State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.
Tianjin Key Laboratory of Early Druggability Evaluation of Innovative Drugs and Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China.
Theranostics. 2020 Jul 11;10(20):9083-9099. doi: 10.7150/thno.46467. eCollection 2020.
Malignant ascites caused by cancer cells results in poor prognosis and short average survival time. No effective treatment is currently available for malignant ascites. In this study, the effects of lentinan (LNT)-functionalized selenium nanoparticles (Selene) on malignant ascites were evaluated. Furthermore, the mechanism of Selene targeting mitochondria of tumor cells were also investigated. Selene were synthesized and characterized by TEM, AFM and particle size analysis. The OVCAR-3 and EAC cells induced ascites models were used to evaluate the effects of Selene on malignant ascites. Proteomic analysis, immunofluorescence, TEM and ICP-MS were used to determine the location of Selene in tumor cells. Mitochondrial membrane potential, ROS, ATP content, and caspase-1/3 activity were detected to evaluate the effect of Selene on mitochondrial function and cell apoptosis. Immunofluorescence, Co-IP, pull-down, duolink, Western blot, and FPLC were used to investigate the pathway of Selene targeting mitochondria. Selene could effectively inhibit ascites induced by OVCAR-3 and EAC cells. Selene was mainly located in the mitochondria of tumor cells and induced apoptosis of tumor cells. The LNT in Selene was involved in caveolae-mediated endocytosis through the interaction between toll-like receptor-4 (TLR4) and caveolin 1 (CAV1). Furthermore, the Selene in the endocytic vesicles could enter the mitochondria via the mitochondrial membrane fusion pathway, which was mediated by TLR4/TNF receptor associated factor 3 (TRAF3)/mitofusin-1 (MFN1) protein complex. Selene is a candidate anticancer drug for the treatment of malignant ascites. And TLR4/TRAF3/MFN1 may be a specific nano-drug delivery pathway that could target the mitochondria.
癌细胞引起的恶性腹水导致预后不良，平均生存时间短。目前尚无有效的恶性腹水治疗方法。本研究评估了香菇多糖（LNT）功能化硒纳米颗粒（Selene）对恶性腹水的影响。此外，还研究了 Selene 靶向肿瘤细胞线粒体的机制。通过 TEM、AFM 和粒径分析合成和表征 Selene。使用 OVCAR-3 和 EAC 细胞诱导的腹水模型来评估 Selene 对恶性腹水的影响。蛋白质组分析、免疫荧光、TEM 和 ICP-MS 用于确定 Selene 在肿瘤细胞中的位置。检测线粒体膜电位、ROS、ATP 含量和 caspase-1/3 活性，以评估 Selene 对线粒体功能和细胞凋亡的影响。免疫荧光、Co-IP、下拉、duolink、Western blot 和 FPLC 用于研究 Selene 靶向线粒体的途径。Selene 能有效抑制 OVCAR-3 和 EAC 细胞诱导的腹水。Selene 主要位于肿瘤细胞的线粒体中，并诱导肿瘤细胞凋亡。Selene 中的 LNT 通过 Toll 样受体 4（TLR4）和窖蛋白 1（CAV1）之间的相互作用，参与小窝蛋白介导的内吞作用。此外，内吞小泡中的 Selene 可通过 TLR4/TNF 受体相关因子 3（TRAF3）/线粒体融合蛋白 1（MFN1）蛋白复合物介导的线粒体融合途径进入线粒体。Selene 是治疗恶性腹水的候选抗癌药物。TLR4/TRAF3/MFN1 可能是一种靶向线粒体的特异性纳米药物递送途径。
