Hijacking the hyaluronan assisted iron endocytosis to promote the ferroptosis in anticancer photodynamic therapy

  • Carbohydr Polym. 2025 Mar 1:351:123123. doi: 10.1016/j.carbpol.2024.123123.
Hong Deng  1 ,  Jiayu Chen  2 ,  Huimin Wang  1 ,  Runmeng Liu  1 ,  Yiyi Zhang  1 ,  Hui Chang  3 ,  Ching-Hsuan Tung  4 ,  Weiqi Zhang  5
Affiliations
  • 1. State Key Laboratory of Complex Severe and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, PR China.
  • 2. State Key Laboratory of Complex Severe and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, PR China; Key Laboratory of Resource Biology and Biotechnology in Western China, College of Life Sciences, Northwest University, Xi'an 710069, PR China.
  • 3. Key Laboratory of Resource Biology and Biotechnology in Western China, College of Life Sciences, Northwest University, Xi'an 710069, PR China.
  • 4. Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY 10065, USA.
  • 5. State Key Laboratory of Complex Severe and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, PR China. Electronic address: [email protected].
PMID: 39779030 DOI: 10.1016/j.carbpol.2024.123123
Abstract

Photodynamic therapy (PDT) eradicates tumor cells by the light-stimulated Reactive Oxygen Species, which also induces lipid peroxidation (LPO) and subsequently Ferroptosis, an iron-depended cell death. Ferroptosis has a tremendous therapeutic potential in Cancer treatment, however, the Ferroptosis efficiency is largely limited by the available iron in cells. Through hijacking the CD44-mediated iron endocytosis of hyaluronan (HA), here PDT with enhanced Ferroptosis was realized by a HA@Ce6 nanogel self-assembled from HA, a Photosensitizer Chlorin e6 (Ce6) and Fe3+ as cross-linkers. Taking advantages of HA's natural affinity towards CD44, HA@Ce6 enabled a targeted Ce6 delivery in CD44-overexpressed breast Cancer cells and meanwhile enhanced iron uptake to "fuel" Ferroptosis together with the light-stimulated LPO. Further, HA@Ce6 demonstrated an excellent Anticancer PDT efficacy and Ferroptosis induction in the murine 4 T1 xenograft model. This HA@Ce6 successfully exploited the role of HA in iron transport to sensitize Ferroptosis, providing a potent strategy to facilitate the Anticancer PDT.

Keywords
Chlorin e6; Ferroptosis; Hyaluronan; Nanogels; Photodynamic therapy; iron transport.
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