Triple drugs co-delivered by a small gemcitabine-based carrier for pancreatic cancer immunochemotherapy

摘要

Poor tumor penetration and highly immunosuppressive tumor microenvironment are two major factors that limit the therapeutic efficacy for the treatment of pancreatic ductal adenocarcinoma (PDA). In this work, a redox-responsive gemcitabine (GEM)-conjugated polymer, PGEM, was employed as a tumor penetrating nanocarrier to co-load an immunomodulating agent (NLG919, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) and a chemotherapeutic drug (paclitaxel (PTX)) for immunochemo combination therapy. The NLG919/PTX co-loaded micelles showed very small size of similar to 15 nm. In vivo tumor imaging study indicated that PGEM was much more effective than the relatively large-sized POEG-co-PVD nanoparticles (similar to 160 nm) in deep tumor penetration and could reach the core of the pancreatic tumor. PTX formulated in the PGEM carrier showed improved tumor inhibition effect compared with PGEM alone. Incorporation of NLG919 in the formulation led to a more immunoactive tumor microenvironment with significantly decreased percentage of Treg cells, and increased percentages of CD4(+) IFN gamma(+) T and CD8(+) IFN gamma(+) T cells. PGEM micelles co-loaded with PTX and NLG919 showed the best anti-tumor activity in pancreatic (PANCO2) as well as two other tumor models compared to PGEM micelles loaded with PTX or NLG919 alone, suggesting that codelivery of NLG919 and PTX via PGEM may represent an effective strategy for immunochemotherapy of PDA as well as other types of cancers.