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已发表论文
RGD 修饰的负载 SAHA 金纳米颗粒通过抑制 HIF-1α-VEGF 信号重塑低氧炎症微环境以增强非小细胞肺癌的放射敏感性
Authors Lin J, Huang X, Wang X, Yu R, Liang J, Song R, Chen W , Shen G
Received 1 April 2025
Accepted for publication 9 October 2025
Published 10 December 2025 Volume 2025:20 Pages 14753—14785
DOI https://doi.org/10.2147/IJN.S531731
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. RDK Misra
Junqi Lin,1,* Xiaoming Huang,1,* Xizhen Wang,1 Ruilin Yu,1 Jie Liang,1 Rui Song,1 Wenbiao Chen,2 Guanle Shen1
1Department of Respiratory Medicine, People’s Hospital of Longhua Shenzhen, Shenzhen, 518109, People’s Republic of China; 2Department of Gastroenterology, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Guanle Shen, Department of respiratory medicine, People’s Hospital of Longhua Shenzhen, No. 38, Jinglong Construction Road, Longhua District, Shenzhen, Guangdong, 518109, People’s Republic of China, Tel +86 0755 29572571, Email shenguanlelh@163.com Wenbiao Chen, Department of Gastroenterology, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, People’s Republic of China, Tel +86 0755 25533018, Email chanwenbiao@sina.com
Objective: This research explored the effectiveness of RGD peptide-functionalized gold nanoparticles (AuNPs) loaded with the histone deacetylase inhibitor SAHA (suberoylanilide hydroxamic acid) to enhance the radiosensitivity of non-small cell lung cancer (NSCLC) by suppressing hypoxia signaling, thereby mitigating oxidative stress and inflammatory responses.
Methods: RGD-AuNPs-SAHA was synthesized via citrate reduction, thiol-gold bonding for RGD modification, and SAHA loading. Structural and chemical characteristics were assessed via dynamic light scattering (DLS), transmission electron microscopy (TEM), UV-Vis spectroscopy, high-performance liquid chromatography (HPLC), Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and X-ray photoelectron spectroscopy (XPS). Elemental distribution was mapped using TEM-EELS. Drug release behavior was evaluated under neutral and acidic conditions (pH 7.4 and 5.5). SAHA release kinetics were assessed at pH 7.4 and 5.5. Cellular uptake and biodistribution were evaluated in A549 cells and xenograft mice using fluorescence labeling and flow cytometry. Therapeutic efficacy was examined via tumor volume measurement, serum cytokine profiling (TNF-α, IL-6, IL-10), oxidative stress markers (SOD, CAT, MDA), and molecular analyses (IHC, IF, Western blot, RT-PCR). DNA damage and apoptosis were quantified using TUNEL and γ-H2AX staining.
Results: RGD-AuNPs-SAHA exhibited uniform size (~20 nm), high SAHA encapsulation (85.2%), and pH-responsive release (60% at pH 5.5 vs 35% at pH 7.4). XPS and EELS mapping further verified the formation of Au–S bonds between thiol-modified RGD and the AuNP surface. Quantitative analysis of surface-bound RGD peptides was performed using UV-Vis spectroscopy combined with the Levenberg–Marquardt algorithm. In vivo, RGD-AuNPs-SAHA reduced tumor volume by 60% and modulated inflammatory cytokines (↓TNF-α/IL-6, ↑IL-10). Oxidative stress markers improved significantly (SOD: 110 U/mL; CAT: 85 U/mL; MDA: ↓ 2 nmol/mL). Hypoxia signaling proteins HIF-1α and VEGF decreased by 50% and 40%, respectively, confirmed by Western blot and RT-PCR. Apoptosis and DNA damage markers increased by 70% (TUNEL) and 65% (γ-H2AX), demonstrating enhanced radiosensitization.
Conclusion: RGD-AuNPs-SAHA effectively remodeled the hypoxic tumor microenvironment, attenuated oxidative stress, and suppressed pro-tumorigenic signaling, leading to significant apoptosis and DNA damage. These findings highlight its potential as a radiosensitizer for NSCLC, offering a promising strategy to improve radiation therapy outcomes.
Keywords: gold nanoparticles, RGD peptide, hypoxic microenvironment, radiosensitivity, non-small cell lung cancer
1Department of Respiratory Medicine, People’s Hospital of Longhua Shenzhen, Shenzhen, 518109, People’s Republic of China; 2Department of Gastroenterology, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Guanle Shen, Department of respiratory medicine, People’s Hospital of Longhua Shenzhen, No. 38, Jinglong Construction Road, Longhua District, Shenzhen, Guangdong, 518109, People’s Republic of China, Tel +86 0755 29572571, Email shenguanlelh@163.com Wenbiao Chen, Department of Gastroenterology, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, People’s Republic of China, Tel +86 0755 25533018, Email chanwenbiao@sina.com
Objective: This research explored the effectiveness of RGD peptide-functionalized gold nanoparticles (AuNPs) loaded with the histone deacetylase inhibitor SAHA (suberoylanilide hydroxamic acid) to enhance the radiosensitivity of non-small cell lung cancer (NSCLC) by suppressing hypoxia signaling, thereby mitigating oxidative stress and inflammatory responses.
Methods: RGD-AuNPs-SAHA was synthesized via citrate reduction, thiol-gold bonding for RGD modification, and SAHA loading. Structural and chemical characteristics were assessed via dynamic light scattering (DLS), transmission electron microscopy (TEM), UV-Vis spectroscopy, high-performance liquid chromatography (HPLC), Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and X-ray photoelectron spectroscopy (XPS). Elemental distribution was mapped using TEM-EELS. Drug release behavior was evaluated under neutral and acidic conditions (pH 7.4 and 5.5). SAHA release kinetics were assessed at pH 7.4 and 5.5. Cellular uptake and biodistribution were evaluated in A549 cells and xenograft mice using fluorescence labeling and flow cytometry. Therapeutic efficacy was examined via tumor volume measurement, serum cytokine profiling (TNF-α, IL-6, IL-10), oxidative stress markers (SOD, CAT, MDA), and molecular analyses (IHC, IF, Western blot, RT-PCR). DNA damage and apoptosis were quantified using TUNEL and γ-H2AX staining.
Results: RGD-AuNPs-SAHA exhibited uniform size (~20 nm), high SAHA encapsulation (85.2%), and pH-responsive release (60% at pH 5.5 vs 35% at pH 7.4). XPS and EELS mapping further verified the formation of Au–S bonds between thiol-modified RGD and the AuNP surface. Quantitative analysis of surface-bound RGD peptides was performed using UV-Vis spectroscopy combined with the Levenberg–Marquardt algorithm. In vivo, RGD-AuNPs-SAHA reduced tumor volume by 60% and modulated inflammatory cytokines (↓TNF-α/IL-6, ↑IL-10). Oxidative stress markers improved significantly (SOD: 110 U/mL; CAT: 85 U/mL; MDA: ↓ 2 nmol/mL). Hypoxia signaling proteins HIF-1α and VEGF decreased by 50% and 40%, respectively, confirmed by Western blot and RT-PCR. Apoptosis and DNA damage markers increased by 70% (TUNEL) and 65% (γ-H2AX), demonstrating enhanced radiosensitization.
Conclusion: RGD-AuNPs-SAHA effectively remodeled the hypoxic tumor microenvironment, attenuated oxidative stress, and suppressed pro-tumorigenic signaling, leading to significant apoptosis and DNA damage. These findings highlight its potential as a radiosensitizer for NSCLC, offering a promising strategy to improve radiation therapy outcomes.
Keywords: gold nanoparticles, RGD peptide, hypoxic microenvironment, radiosensitivity, non-small cell lung cancer