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

Abstract

Background 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. Methods 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. Results 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. Conclusion 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. Graphical abstract

A cyclodextrin-based nanoformulation achieves co-delivery of ginsenoside Rg3 and quercetin for chemo-immunotherapy in colorectal cancer

“…It must be borne in mind that the identified features of ICD are only “thin end of the wedge”, therefore, future investigation of ICD hallmarks is of critical importance for progress in the validation of emerging ICD inducers. In addition, the hepatic metastasis is known as the commonest form of distant metastasis in CRC, therefore, therapeutic efficacy of “targeted co-formulation + PD-L1 blockade” strategy will be assessed using mice with experimental CRC liver metastases 85 , in order to confirm the potential for the treatment of CRC liver metastasis.…”

Biointerfacing Antagonizing T‐Cell Inhibitory Nanoparticles Potentiate Hepatocellular Carcinoma Checkpoint Blockade Therapy

“…Anti-PD-L1 checkpoint blockade therapy has been proven to benefit the survival of HCC patients and is listed as an adjuvant management strategy for advanced HCC. [45][46][47] However, its use is often limited because the separate application often induces drug resistance in tumor cells, and checkpoint blockade is often ineffective in HCC with low PD-L1 expression. Therefore, we tried to combine BAT NPs with anti-PD-L1 therapy to protect and deliver both antibodies simultaneously.…”

Cancer nanotechnology: current status and perspectives

“…Previous research has shown that radiotherapy can be utilized to activate the immune system by inducing immunogenic cell death (ICD), an immune response against the antigens of dead or dying tumor cells [339]. ICD-associated damage via ROS production could possibly promote the activation and migration of dendritic cells to prime T cells for systemic anti-tumor immune responses [340,341]. However, radiation-stimulated immune responses have shown limited efficacy, particularly when tumors exhibit low X-ray absorption and energy deposition capacities [342,343].…”