Abstract
BackgroundFOLFOX 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.MethodsA 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.ResultsSynergistic 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.ConclusionThis 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.Graphical abstract
Highlights
The FOLFOX regimen including folinic acid (FnA), fluorouracil (5-Fu) and oxaliplatin (OxP) has been used as the standard chemotherapy for patients with colorectal cancer (CRC) and hepatocellular carcinoma (HCC) at advanced stages [1, 2]
Preparation and physicochemical characterization of nano-Fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) One water-in-oil microemulsion containing CaCl2 and FdUMP was mixed with another water-in-oil microemulsion containing Na2HPO4, in order to generate Ca3(PO4)2 amorphous precipitate in which FdUMP was entrapped
The Ca3(PO4)2-FdUMP nanoprecipitate was stabilized by 1,2-dioleoyl-sn-glycero-3-phosphate (DOPA), and the stabilized nanoprecipitate was coated with 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG2000 (DSPE-polyethylene glycol (PEG)) and DSPE-PEGAEAA, resulting in Nano-FdUMP
Summary
The FOLFOX regimen including folinic acid (FnA), fluorouracil (5-Fu) and oxaliplatin (OxP) has been used as the standard chemotherapy for patients with colorectal cancer (CRC) and hepatocellular carcinoma (HCC) at advanced stages [1, 2]. Development of nano delivery systems holds great promise for overcoming the barriers associated with FOLFOX. 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. 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
