Two nanoformulations induce reactive oxygen species and immunogenetic cell death for synergistic chemo-immunotherapy eradicating colorectal cancer and hepatocellular carcinoma

• Published in: Molecular cancer Vol. 20; no. 1; pp. 10 - 17
• Main Authors: Guo, Jianfeng, Yu, Zhuo, Sun, Dandan, Zou, Yifang, Liu, Yun, Huang, Leaf
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 06.01.2021; BioMed Central; BMC
• Subjects: 5-Fluorouracil; Analysis; Animal models; Animals; Antigens; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - metabolism; Biochemistry; Cancer; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - immunology; Cell death; Cell Line, Tumor; Chemotherapy; Cholesterol; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - immunology; Combination therapy; Disease Models, Animal; Drug Compounding; Drug delivery; Drug delivery systems; Drug Synergism; Drug therapy; Drugs; Ethanol; Female; Fluorodeoxyuridylate - metabolism; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Folinic acid; Hepatocellular carcinoma; Hepatoma; Immune response; Immunogenetics; Immunogenic cell death; Immunogenic Cell Death - drug effects; Immunogenicity; Immunotherapy; Leucovorin; Leucovorin - pharmacology; Leucovorin - therapeutic use; Lipids; Liver; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - immunology; Liver Neoplasms - pathology; Lymphocytes; Metabolites; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Microemulsions; Nanoparticles; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Neoplasm Metastasis; Organoplatinum Compounds - pharmacology; Organoplatinum Compounds - therapeutic use; Oxaliplatin; PD-L1 protein; Polyethylene glycol; Reactive oxygen species; Reactive Oxygen Species - metabolism; Tissue Distribution; Tumors; Vehicles; Nanoparticles; Reactive oxygen species; Drug delivery; Combination therapy; Immunogenic cell death
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-020-01297-0

FOLFOX is a combinational regimen of folinic acid (FnA, FOL), fluorouracil (5-Fu, F) and oxaliplatin (OxP, OX), and has been long considered as the standard treatment of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Recent developments of nano delivery systems have provided profound promise for improving anticancer efficacy and alleviating side effects of FOLFOX. Previously, a nanoformulation (termed Nano-Folox) containing OxP derivative and FnA was developed in our laboratory using nanoprecipitation technique. Nano-Folox induced OxP-mediated immunogenic cell death (ICD)-associated antitumor immunity, which significantly suppressed tumor growth in the orthotopic CRC mouse model when administrated in combination with free 5-Fu. A nanoformulation (termed Nano-FdUMP) containing FdUMP (5-Fu active metabolite) was newly developed using nanoprecipitation technique and used in combination with Nano-Folox for CRC and HCC therapies. Synergistic efficacy was achieved in orthotopic CRC and HCC mouse models. It resulted mainly from the fact that Nano-FdUMP mediated the formation of reactive oxygen species (ROS), which promoted the efficacy of ICD elicited by Nano-Folox. In addition, combination of Nano-Folox/Nano-FdUMP and anti-PD-L1 antibody significantly inhibited CRC liver metastasis, leading to long-term survival in mice. This study provides proof of concept that combination of two nano delivery systems can result in successful FOLFOX-associated CRC and HCC therapies. Further optimization in terms of dosing and timing will enhance clinical potential of this combination strategy for patients.