1. A cyclodextrin-based nanoformulation achieves co-delivery of ginsenoside Rg3 and quercetin for chemo-immunotherapy in colorectal cancer
- Author
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Yun Dai, Zhuo Yu, Dandan Sun, Hao Yang, Liu Song, Shulan Han, Caitriona M. O'Driscoll, Jianfeng Guo, Di Chu, Jie Ma, and Yifang Zou
- Subjects
PERK, PKR-like ER kinase ,Colorectal cancer ,medicine.medical_treatment ,CXCL9, C-X-C motif chemokine 9 ,ECL, enhanced chemiluminescence ,EE, encapsulation efficiency ,chemistry.chemical_compound ,CRT, calreticulin ,UPR, unfolded protein response ,0302 clinical medicine ,Cancer immunotherapy ,NP, nanoparticle ,CTLA-4, cytotoxic T lymphocyte antigen 4 ,General Pharmacology, Toxicology and Pharmaceutics ,IL-6, interleukin-6 ,chemistry.chemical_classification ,0303 health sciences ,Nano drug delivery system ,TME, tumor microenvironment ,IL-10, interleukin-10 ,FA, folate ,CXCL10, C-X-C motif chemokine 10 ,LC, loading capacity ,TAAs, tumor-associated antigens ,Tumor microenvironment ,Ginsenoside ,030220 oncology & carcinogenesis ,CRC, colorectal cancer ,Immunogenic cell death ,Original Article ,Immunotherapy ,DCs, dendritic cells ,HMGB1, high-mobility group box 1 ,ATP, adenosine triphosphate ,PVDF, polyvinylidene fluoride ,ATF6, activating transcription factor 6 ,ICD, immunogenic cell death ,p-PERK, phosphorylation of PERK ,IRE1, inositol-requiring enzyme 1 ,QTN, quercetin ,MMR, mismatch repair ,RM1-950 ,ER, endoplasmic reticulum ,03 medical and health sciences ,ROS, reactive oxygen species ,medicine ,Chemotherapy ,IL-12, interleukin-12 ,Combination therapy ,IFN-γ, interferon-gamma ,PEG, polyethylene glycol ,030304 developmental biology ,Reactive oxygen species ,business.industry ,MDSCs, myeloid derived suppressor cells ,CI, combination index ,NAC, N-acetyl-l-cysteine ,medicine.disease ,Immune checkpoint ,Blockade ,PD-L1, programmed death-ligand 1 ,chemistry ,DAMPs, damage-associated molecular patterns ,MR, molar ratio ,p-IRE1, phosphorylation of IRE1 ,Cancer research ,IL-4, interleukin-4 ,Therapeutics. Pharmacology ,PFA, paraformaldehyde ,business - 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., Graphical abstract A folate-targeted PEGylated cyclodextrin-based nanoparticle was developed for co-delivery of Rg3 and QTN. The combination of the resultant co-formulation and anti-PD-L1 antibody achieved chemo-immunotherapy for colorectal cancer.Image 1 more...
- Published
- 2022