通过延长植物病毒纳米颗粒呈现和传递肿瘤坏死因子相关凋亡诱导配体增强抗肿瘤疗效。

Presentation and Delivery of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand via Elongated Plant Viral Nanoparticle Enhances Antitumor Efficacy.

机构信息

Department of Biomedical Engineering , Case Western Reserve University School of Medicine , Cleveland , Ohio 44106 , United States.

Department of Molecular Biology , RWTH-Aachen University , Aachen 52064 , Germany.

出版信息

ACS Nano. 2019 Feb 26;13(2):2501-2510. doi: 10.1021/acsnano.8b09462. Epub 2019 Jan 22.

Abstract

Potato virus X (PVX) is a flexuous plant virus-based nanotechnology with promise in cancer therapy. As a high aspect ratio biologic (13 × 515 nm), PVX has excellent spatial control in structures and functions, offering high-precision nanoengineering for multivalent display of functional moieties. Herein, we demonstrate the preparation of the PVX-based nanocarrier for delivery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a promising protein drug that induces apoptosis in cancer cells but not healthy cells. TRAIL bound to PVX by coordination bonds between nickel-coordinated nitrilotriacetic acid on PVX and His-tag on the protein could mimic the bioactive "membrane-bound" state in native TRAIL, resulting in an elongated nanoparticle displaying up 490 therapeutic protein molecules. Our data show that PVX-delivered TRAIL activates caspase-mediated apoptosis more efficiently compared to soluble TRAIL; also in vivo the therapeutic nanoparticle outperforms in delaying tumor growth in an athymic nude mouse model bearing human triple-negative breast cancer xenografts. This proof-of-concept work highlights the potential of filamentous plant virus nanotechnologies, particularly for targeting protein drug delivery for cancer therapy.

摘要

马铃薯 X 病毒(PVX)是一种基于柔韧植物病毒的纳米技术,在癌症治疗方面具有广阔的前景。作为一种高纵横比的生物(13×515nm),PVX 在结构和功能上具有极好的空间控制能力,为多功能部分的多价展示提供了高精度的纳米工程。在此,我们展示了基于 PVX 的纳米载体的制备,用于递送肿瘤坏死因子相关凋亡诱导配体(TRAIL),这是一种有前途的蛋白药物,能够诱导癌细胞凋亡而不影响健康细胞。TRAIL 通过 PVX 上镍配位的三嗪二酸和蛋白上 His 标签之间的配位键与 PVX 结合,能够模拟天然 TRAIL 中的生物活性“膜结合”状态,从而形成一个展示多达 490 个治疗性蛋白分子的长纳米颗粒。我们的数据表明,与可溶性 TRAIL 相比,PVX 递送的 TRAIL 更有效地激活半胱天冬酶介导的细胞凋亡;此外,在携带人三阴性乳腺癌异种移植物的无胸腺裸鼠模型中,治疗性纳米颗粒在延迟肿瘤生长方面表现优于可溶性 TRAIL。这项概念验证工作突出了丝状植物病毒纳米技术的潜力,特别是在靶向蛋白药物递送用于癌症治疗方面。

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