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Updated: Jun 30, 2025
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
An "All-In-One" Immunomodulator-Engineered Clinical Translatable Immunotherapy of Advanced Hepatocellular Carcinoma
Ting Xie1, Cong Huang1, Yuqing Wang1
1Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China.
Abstract:
Clinical treatment of advanced hepatocellular carcinoma (HCC) remains a significant challenge. Utilizing 1-bromoacetyl-3,3-dinitroazetidine (RRx-001) to downregulate the expression of innate immune checkpoint molecule, cluster of differentiation 47 (CD47), provides a powerful means for treating advanced HCC containing abundant immunosuppressive macrophages. Herein engineering of a previously optimized Doxorubicin (DOX)-delivery nanoplatform based on sodium alginate is reported to further co-deliver RRx-001 (biotinylated aldehyde alginate-doxorubicin micelle prodrug nanoplatform, BEA-D@R) for efficient immunotherapy of advanced HCC. This groundbreaking technique reveals the "all-in-one" immunotherapeutic functionalities of RRx-001. Besides the previously demonstrated functions of downregulating CD47 expression and increasing reactive nitrogen species (RNS) generation, another key function of RRx-001 for downregulating the expression of the adaptive immune checkpoint molecule programmed cell death 1 ligand 1 (PDL1) is first uncovered here. Combined with the reactive oxygen species (ROS) generation and an upregulated "eat me" signal level of DOX, BEA-D@R collectively increases RNS generation, enhances T-cell infiltration, and maximizes macrophage phagocytosis, leading to an average of 40% tumor elimination in a mice model bearing an initial tumor volume of ≈300 mm3 that mimics advanced HCC. Overall, the "all-in-one" immunotherapeutic functionalities of a clinical translatable nanoplatform are uncovered for enhanced immunotherapy of advanced HCC.
Insights
This study introduces a novel nanoplatform (BEA-D@R) for advanced hepatocellular carcinoma (HCC) treatment. It co-delivers RRx-001 and Doxorubicin to enhance immunotherapy by targeting immune checkpoints and promoting tumor elimination.
Area of Science:
- Oncology
- Immunotherapy
- Nanomedicine
Background:
- Advanced hepatocellular carcinoma (HCC) presents significant clinical challenges.
- Targeting immune checkpoints like CD47 and PD-L1 is crucial for effective HCC immunotherapy.
- Immunosuppressive macrophages in HCC hinder anti-tumor immune responses.
Purpose of the Study:
- To engineer a novel nanoplatform for co-delivery of RRx-001 and Doxorubicin (DOX) for advanced HCC immunotherapy.
- To uncover the full "all-in-one" immunotherapeutic potential of RRx-001.
- To enhance anti-tumor immunity by modulating immune checkpoints and macrophage activity.
Main Methods:
- Development of a biotinylated aldehyde alginate-doxorubicin micelle prodrug nanoplatform (BEA-D@R) for co-delivering RRx-001 and DOX.
- Evaluation of RRx-001's role in downregulating CD47 and PD-L1 expression.
- Assessment of the nanoplatform's effect on reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation, T-cell infiltration, and macrophage phagocytosis in a mouse model.
Main Results:
- The BEA-D@R nanoplatform effectively co-delivers RRx-001 and DOX, downregulating both CD47 and PD-L1.
- RRx-001 demonstrates novel function in downregulating PD-L1, in addition to CD47.
- The combined therapy significantly increased RNS generation, enhanced T-cell infiltration, and maximized macrophage phagocytosis, leading to an average of 40% tumor elimination in advanced HCC mouse models.
Conclusions:
- The BEA-D@R nanoplatform exhibits "all-in-one" immunotherapeutic functionalities for advanced HCC.
- RRx-001 plays a dual role in downregulating innate (CD47) and adaptive (PD-L1) immune checkpoints.
- This clinically translatable nanoplatform offers a promising strategy for enhanced HCC immunotherapy.
