物载体。利用纳米药物载体的小尺寸和在肿瘤组织微酸环境诱导的逐步聚集，使其既能在肿瘤组织有效渗透，又能在肿瘤组织高效滞留。利用化学键合化疗药物和上转换纳米粒子辅助的近红外光响应药物释放，解决药物既不能在运输过程中泄漏，又能在病灶处快速释放这一矛盾，为癌症治疗中纳米药物载体的优化设计提供科学依据。

Pancreatic cancer is one of the most lethal malignancies. Five-year survival rate for pancreatic cancer is only less than 5%. 85% of patients have tumors that cannot be surgically resected, so chemotherapy is one of the best options for pancreatic cancer therapy. However, because of the low efficacy and high toxicity of the drug delivery system, the outcome of chemotherapy is always not satisfactory. It is very urgent and crucial to develop new safe and efficient drug delivery systems. This proposal focuses on the development of new nearinfrared (NIR) laser responsive drug nanocarriers with high tumor penetration and tumor retention. The chemotherapeutic drug 5-Fluorouracil (5-FU) was chemical conjugated to the upconverting nanoparticles with UV light-responsive bonds. Because of the small size, the drug nanocarriers can be penetrated into tumor tissue successfully. What’s more, the drug nanocarriers were tumor microenvironment responsive, they were aggregated gradually during penetration. Therefore, the drug nanocarriers exhibited high tumor penetration and tumor retention abilities. Furthermore, since 5-FU was chemical conjugated to the drug nanocarriers, 5-FU cannot be released during circulation. However, since the upconverting nanoparticles can be used as nanotransducers to absorb NIR light having high tissue penetration power and negligible phototoxicity and emit UV light locally, 5-FU can be released in vivo after NIR irradiation. The novel drug nanocarriers will provide a new strategy for more efficient treatment of pancreatic cancer.