1. Harnessing the Power of Sugar-Based Nanoparticles: A Drug-Free Approach to Enhance Immune Checkpoint Inhibition against Glioblastoma and Pancreatic Cancer.
- Author
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Hsu FT, Chen YT, Chin YC, Chang LC, Chiang SC, Yang LX, Liu HS, Yueh PF, Tu HL, He RY, Jeng LB, Shyu WC, Hu SH, Chiang IT, Liu YC, Chiu YC, Wu GC, Yu CC, Su WP, and Huang CC
- Subjects
- Humans, Animals, Mice, Immune Checkpoint Inhibitors chemistry, Immune Checkpoint Inhibitors pharmacology, Galactose chemistry, Cell Line, Tumor, Reactive Oxygen Species metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Sugars chemistry, Tumor Microenvironment drug effects, Nanoparticles chemistry, Glioblastoma drug therapy, Glioblastoma pathology, Glioblastoma metabolism, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms pathology, Pancreatic Neoplasms metabolism
- Abstract
Cancer cells have a high demand for sugars and express diverse carbohydrate receptors, offering opportunities to improve delivery with multivalent glycopolymer materials. However, effectively delivering glycopolymers to tumors while inhibiting cancer cell activity, altering cellular metabolism, and reversing tumor-associated macrophage (TAM) polarization to overcome immunosuppression remains a challenging area of research due to the lack of reagents capable of simultaneously achieving these objectives. Here, the glycopolymer-like condensed nanoparticle (∼60 nm) was developed by a one-pot carbonization reaction with a single precursor, promoting multivalent interactions for the galactose-related receptors of the M2 macrophage (TAM) and thereby regulating the STAT3/NF-κB pathways. The subsequently induced M2-to-M1 transition was increased with the condensed level of glycopolymer-like nanoparticles. We found that the activation of the glycopolymer-like condensed galactose (CG) nanoparticles influenced monocarboxylate transporter 4 (MCT-4) function, which caused inhibited lactate efflux (similar to inhibitor effects) from cancer cells. Upon internalization via galactose-related endocytosis, CG NPs induced cellular reactive oxygen species (ROS), leading to dual functionalities of cancer cell death and M2-to-M1 macrophage polarization, thereby reducing the tumor's acidic microenvironment and immunosuppression. Blocking the nanoparticle-MCT-4 interaction with antibodies reduced their toxicity in glioblastoma (GBM) and affected macrophage polarization. In orthotopic GBM and pancreatic cancer models, the nanoparticles remodeled the tumor microenvironment from "cold" to "hot", enhancing the efficacy of anti-PD-L1/anti-PD-1 therapy by promoting macrophage polarization and activating cytotoxic T lymphocytes (CTLs) and dendritic cells (DCs). These findings suggest that glycopolymer-like nanoparticles hold promise as a galactose-elicited adjuvant for precise immunotherapy, particularly in targeting hard-to-treat cancers.
- Published
- 2024
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