Glutathione Depletion‐Induced Activation of Dimersomes for Potentiating the Ferroptosis and Immunotherapy of “Cold” Tumor

The abundant glutathione (GSH) in “cold” tumors weakens ferroptosis therapy and the immune response. Inspired by lipids, we fabricated cinnamaldehyde dimers (CDC) into lipid‐like materials to form dimersomes capable of depleting GSH and delivering therapeutics to potentiate the ferroptosis and immun...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2022-05, Vol.61 (22), p.e202202843-n/a
Main Authors: Zhou, Zhanwei, Liang, Huan, Yang, Ruoxi, Yang, Ying, Dong, Jingwen, Di, Yongxiang, Sun, Minjie
Format: Article
Language:English
Subjects:
Animals
Breast cancer
Cancer Immunotherapy
CD8 antigen
CD8-Positive T-Lymphocytes
Cell Line, Tumor
Cinnamaldehyde
Conjugation
Cytosol
Dendritic cells
Depletion
Drug Delivery
Ferroptosis
Fluorescence
Glutathione
GSH Depletion
Immune response
Immune system
Immunotherapy
Lipids
Lymphocytes
Lymphocytes T
Mice
Neoplasms - drug therapy
Priming
Shelf life
Sorafenib - pharmacology
Sorafenib - therapeutic use
Storage stability
Tumors
Vesicles
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Summary:The abundant glutathione (GSH) in “cold” tumors weakens ferroptosis therapy and the immune response. Inspired by lipids, we fabricated cinnamaldehyde dimers (CDC) into lipid‐like materials to form dimersomes capable of depleting GSH and delivering therapeutics to potentiate the ferroptosis and immunotherapy of breast cancer. The dimersomes exhibited superior storage stability for over one year. After reaching the tumor, they quickly underwent breakage in the cytosol owing to the conjugation of hydrophilic GSH on CDC by Michael addition, which not only triggered the drug release and fluorescence switch “ON”, but also led to the depletion of intracellular GSH. Ferroptosis was significantly enhanced after combination with sorafenib (SRF) and elicited a robust immune response in vivo by promoting the maturation of dendritic cells and the priming of CD8+ T cells. As a result, the CDC@SRF dimersomes cured breast cancer in all the mice after four doses of administration. Vesicles based on cinnamaldehyde dimers (CDC dimersomes) were prepared to enhance the ferroptosis and immunotherapy of “cold” tumors. The dimersomes depleted intracellular glutathione (GSH) by in situ Michael addition and underwent breakage during GSH depletion, which promoted the release of the drug contained inside the vesicle and switching “ON” of near‐infrared (NIR) dyes.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202202843