To Explore How X-Ray Controlled Release, Folic Acid Receptor-Guided Nanoparticles Exert Their Function in Pancreatic Cancer

(Part I) Pancreatic cancer is among the leading causes of cancer-related death. Methotrexate (MTX), which is recognized as a refractory drug for pancreatic cells, was conjugated to the surface of LiYF4:Ce3+ nanoparticles (NPMTX) through a photo-cleavable linker molecule. When LiYF4:Ce3+ NPs are stimulated by X-ray, they emit light, which induces the photo-cleavage of the photo-liable linker molecule to release MTX. MTX can target pancreatic tumors, which overexpress folic acid (FA) receptors, and are internalized into the cell through receptor-mediated endocytosis. The synergistic effect of the NP-MTX treatment initiated by X-ray irradiation occurs due to the combination of nanoparticle sensitization and the radiosensitizing chemotherapy of the photo-cleaved MTX molecule. This dual sensitization effect mediated by NP-MTX enabled 40% dose enhancement, which corresponded with an increase in the generation of cytotoxic cellular reactive oxygen species (ROS) and enhanced S phase arrest within the cell cycle. The delivery of the ultra-low radiation dose of 0.1 Gy resulted in the photo-cleavage of MTX from NP-MTX, and this strategy demonstrated in vivo efficacy against AsPC-1 and PANC-1 xenografted pancreatic tumors. (Part II) Au@PG nanoparticles (NPs) are gold (Au)-based NPs featuring a polyaniline-based glyco structure (PG) generated from the polymerization of ortho-nitrophenyl-βD-galactopyranoside (ONPG) with promising M1 macrophage polarization activity, resulting in tumor remodeling and from a cold to a hot microenvironment, which promotes the cytotoxic T cell response and tumor inhibition. A one-pot synthetic method was developed to achieve glycocondensation during the formation of Au@PG NPs, which induced macrophage polarization more efficiently than Au@glucose, Au@mannose, and Au@galactose NPs. The switch from M2 to M1 macrophages was dependent on NP size. Cellular uptake by endocytosis induced size-dependent endoplasmic reticulum (ER) stress, which resulted in the activation of spleen tyrosine kinase (SYK), leading to immune modulations and macrophage polarization. The combination of Au@PG NPs and anti-programmed cell death protein 1 (PD-1) therapy improved tumor inhibition and immunosuppression, accompanied by the secretion of immunogenic cytokines.
(Part III) Single-atom catalysts have emerged as a form of nanocatalytic medicine to perform chemodynamic therapy following •OH generation. Unfortunately, the endogenous H2O2 is not sufficient to drive the reaction kinetics for ROS production due to the cell’s antioxidative mechanisms. Herein, we employ a galvanic replacement approach to create atomically dispersed Au on degradable zero-valent Cu nanocubes for tumor treatments on female mice. Controlling the addition of precursor HAuCl4— allows for the fabrication of different atomic ratios of AuxCuy (i.e. Au0.02Cu0.98, Au0.05Cu0.95, Au0.1Cu0.9, and Au0.5Cu0.5). Xray absorption near edge spectra indicates that Au and Cu are the predominant oxidation states of zero valence. This suggests that the charges of Au and Cu remain unchanged after galvanic replacement. Specifically, Au0.02Cu0.98 composition reveals the enhanced •OH generation following O2→H2O2→•OH. The degradable Au0.02Cu0.98 released Cu+ and Cu2+ resulting in oxygen reduction and Fenton-like reactions. Simulation studies indicate that Au single atoms boot zero-valent copper to reveal the catalytic capability of Au0.02Cu0.98 for O2→H2O2→•OH as well. Instead of using endogenous H2O2, H2O2 can be sourced from the O2 in the air through the use of nanocubes.