In situ tuning proangiogenic factor-mediated immunotolerance synergizes the tumoricidal immunity via a hypoxia-triggerable liposomal bio-nanoreactor.

Abstract

Rationale: Vascular abnormality stemming from the hypoxia-driven elevation of proangiogenic factors is a hallmark for many solid malignant tumors, including colorectal cancer (CRC) and its liver metastasis. We report a hypoxia-triggered liposome-supported metal-polyphenol-gene bio-nanoreactor to tune the proangiogenic factor-mediated immunotolerance and synergize the elicited tumoricidal immunity for CRC treatment. Methods: With the aid of polyphenol gallic acid, Cu2+ ion-based intracellular bio-nanoreactor was synthesized for the delivery of small interfering RNA targeting vascular endothelial growth factor and then cloaked with a hybrid liposomal membrane that harbored a hypoxia-responsive azobenzene derivative. In hypoxic tumor, the liposomal shell disintegrated, and a shrunk-size bio-nanoreactor was burst released. Intracellularly, Cu2+ from the bio-nanoreactor catalyzed a Fenton-like reaction with glutathione, which efficiently converted H2O2 to •OH and enabled a chemodynamic therapy (CDT) in tumor sites. With the alleviation of proangiogenic factor-mediated immunotolerance and high production of CDT-induced tumor-associated antigens, robust tumoricidal immunity was co-stimulated. Results: With colorectal tumor and its liver metastasis models, we determined the underlying mechanism of proangiogenic factor-mediated immunotolerance and highlighted that the liposomal bio-nanoreactor could create positive feedback among the critical players in the vascular endothelium and synergize the elicited tumoricidal immunity. Conclusion: Our work provides an alternative strategy for exerting efficient tumoricidal immunity in the proangiogenic factor-upregulated subpopulation of CRC patients and may have a wide-ranging impact on cancer immune-anti-angiogenic complementary therapy in clinics.

• Authors: Chen Chen, Shengchang Zhang, Rui Zhang, Peng Sun, Chongdeng Shi, Mohnad Abdalla, Anning Li, Jiawen Xu, Wei Du, Jing Zhang, Ying Liu, Chunwei Tang, Zhenmei Yang, Xinyi Jiang
• Journal: Theranostics (Theranostics) Vol. 10 Issue 26 Pg. 11998-12010 ( 2020) ISSN: 1838-7640 [Electronic] Australia
• PMID: 33204325 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Angiogenesis Inhibitors
• Liposomes
• Polyphenols
• RNA, Small Interfering
• Reactive Oxygen Species
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Gallic Acid
• Copper

Topics

• Angiogenesis Inhibitors (administration & dosage)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy, immunology, pathology)
• Copper (chemistry)
• Drug Synergism
• Female
• Gallic Acid
• Humans
• Liposomes
• Liver Neoplasms (drug therapy, immunology, secondary)
• Metal Nanoparticles (administration & dosage, chemistry)
• Mice
• Polyphenols (chemistry)
• RNA, Small Interfering (administration & dosage)
• Reactive Oxygen Species (metabolism)
• Theranostic Nanomedicine (methods)
• Tumor Escape (drug effects)
• Tumor Hypoxia (drug effects, genetics, immunology)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, genetics)
• Xenograft Model Antitumor Assays