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首页> 外文期刊>Biochimica et biophysica acta. Biomembranes >Penetration in 3D tumor spheroids and explants: Adding a further dimension to the structure-activity relationship of cell-penetrating peptides
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Penetration in 3D tumor spheroids and explants: Adding a further dimension to the structure-activity relationship of cell-penetrating peptides

机译：3D肿瘤球状体和外植体的渗透：为细胞穿透肽的结构 - 活性关系添加进一步的尺寸

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摘要

Drug delivery into tumors and metastases is a major challenge in the eradication of cancers such as epithelial ovarian carcinoma. Cationic cell-penetrating peptides (CPPs) are a promising group of delivery vehicles to mediate cellular entry of molecules that otherwise poorly enter cells. However, little is known about their penetration behavior in tissues. Here, we investigated penetration of cationic CPPs in 3D ovarian cancer spheroids and patient-derived 3D tumor explants. Penetration kinetics and distribution after long-term incubation were imaged by confocal microscopy. In addition, spheroids and tumor explants were dissociated and cell-associated fluorescence determined by flow cytometry. CPPs with high uptake activity showed enhanced sequestration in the periphery of the spheroid, whereas less active CPPs were able to penetrate deeper into the tissue. CPPs consisting of u-amino acids were advantageous over L-amino acid CPPs as they showed less but long lasting cellular uptake activity, which benefitted penetration and retention over time. In primary tumor cultures, in contrast to nonaarginine, the amphipathic CPP penetratin was strongly sequestered by cell debris and matrix components pointing towards arginine-rich CPPs as a preferred choice. Overall, the data show that testing in 3D models leads to a different choice of the preferred peptide in comparison to a standard 2D cell culture.
机译：药物递送到肿瘤和转移是根除上皮卵巢癌等癌症中的主要挑战。阳离子细胞穿透肽（CPP）是促进递送载体的有希望的递送载体，以介导进入细胞的分子细胞入口。然而，关于它们在组织中的渗透行为几乎是知之甚少。在这里，我们研究了阳离子CPP在3D卵巢癌球体和患者衍生的3D肿瘤外植体的渗透。通过共聚焦显微镜对长期孵育后的渗透动力学和分布。此外，通过流式细胞术确定球状体和肿瘤外植体和细胞相关的荧光。具有高摄取活性的CPP在球状外围的周边显示出增强的隔离，而较少的活性CPP能够深入渗透到组织中。由U-氨基酸组成的CPP在L-氨基酸CPP上有利，因为它们表现出较少但长的持久性蜂窝摄取活性，这会受益于渗透和保留随时间。在原发性肿瘤培养物中，与非胰岛相比，通过细胞碎片和基质组分强烈地隔离两亲性CPP渗透素，指向精氨酸的CPP作为优选的选择。总的来说，数据显示3D模型中的测试与标准的2D细胞培养相比，3D模型的测试导致优选的肽的不同选择。

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