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已发表论文
通过 DPPA-LNPs 共递送化疗药物和抗血管生成脂质可增强抗 PD-1 免疫疗法的效果
Authors Tan J, Fang J , Luo W, Chen X, Liang Y, Huang Z, Tan S, Ren M, Xu X , Zhang W , Saw PE
Received 4 June 2025
Accepted for publication 22 October 2025
Published 25 November 2025 Volume 2025:20 Pages 14057—14073
DOI https://doi.org/10.2147/IJN.S544668
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Dong Wang
Jiabao Tan,1– 3,* Junyue Fang,1,2,4,* Wanrong Luo,1,2,5,* Xiaojiang Chen,6 Yixia Liang,1,2 Ziqi Huang,1,2 Shiyu Tan,1,2 Meng Ren,3 Xiaoding Xu,1,2 Wenyue Zhang,1,2,5 Phei Er Saw1,2
1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China; 2Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, People’s Republic of China; 3Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 4Cellular and Molecular Diagnostics Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China; 5Department of Ultrasound, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China; 6Department of Gastric Surgery, Sun Yat-sen University Cancer Center; Sun Yat-sen University, Guangzhou, 510060, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Wenyue Zhang, Email zhangwy226@mail.sysu.edu.cn Phei Er Saw, Email caipeie@mail.sysu.edu.cn
Background: Immune checkpoint inhibitor (ICI) therapies have marked a significant breakthrough in tumor immunotherapy. However, their clinical efficacy remains suboptimal in many cases. Emerging evidence indicates that resistance to ICIs is largely driven by the immunosuppressive nature of the tumor microenvironment (TME). Modulating the TME-through conventional chemotherapy or anti-angiogenic therapies has been shown to enhance immune activation and improve the therapeutic response to ICIs.
Methods: In this study, we developed epirubicin (EPI)-loaded lipid nanoparticles, termed DPPA(EPI) LNPs, which integrate the chemotherapeutic agent EPI with the anti-angiogenic lipid DPPA, enabling co-delivery and targeted enrichment within tumors. The cytotoxicity and anti-vascular endothelial cell tube formation properties of DPPA(EPI) LNPs were tested in vitro. The biosafety, anti-tumor ability and immunoactivities were tested on orthotopic tumor models of both breast cancer and hepatoma in vivo.
Results: DPPA(EPI) LNPs showed the advantages of uniformed particle size, high stability, good sustained-release effect. Compared to free drug, DPPA(EPI) LNPs significantly prolonged blood circulation (21.7% remaining at 12 h vs.16.5% at 30 min for free drug), enhanced tumor accumulation (18.4-fold change than free drug) and had well biological safety. In vivo, DPPA (EPI) LNPs showed excellent anti-tumor therapeutic efficacy by significantly inhibiting tumor cell proliferation (Ki67† cells reduced by 55%), reducing tumor angiogenesis (vascular density by 60%), and inducing stronger immunogenic cell death effect both in 4T1 orthotopic tumor model and Hepa1-6 orthotopic tumor model. And the treatment of DPPA (EPI) LNPs combined with programmed cell death protein 1 (PD-1) inhibitor further improved the activation of anti-tumor immunity in the TME, which leads to more significant inhibition of the tumor growth.
Conclusion: This dual-function nanoplatform—combining chemotherapy and anti-angiogenic therapy—substantially improved the efficacy of PD-1 blockade in both breast cancer and hepatocellular carcinoma (HCC) models. These findings offer a promising strategy and experimental foundation for TME modulation and the advancement of combination immunotherapy.
Keywords: dipalmitoyl phosphatidic acid, DPPA, programmed cell death protein 1, PD-1, tumor microenvironment, TME, immunogenic cell death, ICD, anti-angiogenesis
1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China; 2Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, People’s Republic of China; 3Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 4Cellular and Molecular Diagnostics Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China; 5Department of Ultrasound, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China; 6Department of Gastric Surgery, Sun Yat-sen University Cancer Center; Sun Yat-sen University, Guangzhou, 510060, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Wenyue Zhang, Email zhangwy226@mail.sysu.edu.cn Phei Er Saw, Email caipeie@mail.sysu.edu.cn
Background: Immune checkpoint inhibitor (ICI) therapies have marked a significant breakthrough in tumor immunotherapy. However, their clinical efficacy remains suboptimal in many cases. Emerging evidence indicates that resistance to ICIs is largely driven by the immunosuppressive nature of the tumor microenvironment (TME). Modulating the TME-through conventional chemotherapy or anti-angiogenic therapies has been shown to enhance immune activation and improve the therapeutic response to ICIs.
Methods: In this study, we developed epirubicin (EPI)-loaded lipid nanoparticles, termed DPPA(EPI) LNPs, which integrate the chemotherapeutic agent EPI with the anti-angiogenic lipid DPPA, enabling co-delivery and targeted enrichment within tumors. The cytotoxicity and anti-vascular endothelial cell tube formation properties of DPPA(EPI) LNPs were tested in vitro. The biosafety, anti-tumor ability and immunoactivities were tested on orthotopic tumor models of both breast cancer and hepatoma in vivo.
Results: DPPA(EPI) LNPs showed the advantages of uniformed particle size, high stability, good sustained-release effect. Compared to free drug, DPPA(EPI) LNPs significantly prolonged blood circulation (21.7% remaining at 12 h vs.16.5% at 30 min for free drug), enhanced tumor accumulation (18.4-fold change than free drug) and had well biological safety. In vivo, DPPA (EPI) LNPs showed excellent anti-tumor therapeutic efficacy by significantly inhibiting tumor cell proliferation (Ki67† cells reduced by 55%), reducing tumor angiogenesis (vascular density by 60%), and inducing stronger immunogenic cell death effect both in 4T1 orthotopic tumor model and Hepa1-6 orthotopic tumor model. And the treatment of DPPA (EPI) LNPs combined with programmed cell death protein 1 (PD-1) inhibitor further improved the activation of anti-tumor immunity in the TME, which leads to more significant inhibition of the tumor growth.
Conclusion: This dual-function nanoplatform—combining chemotherapy and anti-angiogenic therapy—substantially improved the efficacy of PD-1 blockade in both breast cancer and hepatocellular carcinoma (HCC) models. These findings offer a promising strategy and experimental foundation for TME modulation and the advancement of combination immunotherapy.
Keywords: dipalmitoyl phosphatidic acid, DPPA, programmed cell death protein 1, PD-1, tumor microenvironment, TME, immunogenic cell death, ICD, anti-angiogenesis