2. Academic Validation
  3. Functional doxorubicin and iron ions dual-loaded carboxymethyl chitin-based microspheres for hepatocellular carcinoma therapy via embolization, ferroptosis, and autophagy-mediated HIF-1α inhibition

Functional doxorubicin and iron ions dual-loaded carboxymethyl chitin-based microspheres for hepatocellular carcinoma therapy via embolization, ferroptosis, and autophagy-mediated HIF-1α inhibition

  • Int J Pharm. 2026 Mar 10:692:126628. doi: 10.1016/j.ijpharm.2026.126628.
Fan Leng 1,  Sai Lei 2,  Si-Han Zhang 2,  Cui Hu 2,  Liu-Gen Li 2,  Ya-Dong Hao 3,  Sheng Chen 2,  Cunqing Kong 2,  Enfu Du 4,  Ning Han 5,  Tong-Fei Li 6
Affiliations

Affiliations

  • 1 Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China; Center for Translational Medicine, Suizhou Hospital, Hubei University of Medicine, Suizhou, Hubei 441300, China; Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China.
  • 2 Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China.
  • 3 Medical Imaging Center, Taihe Hospital, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China.
  • 4 Medical Imaging Center, Taihe Hospital, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China. Electronic address: [email protected].
  • 5 Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China. Electronic address: [email protected].
  • 6 Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China; Center for Translational Medicine, Suizhou Hospital, Hubei University of Medicine, Suizhou, Hubei 441300, China. Electronic address: [email protected].
PMID: 41616983 DOI: 10.1016/j.ijpharm.2026.126628
Abstract

Embolic microspheres have been applied in transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC), a promising anti-cancer strategy. Herein, our team prepared functional doxorubicin (DOX) and iron ions dual-loaded acrylic acid-grafted carboxymethyl chitin microspheres (CMA) microspheres (CMA/DOX-Fe), whose anti-HCC efficacy, targets, and molecular mechanisms were systematically investigated. The CMA/DOX-Fe were successfully constructed, as characterized by scanning electron microscopy, and exhibited favorable suspension and degradation properties with rapid adsorption of blood cells and procoagulant activity. Crucially, the strong embolic performance and anti-HCC efficacy of CMA/DOX-Fe were confirmed in rabbit models involving the marginal ear vein, renal vessels, and VX2 cell xenografts. Additionally, the CMA/DOX-Fe can trigger Ferroptosis and suppress HCC cells by releasing DOX and iron ions, which can also induce Autophagy through ATG5 binding. Furthermore, pronounced co-localization of HIF-1α and LC3-lysosomes was observed in the presence of CMA/DOX-Fe, demonstrating autophagy-mediated HIF-1α degradation and downstream signaling inhibition. Finally, the prepared CMA/DOX-Fe demonstrated a favorable safety profile and good biocompatibility. In conclusion, the as-synthesized CMA/DOX-Fe exhibits rapid embolization in HCC with subsequent release of DOX and iron ions, thereby inducing Ferroptosis and Autophagy. The autophagy-mediated suppression of the HIF-1α signaling pathway blocks metastasis of HCC. The present research provides a novel approach for Cancer TACE therapy with embolic microspheres.

Keywords

Autophagy; Carboxymethyl chitin-based embolic microspheres; HIF-1αsignaling pathway; Hepatocellular carcinoma; Transcatheter arterialchemoembolization.

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