Synergistic Target of Intratumoral Microbiome and Tumor by Metronidazole–Fluorouridine Nanoparticles

Clinical and experimental evidence confirmed bacterial infiltration in a variety of tumors, which is related to the progression and therapeutic effects of the tumors. Although the administration of antibiotics inhibits the growth of bacteria inside the tumor, systemic distribution of antibiotics induces an imbalance of other microbiomes in the body, which in turn leads to the development of new diseases. To address this clinical challenge, we nanonized an antibiotic in this study. Metronidazole, an antibiotic against broad anaerobes, was linked to fluorouridine to form an amphiphilic small molecule, metronidazole–fluorouridine, which further autoassembled as metronidazole–fluorouridine nanoparticles (MTI-FDU) in a hydrophilic solution. The disulfide bond in the linker cleaves in response to high levels of glutathione (GSH) in the tumor microenvironment. The synergistic antitumor effect of MTI-FDU was observed in two animal models of gut cancer with intratumoral bacteria. Analysis revealed that metronidazole delivered by nanoparticles attacked bacteria inside the tumor, while it had minimal effect on gut microbial homeostasis. Further experiments at the cellular and molecular levels disclosed that MTI-FDU shaped the tumor immune microenvironment through clearance of bacteria and bacterial products. In conclusion, we achieved a synergistic antitumor effect by a dual target of both the intratumoral microbiome and tumor cells. Antibiotic-composed nanoparticles have a clinical advantage in the treatment of tumors with bacteria infiltration, which kill pro-tumor bacteria efficiently as well as keep a balanced microbiota of the patient.