期刊
SMALL METHODS
卷 -, 期 -, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/smtd.202200888
关键词
combinatory therapy; dual stimuli-responsive; ferroptosis; immunotherapy; pancreatic cancer
资金
- National Natural Science Foundation of China [81972287, 51873228]
- Science and Technology Commission of Shanghai Municipality [20430711800, 19ZR1447600]
- Open Funds of State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, CAS [SIMM2105KF-12]
This study reveals that a combination therapy of dihydroartemisinin (DHA) and RSL-3 can induce ferroptosis of pancreatic ductal adenocarcinoma (PDAC) tumor cells. Nanoparticles that can deliver DHA and RSL-3 are synthesized and shown to inhibit tumor growth effectively in mouse models. This study provides novel insights for the treatment of PDAC with ferroptosis-based immunotherapy.
Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and resistant to conventional therapies, including chemo-, radio-, and immunotherapy. In this study, it is first determined that a combination of dihydroartemisinin (DHA) and RSL-3 (a glutathione peroxidase 4 (GPX4) inhibitor) markedly induced ferroptosis of PDAC tumor cells. A mechanistic study revealed that DHA can react with iron ions to generate carbon radicals and deplete intracellular glutathione, thereby cumulatively triggering the lipid peroxidation of tumor cells with RSL-3-mediated GPX4 inhibition. A DHA-conjugated amphiphilic copolymer is subsequently synthesized, and intracellular acidity and oxidation dual-responsive DHA nanoparticles are further engineered for the tumor-specific co-delivery of DHA and RSL-3. The resultant nanoparticles (PDBA@RSL-3) efficiently induce ferroptosis of tumor cells in the Panc02 tumor-bearing immune-deficient mouse model, and elicit T-cell-based antitumor immunity in the immune-competent mouse model. The combination of PDBA@RSL-3 nanoparticles and programmed death ligand 1 blockade therapy efficiently inhibits PDAC tumor growth in the immune-competent mouse models. This study may provide novel insights for treatment of PDAC with ferroptosis-based immunotherapy.
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