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

Dandan Sun; Yifang Zou; Liu Song; Shulan Han; Hao Yang; Di Chu; Yun Dai; Jie Ma; Caitriona M O'Driscoll; Zhuo Yu; Jianfeng Guo

doi:10.1016/j.apsb.2021.06.005

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

Acta Pharm Sin B. 2022 Jan;12(1):378-393. doi: 10.1016/j.apsb.2021.06.005. Epub 2021 Jun 18.

Authors

Dandan Sun¹, Yifang Zou¹, Liu Song¹, Shulan Han¹, Hao Yang¹, Di Chu¹, Yun Dai², Jie Ma¹, Caitriona M O'Driscoll³, Zhuo Yu⁴, Jianfeng Guo¹

Affiliations

¹ School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.
² Laboratory of Cancer Precision Medicine, The First Hospital of Jilin University, Changchun 130021, China.
³ Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork T12 YT20, Ireland.
⁴ Department of Hepatopathy, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

Abstract

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 glycol (PEG)-modified amphiphilic cyclodextrin nanoparticle (NP) was developed for co-encapsulation of Rg3 and QTN. The resultant nanoformulation (CD-PEG-FA.Rg3.QTN) significantly prolonged blood circulation 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.

Keywords: ATF6, activating transcription factor 6; ATP, adenosine triphosphate; CI, combination index; CRC, colorectal cancer; CRT, calreticulin; CTLA-4, cytotoxic T lymphocyte antigen 4; CXCL10, C-X-C motif chemokine 10; CXCL9, C-X-C motif chemokine 9; Chemotherapy; Colorectal cancer; Combination therapy; DAMPs, damage-associated molecular patterns; DCs, dendritic cells; ECL, enhanced chemiluminescence; EE, encapsulation efficiency; ER, endoplasmic reticulum; FA, folate; HMGB1, high-mobility group box 1; ICD, immunogenic cell death; IFN-γ, interferon-gamma; IL-10, interleukin-10; IL-12, interleukin-12; IL-4, interleukin-4; IL-6, interleukin-6; IRE1, inositol-requiring enzyme 1; Immunogenic cell death; Immunotherapy; LC, loading capacity; MDSCs, myeloid derived suppressor cells; MMR, mismatch repair; MR, molar ratio; NAC, N-acetyl-l-cysteine; NP, nanoparticle; Nano drug delivery system; PD-L1, programmed death-ligand 1; PEG, polyethylene glycol; PERK, PKR-like ER kinase; PFA, paraformaldehyde; PVDF, polyvinylidene fluoride; QTN, quercetin; ROS, reactive oxygen species; Reactive oxygen species; TAAs, tumor-associated antigens; TME, tumor microenvironment; Tumor microenvironment; UPR, unfolded protein response; p-IRE1, phosphorylation of IRE1; p-PERK, phosphorylation of PERK.