Macrophage-Hitchhiked Orally Administered β-Glucans-Functionalized Nanoparticles as "Precision-Guided Stealth Missiles" for Targeted Pancreatic Cancer Therapy
Journal
Advanced materials (Deerfield Beach, Fla.)
Journal Volume
35
Journal Issue
40
Date Issued
2023-10
Author(s)
Chen, Kuan-Hung
Nguyen, Nhien
Huang, Tun-Yu
Lin, Yu-Jung
Yu, Yu-Tzu
Wang, Jui-To
Nguyen, Van Khanh
Chen, Hsin-Lung
Chu, Li-An
Chiang, Hui-Hua Kenny
Sung, Hsing-Wen
Abstract
The prognosis in cases of pancreatic ductal adenocarcinoma (PDAC) with current treatment modalities is poor owing to the highly desmoplastic tumor microenvironment (TME). Herein, a β-glucans-functionalized zinc-doxorubicin nanoparticle system (βGlus-ZnD NPs) that can be orally administered, is developed for targeted PDAC therapy. Following oral administration in PDAC-bearing mice, βGlus-ZnD NPs actively target/transpass microfold cells, overcome the intestinal epithelial barrier, and then undergo subsequent phagocytosis by endogenous macrophages (βGlus-ZnD@Mϕ). As hitchhiking cellular vehicles, βGlus-ZnD@Mϕ transits through the intestinal lymphatic system and enters systemic circulation, ultimately accumulating in the tumor tissue as a result of the tumor-homing and "stealth" properties that are conferred by endogenous Mϕ. Meanwhile, the Mϕ that hitchhikes βGlus-ZnD NPs is activated to produce matrix metalloproteinases, destroying the desmoplastic stromal barrier, and differentiates toward the M1 -like phenotype, modulating the TME and recruiting effector T cells, ultimately inducing apoptosis of the tumor cells. The combination of βGlus-ZnD@Mϕ and immune checkpoint blockade effectively inhibits the growth of the primary tumor and suppresses the development of metastasis. It thus represents an appealing approach to targeted PDAC therapy.
Subjects
desmoplastic stromal barrier; immune checkpoint blockade; intestinal epithelial barrier; macrophage hitchhiking; tumor microenvironment
Type
journal article