高效原位瘤及淋巴转移瘤靶向的可变粒径纳米递药系统的研究

Nano-drug delivery systems were widely used in the diagnosis and treatment of cancer. However, the anti-tumor effect has not been improved significantly. On the one hand, tumor cells were easily spread through the lymphatic system, and the traditional nano-delivery systems were difficult to effectively accumulate in the lymphatic system to prevent tumor metastasis. On the other hand, the nano-delivery systems were hardly to reach to the deep tumor to achieve efficient "penetration" and long-term "retention" simultaneously. In order to effectively cure the tumor, we intended to establish a small particle size micelle modified with functional groups for click chemical reaction and tumor targeting peptide TR, containing both the photothermal agent indocyanine green and chemotherapeutic drug doxorubicin. This drug delivery system could not only accumulate in the lymph nodes to treat the metastatic tumor due to the small particle size, but also penetrate into the deep tumor through the EPR effect and the active targeting of the TR peptide. After that, the near infrared laser irradiation was given and the local temperature increased, which could cause cell apoptosis and catalyze the rapid reaction of click chemical functional groups on the surface of micelle, leading to the polymerization of micelle and retention in the tumor tissue. In short, the photothermal catalyzed nano drug delivery system could realize the lymphatic system delivery, tumor deep delivery and effective retention, to exert optimal synergistic effect of photothermal therapy and chemotherapy.

纳米递药系统在肿瘤的诊断和治疗方面具有广阔前景，但其抗肿瘤效果并未得到突破性提高。究其原因，一方面是肿瘤细胞易通过淋巴系统扩散，而传统纳米递药系统很难通过在淋巴系统的有效蓄积阻止肿瘤转移；另一方面是纳米递药系统难以同时实现在原位瘤深部治疗盲区的高效“渗透”和长效“滞留”。本项目拟制备表面修饰点击化学反应官能团及靶向肽TR的小粒径胶束，同时包载光热剂吲哚菁绿和化疗药物阿霉素。该系统首先依托小粒径胶束更易蓄积在淋巴结部位以治疗转移瘤；同时通过肿瘤部位EPR效应和TR肽的主动靶向性高效渗透至肿瘤深部，再给予近红外激光照射，使肿瘤局部温度升高，促进肿瘤细胞凋亡，并催化表面官能团快速进行点击化学反应，使胶束聚合，粒径增大，更加长效地滞留于肿瘤组织。简言之，本项目所构建的光热催化的粒径可变纳米递药系统能够同时实现药物的淋巴系统传递、肿瘤深部递送和有效滞留，从而发挥光热治疗和化疗的最优协同作用。

纳米递药系统在肿瘤的诊断和治疗方面具有广阔的前景，但其抗肿瘤效果并未得到突破性提高。传统的纳米递药系统难以在淋巴系统蓄积而遏制肿瘤转移；且难以同时实现在原位肿瘤深部治疗盲区的高效“渗透”和长效“滞留”。因此，本项目聚焦于提高抗肿瘤药物在淋巴系统的转运，同时提高药物在肿瘤部位的渗透性和滞留性，增强纳米递药系统的抗肿瘤效果。. 本项目首先以小粒径DSPE-PEG为主体胶束，可靶向蓄积于淋巴结转移瘤，同时实现实体肿瘤的深层穿透；胶束表面分别修饰能进行点击化学反应的官能团叠氮（N3）和炔基（ALK），在催化剂作用下发生点击化学反应而聚集，粒径增大，实现药物在肿瘤部位的长效滞留。采用该粒径可变胶束包载化疗药物PTX有效抑制了乳腺癌原位生长及其淋巴结转移；共载化疗药物和免疫佐剂MPLA、并与PD-L1单抗联用，进一步优化了抑瘤作用。.考虑到通过瘤内注射给予催化剂（亚铜离子）使得给药过程较为复杂，我们进一步以PCL-PEG2000为小粒径胶束，表面分别修饰可发生无铜催化点击反应基团叠氮和DBCO，并用酸敏感可断裂的长链PEG5000屏蔽两种基团，在肿瘤微环境中定点暴露从而快速发生点击反应，增强肿瘤滞留。采用该胶束分别包载化疗药物阿霉素和小分子抑制剂SIS3，有效激活了基于NK细胞的抗肿瘤免疫并显著抑制了肿瘤的生长。. 在该项目资助下，已发表学术论文19篇，包括Adv Mater （IF=27.398）1篇，Theranostics（IF= 11.556）2篇，J Control Release（IF=9.776）5篇，ACS Appl Mater（IF=9.229）3篇, Acta Biomater（IF=8.947）2篇，Nanoscale（IF=7.790）3篇, Int J Pharm（IF=5.875）1篇，Pharmaceutical Fronts(新刊)综述1篇，中文文章1篇。培养博士生3名和硕士生3名。作学术报告10次。