超快激活细胞穿膜肽增强纳米药物治疗胰腺癌的研究

The dense stroma of pancreatic cancer hindered the delivery of chemotherapy drugs into pancreatic cancer cells, resulting the lack of effective therapeutics drugs in the clinic for the treatment of pancreatic cancer. In recent years, it has been demonstrated that nanocarrier modified targeting molecules could enhance the delivery of drug into pancreatic cancer cells via receptor-mediated endocytosis, which improved the therapeutics efficiency. However, it should be noted that the overexpression of these receptors in pancreatic cancer cells is heterogeneous, which limits their clinical application. Cell-penetrating peptide (CPP) modifications enhance the uptake of nanocarriers into pancreatic cancer cells independent of receptors. However, they also enhance the cellular uptake by normal tissues and cells, resulting in nonspecific targeting. Our previous study found that activating the CPP targeting molecules in the tumor site via the rational design of nanocarriers can achieve pancreatic cancer cell-specific targeted drug delivery, and improve the anticancer effect. In this project, we will further develop tumor acidity and ligh responsive nanocarriers for the ultrafast activation of CPP-targeting molecules at the tumor site, thereby greatly enhancing the uptake by pancreatic cancer cells while avoiding the non-specific targeted delivery. This project will provide new technologies and concepts for the development of the next generation of targeted nanodrugs.

胰腺癌密集增生的基质使得化疗药物难以递送到胰腺癌细胞内发挥功效，导致临床上缺乏治疗胰腺癌的有效药物。近年来研究结果表明纳米载体修饰靶向分子，可与胰腺癌细胞表面高表达的受体相互作用，提高化疗药物递送效率。但需要指出的是，这些受体在胰腺癌细胞表达具有异质性，制约了其临床应用。细胞穿膜肽（CPP）修饰可不依赖于表面受体而增强纳米载体被胰腺癌细胞摄取，但其同样增强正常组织和细胞的摄取，造成非特异性靶向。本项目前期研究发现，通过纳米载体的合理设计，在肿瘤部位激活CPP靶向分子能实现胰腺癌细胞特异性的靶向药物递送，提高疗效。本项目拟在此基础上，进一步发展肿瘤酸度、光等响应性纳米载体，实现CPP靶向分子在肿瘤部位的超快激活，从而大大增强被胰腺癌细胞摄取，同时避免CPP靶向分子对正常组织和细胞的非特异性靶向递送。本项目将为发展下一代靶向纳米药物提供了新的技术和理念。

本项目按照原计划顺利进行，构建了多种纳米载体针对胰腺癌等肿瘤细胞进行靶向治疗。通过超声、ROS响应等，触发纳米药物的释放，通过光热、光动力、化疗等手段联合更大程度的发挥抑制胰腺癌等肿瘤。主要成果包括:1.发展了ROS响应释放药物的纳米载体在肿瘤治疗中的运用。2.发展了超声触发的声动力疗法在胰腺癌治疗中的运用。3.发展了基于有机功能纳米材料的肿瘤治疗新策略。4.发展了空心硫化铜纳米材料的胰腺癌治疗新策略。5发展新型miRNA超灵敏检测技术用于胰腺癌等肿瘤的早期诊断。相关研究成果发表在 Analyst，Talanta，Science China Chemistry，ACS Applied Materials & Interfaces，Biomaterials Science等杂志。已培养7名硕士毕业,1名博士毕业。