Metal-drug self-delivery nanomedicine alleviates tumor immunosuppression to potentiate synergistic chemo/chemodynamic therapy against hepatocellular carcinoma
image: (A) Tumor growth profiles after the different treatments (mean ± SD, n = 4). The subcutaneous tumor model of hepatocellular carcinoma (HCC) was established by injecting 1 × 107 HepG2 cells subcutaneously into the right leg of female BALB/c nude mice aged 4-5 weeks. Once the tumor volume reached approximately 50 mm³, the mice were randomly divided into five groups: PBS, DOX, FDH, FDAP, and FDAH. Nanoparticles were administered intravenously every two days at a dose equivalent to 10 mg/kg of DOX. Tumor growth and body weight were monitored every two days. (B) The inhibition rate of the tumor after the different treatments (mean ± SD, n = 4). (C) Photos of the tumors excised from the mice after the different treatments. (D) The weight of the tumors excised from the mice after the different treatments (mean ± SD, n = 4). #, P < 0.05; ##, P < 0.01 between indicated group and PBS group; ∗, P < 0.05; ∗∗, P < 0.01 between indicated groups. (E) H&E staining of the excised tumors after the different treatments. Scale bar = 200 μm.
Credit: Guo C, Dou R, Wang L B, et al.
Hepatocellular carcinoma (HCC) ranks as the sixth most commonly diagnosed cancer worldwide, and is the third leading cause of cancer-related deaths. Despite continuous research advances, half of all patients succumbto disease progression each year. Systemic chemotherapy continues to be a first-line clinical option, yet its efficacy is limited.”
"The liver possesses unique immune tolerance mechanisms, which act as a natural barrier to protect the organ,” explains Professor Han-Qing Chen, corresponding author of a new study published in Fundamental Research. “However, this organ has also unexpectedly become a stumbling block for chemotherapy—it creates a highly immunosuppressive microenvironment that significantly weakens the chemotherapeutic effect."
Chen, who is from the Department of Nutrition & Food Hygiene, School of Public Health, Capital Medical University, built the study on a fundamental question: can we reshape this microenvironment while administering chemotherapy, achieving a dual-pronged approach?"
The team's breakthrough came from the clever design of a self-delivering metal-drug nanomedicine named FDAH. The system features an iron-based framework co-loaded with the chemotherapeutic drug Doxorubicin (DOX) and the immunomodulatory agent Plerixafor (AMD3100), encapsulated within a hyaluronic acid (HA) shell that enables tumor targeting. The success of this nanoplatform stems from three synergistic mechanisms:
- Precision Drug Delivery: Leveraging the EPR effect and HA/CD44-specific interactions, the nanodrugs efficiently accumulate in and enter tumor cells, releasing their therapeutic "weapons" precisely where needed.
- Chemodynamic-Chemotherapy Synergy: Iron ions released intracellularly trigger the Fenton reaction, generating reactive oxygen species (ROS). This not only directly damages tumor cells but also disrupts their redox homeostasis, sensitizing them to subsequent DOX chemotherapy.
- Reversal of the Immunosuppressive Microenvironment: AMD3100 blocks the CXCL12/CXCR4 axis, effectively inhibiting the recruitment of immunosuppressive cells. This helps convert "cold" tumors into "hot" ones, creating a more favorable immune context for chemotherapy.
“In proof-of-concept studies, this multi-mechanism strategy demonstrated significant tumor suppression with minimal systemic toxicity.” says Chen. "This nanoplatform does not require a complex carrier; it enables coordinated delivery of multiple drugs on its own.”
The study, conducted collaboratively by a team comprising researchers from the Institute of High Energy Physics (Chinese Academy of Sciences) and Peking University Third Hospital, presents a promising paradigm for enhancing chemotherapy outcomes in HCC. The team's future work will focus on advancing this technology toward clinical translation.
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Contact the author: Jun Chen, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Multi-disciplinary Research Division, Institute of High Energy Physics and University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, China, chenjun@ihep.ac.cn
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