Tumor-Targeting NHC-Au(I) Complex Induces Immunogenic Cell Death in Hepatocellular Carcinoma
Zhibin Yang1,2, Mianli Bian1, Lin Lv1
1Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China.
Abstract:
Immunogenic cell death (ICD) is a promising direction of cancer immunotherapy in hepatocellular carcinoma (HCC). A series of novel NHC-Au(I) complexes derived from 4,5-diarylimidazole, containing glycyrrhetinic acid (GA) as an efficient targeting ligand for HCC, were herein designed and synthesized. Among these, complex 4C exhibited excellent effectiveness for tumor targeting and antitumor activity, which induced the occurrence of ICD in HCC cells. Additionally, 4C can effectively inhibit TrxR enzyme activity, increase reactive oxygen species (ROS) expression, lead to redox homeostasis disorder, mediate mitochondrial dysfunction and endoplasmic reticulum stress (ERS), and cause the characteristic discharge of damage-associated molecular patterns (DAMPs) in HCC cells. More importantly, 4C showed a great ICD-inducing effect in a vaccination mouse model and activated antitumor immunity in a tumor-bearing C57BL/6 mouse model, which is consistent with the in vitro results. In conclusion, we found the potential of Au(I) complex with HCC-targeted capability for effective tumor immunotherapy.
Insights
Researchers developed a novel gold(I) complex targeting hepatocellular carcinoma (HCC) that induces immunogenic cell death (ICD). This compound shows promise for effective cancer immunotherapy by activating antitumor immunity.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Immunogenic cell death (ICD) is a crucial immunotherapy strategy for hepatocellular carcinoma (HCC).
- Targeted drug delivery systems are needed to enhance therapeutic efficacy in HCC treatment.
Purpose of the Study:
- To design and synthesize novel NHC-Au(I) complexes for HCC targeting and immunotherapy.
- To evaluate the ICD-inducing potential and antitumor activity of these complexes in HCC.
Main Methods:
- Synthesis of NHC-Au(I) complexes incorporating glycyrrhetinic acid (GA) for HCC targeting.
- In vitro assessment of complex 4C's effect on ICD markers, ROS levels, redox balance, mitochondrial function, and ER stress in HCC cells.
- In vivo evaluation of complex 4C's ICD-inducing effect and antitumor immunity activation in mouse models.
Main Results:
- Complex 4C demonstrated significant tumor targeting and antitumor activity.
- 4C induced ICD in HCC cells by inhibiting TrxR, increasing ROS, disrupting redox homeostasis, causing mitochondrial dysfunction, and ER stress.
- 4C effectively induced ICD and activated antitumor immunity in vivo.
Conclusions:
- The synthesized Au(I) complex 4C exhibits potent HCC-targeting capability and induces immunogenic cell death.
- Complex 4C holds significant potential for developing effective cancer immunotherapies against HCC.
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