Department of Radiology, Guangxi Medical University Cancer Hospital, Nanning, 530021, People's Republic of China.
Department of Emergency, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, People's Republic of China.
Int J Nanomedicine. 2024 Feb 7;19:1249-1272. doi: 10.2147/IJN.S445879. eCollection 2024.
The anti-Programmed Death-Ligand 1 (termed aPD-L1) immune checkpoint blockade therapy has emerged as a promising treatment approach for various advanced solid tumors. However, the effect of aPD-L1 inhibitors limited by the tumor microenvironment makes most patients exhibit immunotherapy resistance.
We conjugated the Sialyl Lewis X with a polyethylene glycol-coated ultrasmall superparamagnetic iron oxide (USPIO-PEG) to form UPS nanoparticles (USPIO-PEG-SLe, termed UPS). The physicochemical properties of UPS were tested and characterized. Transmission electron microscopy and ICP-OES were used to observe the cellular uptake and targeting ability of UPS. Flow cytometry, mitochondrial membrane potential staining, live-dead staining and scratch assay were used to verify the in vitro photothermal effect of UPS, and the stimulation of UPS on immune-related pathways at the gene level was analyzed by sequencing. Biological safety analysis and pharmacokinetic analysis of UPS were performed. Finally, the amplification effect of UPS-mediated photothermal therapy on aPD-L1-mediated immunotherapy and the corresponding mechanism were studied.
In vitro experiments showed that UPS had strong photothermal therapy ability and was able to stimulate 5 immune-related pathways. In vivo, when the PTT assisted aPD-L1 treatment, it exhibited a significant increase in CD4 T cell infiltration by 14.46-fold and CD8 T cell infiltration by 14.79-fold, along with elevated secretion of tumor necrosis factor-alpha and interferon-gamma, comparing with alone aPD-L1. This PTT assisted aPD-L1 therapy achieved a significant inhibition of both primary tumors and distant tumors compared to the alone aPD-L1, demonstrating a significant difference.
The nanotheranostic agent UPS has been introduced into immunotherapy, which has effectively broadened its application in biomedicine. This photothermal therapeutic approach of the UPS nanotheranostic agent enhancing the efficacy of aPD-L1 immune checkpoint blockade therapy, can be instructive to address the challenges associated with immunotherapy resistance, thereby offering potential for clinical translation.
抗程序性死亡配体 1（简称 aPD-L1）免疫检查点阻断疗法已成为治疗各种晚期实体瘤的一种有前途的治疗方法。然而，aPD-L1 抑制剂的效果受到肿瘤微环境的限制，使得大多数患者表现出免疫治疗抵抗。
我们将唾液酸化路易斯 X 与聚乙二醇包覆的超顺磁性氧化铁纳米颗粒（USPIO-PEG）偶联，形成 UPS 纳米颗粒（USPIO-PEG-SLe，称为 UPS）。测试和表征了 UPS 的物理化学性质。透射电子显微镜和电感耦合等离子体发射光谱法（ICP-OES）用于观察 UPS 的细胞摄取和靶向能力。流式细胞术、线粒体膜电位染色、死活染色和划痕实验用于验证 UPS 的体外光热效应，并通过测序分析 UPS 在基因水平上对免疫相关途径的刺激作用。进行了 UPS 的生物安全性分析和药代动力学分析。最后，研究了 UPS 介导的光热治疗对 aPD-L1 介导的免疫治疗的放大作用及其相应机制。
体外实验表明，UPS 具有很强的光热治疗能力，并能刺激 5 条免疫相关途径。在体内，当 PTT 辅助 aPD-L1 治疗时，与单独使用 aPD-L1 相比，CD4 T 细胞浸润增加了 14.46 倍，CD8 T 细胞浸润增加了 14.79 倍，同时肿瘤坏死因子-α和干扰素-γ的分泌也增加了。与单独使用 aPD-L1 相比，这种 PTT 辅助 aPD-L1 治疗对原发性肿瘤和远处肿瘤均有显著抑制作用，差异具有统计学意义。
将纳米诊疗剂 UPS 引入免疫治疗中，有效地拓宽了其在生物医学中的应用。这种 UPS 纳米诊疗剂的光热治疗方法增强了 aPD-L1 免疫检查点阻断治疗的疗效，为解决免疫治疗抵抗所面临的挑战提供了指导，从而为临床转化提供了潜力。
Zotero 插件
