Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, China.
College of Polymer Science and Engineering, Sichuan university, Chengdu 610065, China.
Nanoscale. 2022 Sep 22;14(36):13098-13112. doi: 10.1039/d2nr03053e.
Dense stroma and an immunosuppressive microenvironment severely hamper the antitumor therapeutic results of pancreatic cancer. Tumor-associated macrophages (TAMs) support the proliferation and invasion of tumor cells and contribute to the information of the immunosuppressive tumor microenvironment (TME). The repolarization of TAMs activates the antitumor immune response and sensitizes chemotherapy. Nevertheless, the difference in distributed mode between TAMs and tumor cells in tumor turns out to be an obstacle for dual targeting. To repolarize TAMs and elevate the chemoimmunotherapy outcome against pancreatic cancer, co-loading the TME responsive micellar system with gemcitabine (GEM) and PI3K inhibitor wortmannin (Wtmn) was used to dual target TAMs and tumor cells. GEM conjugated dendritic poly-lysine DGL (GD) nanoparticles were linked to polycaprolactone-polyethylene glycol micelles encapsulated with Wtmn (PP/Wtmn) a cathepsin B (CTSB) substrate peptide to obtain raspberry-like GD@PP/Wtmn micelles. Upon arrival at the TME, GD was released in response to highly expressed CTSB, allowing deep penetration of the tumor and overcoming of the stromal barrier, while PP/Wtmn remained in the perivascular area where TAMs abundantly resided. By inhibiting the PI3K pathway, the M2-like TAMs were repolarized into M1-like TAMs and then activated antitumor immunity, further synergizing with GEM to suppress tumor growth. This tumor and TAMs dual targeting nanoplatform provides an alternative approach to sensitize chemoimmunotherapy against pancreatic cancer.
致密的基质和免疫抑制的微环境严重阻碍了胰腺癌的抗肿瘤治疗效果。肿瘤相关巨噬细胞（TAMs）支持肿瘤细胞的增殖和侵袭，并有助于免疫抑制肿瘤微环境（TME）的信息传递。TAMs 的重极化激活了抗肿瘤免疫反应，并使化疗更加敏感。然而，肿瘤中 TAMs 和肿瘤细胞分布模式的差异成为双重靶向的障碍。为了使 TAMs 重极化并提高针对胰腺癌的化疗免疫治疗效果，使用载有吉西他滨（GEM）和 PI3K 抑制剂渥曼青霉素（Wtmn）的 TME 响应胶束系统对 TAMs 和肿瘤细胞进行双重靶向。将连接有 PI3K 抑制剂渥曼青霉素（Wtmn）的聚己内酯-聚乙二醇胶束封装的树枝状聚赖氨酸 DGL（GD）纳米颗粒与 cathepsin B（CTSB）底物肽进行链接，得到覆盆子状 GD@PP/Wtmn 胶束。到达 TME 后，GD 在高表达的 CTSB 作用下释放，允许肿瘤的深层渗透并克服基质屏障，而 PP/Wtmn 则保留在富含 TAMs 的血管周围区域。通过抑制 PI3K 通路，M2 样 TAMs 被重极化成为 M1 样 TAMs，从而激活抗肿瘤免疫，与 GEM 协同抑制肿瘤生长。这种肿瘤和 TAMs 双重靶向纳米平台为增强化疗免疫治疗胰腺癌提供了一种替代方法。
