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基于前药的组合纳米药物重塑脂质代谢以增强铁死亡和免疫激活。

Prodrug-based combinational nanomedicine remodels lipid metabolism for reinforced ferroptosis and immune activation.

作者信息

Lin Ling, Fang Zaixiang, Liu Guohao, Liu Yiwei, Li Zhiqian, Pan Dayi, Li Yunkun, Kang Hemi, Shen Xiaoding, Zhang Jingyao, Gong Qiyong, Luo Kui, Jing Jing

机构信息

Department of Radiology, Huaxi MR Research Center (HMRRC), Institution of Radiology and Medical Imaging, Breast Center, Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, Core Facilities, West China Hospital, Sichuan University, Chengdu 610041, China.

College of Chemical Engineering, Sichuan University, Chengdu 610041, China.

出版信息

Acta Pharm Sin B. 2025 May;15(5):2746-2763. doi: 10.1016/j.apsb.2025.03.016. Epub 2025 Mar 13.

DOI:10.1016/j.apsb.2025.03.016
PMID:40487644
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12145006/
Abstract

Ferroptosis is a form of programmed cell death characterized by overwhelmed lipid oxidation, and it has emerged as a promising strategy for cancer therapy. Enhanced ferroptosis could overcome the limitations of conventional therapeutic modalities, particularly in difficult-to-treat tumors. In this study, we developed a dual-modality therapy in nanomedicine by combining paclitaxel (PTX) chemotherapy and pyropheophorbide-a (Ppa) phototherapy. Heparin (HP) was grafted with poly(-(2'-hydroxy) propyl methacrylamide) (pHPMA) using reversible addition-fragmentation chain transfer polymerization to form HP-pHPMA (HH), which was utilized to deliver Ppa and PTX, yielding HP-pHPMA-Ppa (HH-Ppa) and HP-pHPMA-PTX (HH-PTX), respectively. The prodrug-based combinational nanomedicine (HH-PP) was formed by co-assembly of HH-PTX and HH-Ppa. It was found that HH-PP treatment significantly disrupted lipid metabolism in triple-negative breast cancer (TNBC) cells, induced extensive lipid oxidation, and promoted ferroptosis. , HH-PP intervention achieved a tumor growth inhibition rate of 86.63% and activated adaptive immunity with an elevated CD8 cytotoxic T cell infiltration level. This combinational nanomedicine offers a promising platform for co-delivery of multiple therapeutic agents. It exerts a promising anti-tumor effect enhanced ferroptosis and ferroptosis-induced immune activation by disrupting lipid metabolism in TNBC cancer cells.

摘要

铁死亡是一种程序性细胞死亡形式，其特征是脂质氧化过度，并且已成为一种有前景的癌症治疗策略。增强铁死亡可以克服传统治疗方式的局限性，尤其是在难以治疗的肿瘤中。在本研究中，我们通过将紫杉醇（PTX）化疗与焦脱镁叶绿酸-a（Ppa）光疗相结合，开发了一种纳米医学双模态疗法。使用可逆加成-断裂链转移聚合将肝素（HP）与聚（甲基丙烯酸-（2'-羟基）丙酯）（pHPMA）接枝，形成HP-pHPMA（HH），其用于递送Ppa和PTX，分别产生HP-pHPMA-Ppa（HH-Ppa）和HP-pHPMA-PTX（HH-PTX）。基于前药的组合纳米药物（HH-PP）由HH-PTX和HH-Ppa共组装形成。研究发现，HH-PP处理显著破坏三阴性乳腺癌（TNBC）细胞中的脂质代谢，诱导广泛的脂质氧化，并促进铁死亡。此外，HH-PP干预实现了86.63%的肿瘤生长抑制率，并通过提高CD8细胞毒性T细胞浸润水平激活适应性免疫。这种组合纳米药物为多种治疗剂的共递送提供了一个有前景的平台。它通过破坏TNBC癌细胞中的脂质代谢发挥有前景的抗肿瘤作用，增强铁死亡和铁死亡诱导的免疫激活。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/b417421634f4/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/7cd2ee2bf19a/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/92669fcfa011/sc1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/94cb06dba2bc/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/0b4302775335/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/af7ee2275bab/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/d9b02b022d8d/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/15b652afa190/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/4d831f8ec0b7/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/b417421634f4/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/7cd2ee2bf19a/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/92669fcfa011/sc1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/94cb06dba2bc/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/0b4302775335/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/af7ee2275bab/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/d9b02b022d8d/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/15b652afa190/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/4d831f8ec0b7/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca82/12145006/b417421634f4/gr7.jpg

相似文献

[1]
Prodrug-based combinational nanomedicine remodels lipid metabolism for reinforced ferroptosis and immune activation.

Acta Pharm Sin B. 2025-5

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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引用本文的文献

[1]
Biomaterials nanoplatform-based tumor vaccines for immunotherapy.

Bioact Mater. 2025-6-30

[2]
Improvement of the Anticancer Efficacy of PD-1/PD-L1 Blockade: Advances in Molecular Mechanisms and Therapeutic Strategies.

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本文引用的文献

[1]
Metformin-based nanomedicines for reprogramming tumor immune microenvironment.

Theranostics. 2025-1-1

[2]
The hallmarks of cancer immune evasion.

Cancer Cell. 2024-11-11

[3]
ROS-Responsive and Self-Catalytic Nanocarriers for a Combination of Chemotherapy and Reinforced Ferroptosis against Breast Cancer.

ACS Biomater Sci Eng. 2024-10-14

[4]
Singlet oxygen detection in vivo is hindered by nonspecific SOSG staining.

Sci Rep. 2024-9-5

[5]
Reprogramming the immunosuppressive tumor microenvironment through nanomedicine: an immunometabolism perspective.

EBioMedicine. 2024-9

[6]
Firing up "cold" tumors: Ferroptosis causes immune activation by improving T cell infiltration.

Biomed Pharmacother. 2024-10

[7]
Research Progress on Ferroptosis and Nanotechnology-Based Treatment in Triple-Negative Breast Cancer.

Breast Cancer (Dove Med Press). 2024-7-15

[8]
Biomarker-driven molecular imaging probes in radiotherapy.

Theranostics. 2024

[9]
Hydrophilic biomaterials: From crosslinked and self-assembled hydrogels to polymer-drug conjugates and drug-free macromolecular therapeutics.

J Control Release. 2024-9

[10]
Ferroptotic therapy in cancer: benefits, side effects, and risks.

Mol Cancer. 2024-5-3

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