BIOMATERIALS
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2025
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IF 12.9
Hao Tian,Hongpei Deng,Xinlong Liu,Chang Liu,Chuan Zhang,Kam W. Leong,Jing Ruan,Xianqun Fan
Uveal melanoma (UM) is the most prevalent primary ocular malignancy in adults, with high lethality and limited effective treatment options. Despite identified driver mutations in GNAQ , GNA11 , and BAP1 , therapeutic advancements have been minimal. This study highlights the pivotal role of N6-methyladenosine (m 6 A) modifications in UM pathogenesis and progression, focusing on the demethylase FTO as a therapeutic target. Elevated FTO expression in UM tissues correlates with decreased m 6 A levels, increased aggressiveness, and poor prognosis. The FTO inhibitor meclofenamic acid (MA) restored m 6 A levels, upregulated SLC7A11, and induced disulfidptosis, a unique form of cell death triggered by GSH depletion and NADPH consumption. To address MA's limitations in bioavailability and tumor targeting, we developed an MA-loaded nucleic acid nanodrug (SNAMA). SNAMA demonstrated effective tumor growth inhibition in orthotopic and metastatic UM models through GSH-responsive release and m 6 A-mediated disulfidptosis activation. Incorporating a PD-L1 aptamer into SNAMA further improved tumor targeting and immune modulation, enhancing therapeutic efficacy. This study identifies FTO as a critical target for UM therapy and introduces SNAMA-apt as a promising nanodrug. The findings offer a foundation for m 6 A-targeted approaches in UM and other malignancies, addressing bioavailability, targeting, and immune evasion challenges.
研究领域:
肿瘤学
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分子生物学
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药理学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
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2024
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IF 4.4
Hui-Zhen Yang,Jia-Jia Chen,Lan Zhang,Xiao-Li Tian,Rong Wang,Lin Pu,Xiao-Qi Yu,Ji Zhang
Nitric oxide (NO) / β-Lapachone (Lap) combined therapy by causing oxidative stress is an effective tumor therapy strategy. Herein, a dual-responsive lipid nanoparticles (LNPs) LSNO for NO / Lap co-delivery were constructed from the zinc-coordinated lipid ( DSNO(Zn) ) and the hydrophobic drug Lap in the presence of helper lipids (DOPE and DSPE-PEG 2000 ). The zinc-coordinated structure in LSNO might elevate the Zn 2+ content in tumor cells, contributing to antioxidant imbalance. The fluorescent assays proved the light-triggered NO release and fluorescent self-reporting abilities of LSNO . In addition, the LNPs had good drug release behavior under high concentration of GSH, indicating the NO / drug co-delivery capacity. In vitro antitumor assays showed that the NO / Lap combination treatment group could induce more significant tumor cell growth inhibition and cell apoptosis than individual NO or Lap treatment. The following mechanism studies revealed that NO / Lap combination treatment led to distinct oxidative stress by producing reactive oxygen species (ROS) and peroxynitrite anion (ONOO – ). On the other hand, the intracellular redox balance could be further disrupted by Lap-induced NADPH consumption and Zn 2+ / NO-induced reductase activities downregulation, thus promoting the degree of cell damage. Besides, it was also found that NO and Lap could directly damage nuclear DNA and induce mitochondrial dysfunction, thereby leading to caspase-3 activation and tumor cell death. These results proved that LSNO could serve as a promising multifunctional tumor therapy platform.
研究领域:
药学
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纳米技术
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癌症研究
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2023
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IF 8.2
Fangying Yu,Xuwei Shang,Zixu Wang,Yun Zhu,Simin Chen,Hong Yuan,Fuqiang Hu
Ferroptosis as promising antitumor therapy strategy could be comprised by intracellular antioxidants, especially GSH and thioredoxin (Trx). They are both cofactors of Gpx4, the enzyme catalyzing the production of lipid peroxides to relieve oxidative stress, which drives the acquired ferroptosis resistance in tumors. Herein, the NADPH-consuming micelles are specially designed, which could collaborate with the ROS generating photodynamics therapy (PDT) by depleting intracellular GSH and Trx under hypoxia condition, resulting in ruined redox homeostasis and the final cascade amplified ferroptosis. The tailored micelle was briefly prepared by conjugating hypoxia-sensitive segment p-nitrobenzyl chloroformate (PNZ-Cl) to the hydrophilic chitosan (CS), the resulting micelle was further modified with photosensitizer Ce6 via PEG linkage. When receiving laser irradiation, the photosensitizer would generate ROS and consume oxygen in the meanwhile. The resulting anabatic hypoxia in turns promote the NTR-catalyzed electron-accepting response of micelles, with evidently enhanced NADPH consumption and ultimately ruined redox homeostasis, contributing to cascade amplified ferroptosis with robust ROS. Most importantly, the accompanied immunogenic cell death (ICD) and releasing danger-associated molecular patterns (DAMPs) could boost dendritic cells (DCs) maturation and the subsequent T-cell-mediated profound immune response. Collectively, the work excavates the other biochemical reaction during the hypoxia-sensitive process of C–N–Ce6 by diminishing intracellular GSH and Trx, providing a candidate of ferroptosis inducers against solid tumors.
研究领域:
癌症生物学
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药学
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免疫治疗
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生物化学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）