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血红蛋白纳米团簇介导的低氧肿瘤微环境中 KPNA4 的调控增强了肝癌的光动力治疗。

Hemoglobin nanoclusters-mediated regulation of KPNA4 in hypoxic tumor microenvironment enhances photodynamic therapy in hepatocellular carcinoma.

机构信息

Department of Anesthesiology, The First Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, China.

Department of breast surgery, The First Hospital of China Medical University, Shenyang, 110001, Liaoning Province, China.

出版信息

J Nanobiotechnology. 2024 Aug 9;22(1):473. doi: 10.1186/s12951-024-02717-9.

DOI:10.1186/s12951-024-02717-9
PMID:39135024
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11318167/
Abstract

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant tumor known for its hypoxic environment, which contributes to resistance against the anticancer drug Sorafenib (SF). Addressing SF resistance in HCC requires innovative strategies to improve tumor oxygenation and effectively deliver therapeutics. RESULTS: In our study, we explored the role of KPNA4 in mediating hypoxia-induced SF resistance in HCC. We developed hemoglobin nanoclusters (Hb-NCs) capable of carrying oxygen, loaded with indocyanine green (ICG) and SF, named HPRG@SF. In vitro, HPRG@SF targeted HCC cells, alleviated hypoxia, suppressed KPNA4 expression, and enhanced the cytotoxicity of PDT against hypoxic, SF-resistant HCC cells. In vivo experiments supported these findings, showing that HPRG@SF effectively improved the oxygenation within the tumor microenvironment and countered SF resistance through combined photodynamic therapy (PDT). CONCLUSION: The combination of Hb-NCs with ICG and SF, forming HPRG@SF, presents a potent strategy to overcome drug resistance in hepatocellular carcinoma by improving hypoxia and employing PDT. This approach not only targets the hypoxic conditions that underlie resistance but also provides a synergistic anticancer effect, highlighting its potential for clinical applications in treating resistant HCC.

摘要

背景：肝细胞癌 (HCC) 是一种高度恶性肿瘤，以其缺氧环境为特征，这导致其对抗癌药物索拉非尼 (SF) 产生耐药性。解决 HCC 中的 SF 耐药性需要创新策略来改善肿瘤氧合并有效输送治疗药物。

结果：在我们的研究中，我们探讨了 KPNA4 在介导 HCC 中缺氧诱导的 SF 耐药性中的作用。我们开发了能够携带氧气的血红蛋白纳米簇 (Hb-NCs)，并将其与吲哚菁绿 (ICG) 和 SF 负载，命名为 HPRG@SF。在体外，HPRG@SF 靶向 HCC 细胞，减轻缺氧，抑制 KPNA4 表达，并增强 PDT 对缺氧、SF 耐药 HCC 细胞的细胞毒性。体内实验支持了这些发现，表明 HPRG@SF 通过联合光动力疗法 (PDT) 有效改善了肿瘤微环境中的氧合作用，并克服了 SF 耐药性。

结论：将 Hb-NCs 与 ICG 和 SF 结合形成 HPRG@SF，提出了一种通过改善缺氧和利用 PDT 来克服肝细胞癌药物耐药性的有效策略。这种方法不仅针对耐药性的缺氧条件，而且还提供了协同的抗癌作用，突出了其在治疗耐药性 HCC 中的临床应用潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/79e2e37c57dc/12951_2024_2717_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/302ae4964f54/12951_2024_2717_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/e06303c3e47c/12951_2024_2717_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/a0980e1c06f1/12951_2024_2717_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/1449cff30339/12951_2024_2717_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/29b7995a4a3f/12951_2024_2717_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/c6915c99a0c4/12951_2024_2717_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/4385a7f25e4b/12951_2024_2717_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/4d88e62d83c1/12951_2024_2717_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/79e2e37c57dc/12951_2024_2717_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/302ae4964f54/12951_2024_2717_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/e06303c3e47c/12951_2024_2717_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/a0980e1c06f1/12951_2024_2717_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/1449cff30339/12951_2024_2717_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/29b7995a4a3f/12951_2024_2717_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/c6915c99a0c4/12951_2024_2717_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/4385a7f25e4b/12951_2024_2717_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/4d88e62d83c1/12951_2024_2717_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0810/11318167/79e2e37c57dc/12951_2024_2717_Fig9_HTML.jpg

相似文献

[1]
Hemoglobin nanoclusters-mediated regulation of KPNA4 in hypoxic tumor microenvironment enhances photodynamic therapy in hepatocellular carcinoma.

J Nanobiotechnology. 2024-8-9

[2]
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Hepatology. 2013-3-14

[3]
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J Photochem Photobiol B. 2023-2

[4]
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Drug Deliv. 2019-12

[5]
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Sci Rep. 2018-6-26

[6]
SOD1 inhibition enhances sorafenib efficacy in HBV-related hepatocellular carcinoma by modulating PI3K/Akt/mTOR pathway and ROS-mediated cell death.

J Cell Mol Med. 2024-7

[7]
Periostin contributes to arsenic trioxide resistance in hepatocellular carcinoma cells under hypoxia.

Biomed Pharmacother. 2017-4

[8]
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Acta Pharmacol Sin. 2024-8

[9]
DNMT3b/OCT4 expression confers sorafenib resistance and poor prognosis of hepatocellular carcinoma through IL-6/STAT3 regulation.

J Exp Clin Cancer Res. 2019-11-26

[10]
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Drug Deliv. 2018-11

本文引用的文献

[1]
pH-Responsive Sorafenib/Iron-Co-Loaded Mesoporous Polydopamine Nanoparticles for Synergistic Ferroptosis and Photothermal Therapy.

Biomacromolecules. 2024-1-8

[2]
RNA helicase DDX5 modulates sorafenib sensitivity in hepatocellular carcinoma via the Wnt/β-catenin-ferroptosis axis.

Cell Death Dis. 2023-11-30

[3]
Integrated single-cell transcriptomics reveals the hypoxia-induced inflammation-cancer transformation in NASH-derived hepatocellular carcinoma.

Cell Prolif. 2024-4

[4]
Roles of long non-coding RNAs in digestive tract cancer and their clinical application.

Zhejiang Da Xue Xue Bao Yi Xue Ban. 2023-8-25

[5]
Hyperthermia-triggered biomimetic bubble nanomachines.

Nat Commun. 2023-8-11

[6]
Fe-binding transferrin nanovesicles encapsulating sorafenib induce ferroptosis in hepatocellular carcinoma.

Biomater Res. 2023-7-1

[7]
Transcription factor glucocorticoid modulatory element-binding protein 1 promotes hepatocellular carcinoma progression by activating Yes-associate protein 1.

World J Gastrointest Oncol. 2023-6-15

[8]
Loss of LncRNA DUXAP8 synergistically enhanced sorafenib induced ferroptosis in hepatocellular carcinoma via SLC7A11 de-palmitoylation.

Clin Transl Med. 2023-6

[9]
Bioinformatics Identification of Regulatory Genes and Mechanism Related to Hypoxia-Induced PD-L1 Inhibitor Resistance in Hepatocellular Carcinoma.

Int J Mol Sci. 2023-5-13

[10]
Hemoglobin-stabilized gold nanoclusters displaying oxygen transport ability, self-antioxidation, auto-fluorescence properties and long-term storage potential.

RSC Adv. 2023-5-23

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