Cancer-Associated Fibroblasts (CAFs) contribute to tumour progression and have received significant attention as a therapeutic target. These cells produce growth factors, cytokines and chemokines, stimulating cancer cell proliferation and inhibiting their apoptosis. Recent advances in drug delivery have demonstrated a significant promise of iron oxide nanoparticles in clinics as theranostic agents, mainly due to their magnetic properties. Here, we designed superparamagnetic iron oxide nanoparticles (SPIONs) to induce apoptosis of human fibroblasts. SPIONs were synthesized via co-precipitation method and coated with sodium citrate (SPION_Cit). We assessed the intracellular uptake of SPIONs by human fibroblast cells, as well as their cytotoxicity and ability to induce thermal effects under the magnetic field. The efficiency and time of nanoparticle internalization were assessed by Prussian Blue staining, flow cytometry and transmission electron microscopy. SPIONs_Cit were detected in the cytoplasm of human fibroblasts 15 min after in vitro exposure, entering into cells mainly via endocytosis. Analyses through Cell Titer Blue assay, AnnexinV-fluorescein isothiocyanate (FITC) and propidium iodide (PI) cellular staining demonstrated that concentrations below 8 × 10-2 mg/mL of SPIONs_Cit did not alter cell viability of human fibroblast. Furthermore, it was also demonstrated that SPIONs_Cit associated with alternating current magnetic field were able to induce hyperthermia and human fibroblast cell death in vitro, mainly through apoptosis (83.5%), activating caspase 8 (extrinsic apoptotic via) after a short exposure period. Collectively these findings suggest that our nanoplatform is biocompatible and can be used for therapeutic purposes in human biological systems, such as inducing apoptosis of CAFs.

中文翻译：

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使用超顺磁性氧化铁纳米粒子诱导人类成纤维细胞凋亡的生物技术方法。

癌症相关的成纤维细胞（CAF）有助于肿瘤的进展，并已作为治疗靶点引起了广泛关注。这些细胞产生生长因子，细胞因子和趋化因子，刺激癌细胞增殖并抑制其凋亡。药物输送的最新进展已证明临床上铁氧化物纳米粒子有望作为治疗治疗剂，这主要归因于其磁性。在这里，我们设计了超顺磁性氧化铁纳米粒子（SPIONs）诱导人类成纤维细胞凋亡。通过共沉淀法合成SPIONs，并用柠檬酸钠（SPION_Cit）包被。我们评估了人类成纤维细胞对SPIONs的细胞内摄取，以及它们的细胞毒性和在磁场下诱导热效应的能力。纳米粒子内在化的效率和时间通过普鲁士蓝染色，流式细胞仪和透射电子显微镜进行评估。体外暴露15分钟后，在人成纤维细胞的细胞质中检测到了SPIONs_Cit，主要通过内吞作用进入细胞。通过细胞滴定蓝分析，AnnexinV-异硫氰酸荧光素（FITC）和碘化丙啶（PI）细胞染色分析表明，低于8×10-2 mg / mL的SPIONs_Cit浓度不会改变人成纤维细胞的细胞活力。此外，还证明了与交流磁场相关的SPIONs_Cit能够在体外（短时间内）主要通过凋亡（83.5％）诱导caspase 8（外源性凋亡通路）活化，从而诱导体外热疗和人成纤维细胞死亡。