Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, People's Republic of China.
Department of Orthopaedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, 200000, People's Republic of China.
Int J Nanomedicine. 2022 Jun 29;17:2823-2841. doi: 10.2147/IJN.S361483. eCollection 2022.
Magnetic iron oxide nanoparticle (MNP) drug delivery system is a novel promising therapeutic option for cancer treatment. Material issues such as fabrication and functionalized modification have been investigated; however, pharmacologic mechanisms of bare MNPs inside cancer cells remain obscure. This study aimed to explore a systems pharmacology approach to understand the reaction of the whole cell to MNPs and suggest drug selection in MNP delivery systems to exert synergetic or additive anti-cancer effects.
HeLa and SiHa cell lines were used to estimate the properties of bare MNPs in cervical cancer through 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) and enzyme activity assays and cellular fluorescence imaging. A systems pharmacology approach was utilized by combining bioinformatics data mining with clinical data analysis and without a predefined hypothesis. Key genes of the MNP onco-pharmacologic mechanism in cervical cancer were identified and further validated through transcriptome analysis with quantitative reverse transcription PCR (qRT-PCR).
Low cytotoxic activity and cell internalization of MNP in HeLa and SiHa cells were observed. Lysosomal function was found to be impaired after MNP treatment. Protein tyrosine kinase 2 beta (PTK2B), liprin-alpha-4 (PPFIA4), mothers against decapentaplegic homolog 7 (SMAD7), and interleukin (IL) 1B were identified as key genes relevant for MNP pharmacology, clinical features, somatic mutation, and immune infiltration. The four key genes also exhibited significant correlations with the lysosome gene set. The qRT-PCR results showed significant alterations in the expression of the four key genes after MNP treatment in HeLa and SiHa cells.
Our research suggests that treatment of bare MNPs in HeLa and SiHa cells induced significant expression changes in PTK2B, PPFIA4, SMAD7, and IL1B, which play crucial roles in cervical cancer development and progression. Interactions of the key genes with specific anti-cancer drugs must be considered in the rational design of MNP drug delivery systems.
磁性氧化铁纳米颗粒（MNP）药物递送系统是癌症治疗的一种有前途的新型治疗选择。已经研究了材料问题，如制造和功能化修饰；然而，裸 MNPs 在癌细胞内的药理机制仍不清楚。本研究旨在探索系统药理学方法来了解整个细胞对 MNPs 的反应，并建议在 MNP 递药系统中选择药物以发挥协同或相加的抗癌作用。
使用 HeLa 和 SiHa 细胞系通过 3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑溴化物（MTT）和酶活性测定以及细胞荧光成像来估计宫颈癌中裸 MNPs 的特性。通过结合生物信息学数据挖掘与临床数据分析的系统药理学方法，而无需预设假设。鉴定了宫颈癌中 MNP 肿瘤药理学机制的关键基因，并通过定量逆转录 PCR（qRT-PCR）的转录组分析进一步验证。
在 HeLa 和 SiHa 细胞中观察到 MNP 的低细胞毒性活性和细胞内化。MNP 处理后发现溶酶体功能受损。蛋白酪氨酸激酶 2β（PTK2B）、脂联素-α-4（PPFIA4）、母系抗颅足畸形蛋白 7（SMAD7）和白细胞介素（IL）1B 被鉴定为与 MNP 药理学、临床特征、体细胞突变和免疫浸润相关的关键基因。这四个关键基因也与溶酶体基因集有显著相关性。qRT-PCR 结果显示，MNP 处理后 HeLa 和 SiHa 细胞中这四个关键基因的表达有显著改变。
我们的研究表明，裸 MNPs 在 HeLa 和 SiHa 细胞中的治疗诱导了 PTK2B、PPFIA4、SMAD7 和 IL1B 的显著表达变化，这些基因在宫颈癌的发展和进展中起着关键作用。在合理设计 MNP 药物递药系统时，必须考虑关键基因与特定抗癌药物的相互作用。
