Spatially targeting and regulating tumor-associated macrophages using a raspberry-like micellar system sensitizes pancreatic cancer chemoimmunotherapy

摘要

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) via 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.