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

The immune checkpoint blockade therapy has profoundly revolutionized the field of cancer immunotherapy. However, despite great promise for a variety of cancers, the efficacy of immune checkpoint inhibitors is still low in colorectal cancer (CRC). This is mainly due to the immunosuppressive feature of the tumor microenvironment (TME). Emerging evidence reveals that certain chemotherapeutic drugs induce immunogenic cell death (ICD), demonstrating great potential for remodeling the immunosuppressive TME. In this study, the potential of ginsenoside Rg3 (Rg3) as an ICD inducer against CRC cells was confirmed using in vitro and in vivo experimental approaches. The ICD efficacy of Rg3 could be significantly enhanced by quercetin (QTN) that elicited reactive oxygen species (ROS). To ameliorate in vivo delivery barriers associated with chemotherapeutic drugs, a folate (FA)-targeted polyethylene gly-col (PEG)-modified amphiphilic cyclodextrin nanoparticle (NP) was developed for co-encapsulation of Rg3 , QTN. The resultant nanoformulation (CD-PEG-FA.Rg3.QTN) significantly prolonged blood cir-culation and enhanced tumor targeting in an orthotopic CRC mouse model, resulting in the conversion of immunosuppressive TME. Furthermore, the CD-PEG-FA.Rg3.QTN achieved significantly longer survival of animals in combination with Anti-PD-L1. The study provides a promising strategy for the treatment of CRC.

Automated summary

This study confirms the potential of ginsenoside Rg3 as an inducer of immunogenic cell death (ICD) against colorectal cancer (CRC) cells. The effectiveness of Rg3 in inducing ICD is significantly enhanced when combined with quercetin (QTN) that induces reactive oxygen species (ROS). A targeted nanoparticle formulation, co-encapsulating Rg3 and QTN, is developed to improve the in vivo delivery and shows enhanced tumor targeting and prolonged blood circulation in a CRC mouse model. The combination of this nanoparticle formulation with anti-PD-L1 leads to significantly longer survival in animals.