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用磁性纳米颗粒加载CAR-T细胞以实现可控靶向,可抑制炎性细胞因子释放并改变肿瘤细胞死亡机制。

Loading of CAR-T cells with magnetic nanoparticles for controlled targeting suppresses inflammatory cytokine release and switches tumor cell death mechanism.

作者信息

Pfister Felix, Carnell Lucas R, Löffler Lisa, Boosz Philipp, Schaft Niels, Dörrie Jan, Stein René, Lenz Malte, Spiecker Erdmann, Huber Christian M, Haddadin Sami, Berking Carola, Alexiou Christoph, Janko Christina

机构信息

Department of Otorhinolaryngology Head and Neck Surgery Section of Experimental Oncology and Nanomedicine (SEON) Else Kröner-Fresenius-Stiftung Professorship Universitätsklinikum Erlangen Erlangen Germany.

Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) Erlangen Germany.

出版信息

MedComm (2020). 2025 Jan 5;6(1):e70039. doi: 10.1002/mco2.70039. eCollection 2025 Jan.

Abstract

Therapies against hematological malignancies using chimeric antigen receptors (CAR)-T cells have shown great potential; however, therapeutic success in solid tumors has been constrained due to limited tumor trafficking and infiltration, as well as the scarcity of cancer-specific solid tumor antigens. Therefore, the enrichment of tumor-antigen specific CAR-T cells in the desired region is critical for improving therapy efficacy and reducing systemic on-target/off-tumor side effects. Here, we functionalized human CAR-T cells with superparamagnetic iron oxide nanoparticles (SPIONs), making them magnetically controllable for site-directed targeting. SPION-loaded CAR-T cells maintained their specific cytolytic capacity against melanoma cells expressing the CAR-specific antigen chondroitin sulfate proteoglycan (CSPG4). Importantly, SPIONs suppressed cytokine release in the loaded CAR-T cells, shifting the cell death phenotype in the tumor cells from pyroptosis to apoptosis. Furthermore, SPION-loaded CAR-T cells could be enriched in a dynamic flow model through an external magnetic field and be detected in MRI. These results demonstrate that lytic cytotoxicity is retained after SPION-functionalization and provides a basis for future site-specific immunotherapies against solid tumors with reduced systemic adverse side effects.

摘要

使用嵌合抗原受体(CAR)-T细胞治疗血液系统恶性肿瘤已显示出巨大潜力;然而,由于肿瘤转运和浸润有限以及癌症特异性实体瘤抗原稀缺,实体瘤的治疗成功受到限制。因此,在所需区域富集肿瘤抗原特异性CAR-T细胞对于提高治疗效果和减少全身性靶向脱瘤副作用至关重要。在此,我们用超顺磁性氧化铁纳米颗粒(SPIONs)对人CAR-T细胞进行功能化,使其具有磁可控性以进行定点靶向。负载SPION的CAR-T细胞保持了对表达CAR特异性抗原硫酸软骨素蛋白聚糖(CSPG4)的黑色素瘤细胞的特异性细胞溶解能力。重要的是,SPIONs抑制了负载CAR-T细胞中的细胞因子释放,使肿瘤细胞中的细胞死亡表型从焦亡转变为凋亡。此外,负载SPION的CAR-T细胞可以通过外部磁场在动态流动模型中富集,并在磁共振成像(MRI)中被检测到。这些结果表明,SPION功能化后溶细胞毒性得以保留,并为未来针对实体瘤的位点特异性免疫治疗提供了基础,同时减少全身性不良副作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd66/11702464/31d3c69f2b61/MCO2-6-e70039-g008.jpg

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