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用于联合免疫治疗的抗癌纳米笼平台,旨在利用免疫检查点并递送抗癌药物。

Anticancer nanocage platforms for combined immunotherapy designed to harness immune checkpoints and deliver anticancer drugs.

机构信息

Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea; CMRI, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea.

Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea.

出版信息

Biomaterials. 2021 Mar;270:120685. doi: 10.1016/j.biomaterials.2021.120685. Epub 2021 Jan 22.


DOI:10.1016/j.biomaterials.2021.120685
PMID:33524811
Abstract

The interaction of programmed cell death 1 ligand 1 (PD-L1) with its receptor, programmed cell death 1 (PD-1), inhibits T cell responses. Monoclonal antibodies that block this interaction have been shown effective as immunotherapy. However, only a subset of cancers exhibits a durable response to PD-1/PD-L1 blockade. Moreover, antibody-based immune checkpoint blockade is costly and is occasionally accompanied by systemic side effects. To overcome these limitations of antibody-based immune checkpoint blockade, an immune checkpoint-blocking ferritin nanocage displaying 24 PD-L1 binding peptides (PD-L1pep1) on its surface was designed and constructed. These ferritin nanocages displaying PD-L1pep1 (PpNF) specifically bind to PD-L1 expressed on cancer cells or to purified PD-L1 with a ~30 nM binding affinity. The addition of PpNF to co-cultures of T cells and cancer cells inhibited PD-1/PD-L1 interactions and restored T cell activities. In a mouse model of syngeneic colon cancer, PpNF specifically targeted tumors and showed antitumor activity. Moreover, PpNF nanocages encapsulating the chemotherapeutic drug doxorubicin had more potent antitumor activity than a monoclonal antibody against PD-L1. These results demonstrate that ferritin nanocages displaying surface PD-L1pep1 can be efficiently applied for immunotherapy, especially when encapsulating small chemotherapeutic drugs. These nanocages may have promise as an immunotherapeutic nanomedicine against various solid tumors.

摘要

程序性细胞死亡蛋白 1 配体 1(PD-L1)与其受体程序性细胞死亡蛋白 1(PD-1)的相互作用抑制了 T 细胞的反应。已证明阻断这种相互作用的单克隆抗体作为免疫疗法是有效的。然而,只有一部分癌症对 PD-1/PD-L1 阻断有持久的反应。此外,基于抗体的免疫检查点阻断费用高昂,偶尔伴有全身副作用。为了克服基于抗体的免疫检查点阻断的这些限制,设计并构建了一种表面展示 24 个 PD-L1 结合肽(PD-L1pep1)的免疫检查点阻断铁蛋白纳米笼。这些展示 PD-L1pep1 的铁蛋白纳米笼(PpNF)特异性结合癌细胞表面表达的 PD-L1 或与纯化的 PD-L1 以约 30 nM 的结合亲和力结合。将 PpNF 添加到 T 细胞和癌细胞的共培养物中,抑制了 PD-1/PD-L1 相互作用并恢复了 T 细胞的活性。在同源结肠癌的小鼠模型中,PpNF 特异性靶向肿瘤并表现出抗肿瘤活性。此外,封装化疗药物阿霉素的 PpNF 纳米笼比针对 PD-L1 的单克隆抗体具有更强的抗肿瘤活性。这些结果表明,表面展示 PD-L1pep1 的铁蛋白纳米笼可以有效地应用于免疫治疗,特别是在封装小化疗药物时。这些纳米笼可能有望成为针对各种实体瘤的免疫治疗纳米医学。

相似文献

[1]
Anticancer nanocage platforms for combined immunotherapy designed to harness immune checkpoints and deliver anticancer drugs.

Biomaterials. 2021-3

[2]
Immune Checkpoint-Blocking Nanocages Cross the Blood-Brain Barrier and Impede Brain Tumor Growth.

ACS Biomater Sci Eng. 2024-1-8

[3]
A Mini-Review for Cancer Immunotherapy: Molecular Understanding of PD-1/PD-L1 Pathway & Translational Blockade of Immune Checkpoints.

Int J Mol Sci. 2016-7-18

[4]
The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma.

Clin Ther. 2015-4-1

[5]
Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy.

Cancer Treat Rev. 2015-11-10

[6]
Combined Inhibition of TGF-β Signaling and the PD-L1 Immune Checkpoint Is Differentially Effective in Tumor Models.

Cells. 2019-4-5

[7]
Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging.

Proc Natl Acad Sci U S A. 2015-11-24

[8]
PD-1/PD-L1 Blockade Therapy in Advanced Non-Small-Cell Lung Cancer: Current Status and Future Directions.

Oncologist. 2019-2

[9]
The Tumor Microenvironment Regulates Sensitivity of Murine Lung Tumors to PD-1/PD-L1 Antibody Blockade.

Cancer Immunol Res. 2017-8-17

[10]
A Systematic Review of Immunotherapy in Urologic Cancer: Evolving Roles for Targeting of CTLA-4, PD-1/PD-L1, and HLA-G.

Eur Urol. 2015-3-29

引用本文的文献

[1]
Reshaping tumor immune microenvironment and modulating T cell function based on hierarchical nanotherapeutics for synergistically inhibiting osteosarcoma.

Mater Today Bio. 2025-7-15

[2]
Design and application of ferritin-based nanomedicine for targeted cancer therapy.

Nanomedicine (Lond). 2025-3

[3]
Endogenous capsid-forming protein ARC for self-assembling nanoparticle vaccines.

J Nanobiotechnology. 2024-8-27

[4]
Knockout cancer by nano-delivered immunotherapy using perfusion-aided scaffold-based tumor-on-a-chip.

Nanotheranostics. 2024

[5]
Photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes to promote PD-L1 multivalent binding for effective immune checkpoint blockade therapy.

Acta Pharm Sin B. 2024-3

[6]
Inhibitors of Immune Checkpoints: Small Molecule- and Peptide-Based Approaches.

J Pers Med. 2024-1-4

[7]
Immune Checkpoint-Blocking Nanocages Cross the Blood-Brain Barrier and Impede Brain Tumor Growth.

ACS Biomater Sci Eng. 2024-1-8

[8]
Ferritin-based nanomedicine for disease treatment.

Med Rev (2021). 2023-3-10

[9]
Peptides as multifunctional players in cancer therapy.

Exp Mol Med. 2023-6

[10]
Ferritin in cancer therapy: A pleiotropic tumoraffin nanocage-based transport.

Cancer Med. 2023-5

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