Antitumor effects of redox-responsive nanoparticles containing platinum(Ⅳ)in ovarian cancer
Objectives To explore the antitumor effects of redox-responsive nanoparticles containing platinum(Ⅳ)—NP@Pt(Ⅳ)in ovarian cancer.Methods Redox-responsive polymer carriers were synthesized.Polymer carriers and platinum(Ⅳ)—Pt(Ⅳ)can self-assemble into NP@Pt(Ⅳ).Inductively coupled plasma mass spectrometry was performed to detect the platinum release from NP@Pt(Ⅳ)in reducing environment and the platinum content in ovarian cancer cells ES2 treated with cisplatin,Pt(Ⅳ)and NP@Pt(Ⅳ).The proliferation ability of the ovarian cancer cells were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay.Cellular apoptosis was assessed by flow cytometry.Collection of primary ovarian cancer tissues from patients with primary high-grade serous ovarian cancer who were surgically treated at the Cancer Hospital of the Chinese Academy of Medical Sciences from October to December 2022.The high-grade serous ovarian cancer patient-derived xenograft(PDX)mice were intravenously injected with Cy7.5 labeled NP@Pt(Ⅳ)followed by in vivo imaging system.Mice were treated with PBS,cisplatin and NP@Pt(Ⅳ).Tumor volume and weight were measured in each group.Necrosis,apoptosis and cell proliferation of tumor tissues were detected by hematoxylin-eosin(HE)staining,TUNEL fluorescence staining and Ki-67 immunohistochemistry staining.Body weight and HE staining of heart,liver,spleen,lung and kidney of mice in each group were measured.Results The platinum release of NP@Pt(Ⅳ)after 48 hours in reducing environment was 76.29％,which was significantly higher than that of 26.82％in non-reducing environment(P＜0.001).The platinum content in ES2 cells after 4 hours and 7 hours of treatment with NP@Pt(Ⅳ)(308.59,553.15 ng/million cells)were significantly higher than those of Pt(Ⅳ)(100.21,180.31 ng/million cells)and cisplatin(43.36,50.36 ng/million cells,P＜0.05).The half inhibitory concentrations of NP@Pt(Ⅳ)in ovarian cancer cells ES2,A2780,A2780DDP were 1.39,1.42 and 4.62 μmol/L,respectively,which were lower than those of Pt(Ⅳ)(2.89,7.27,and 16.74 μmol/L)and cisplatin(5.21,11.85,and 71.98μmol/L).The apoptosis rate of ES2 cells treated with NP@Pt(Ⅳ)was(33.91±3.80)％,which was significantly higher than that of Pt(Ⅳ)[(16.28±2.41)％]and cisplatin[(15.01±1.17)％,P＜0.05].In high-grade serous ovarian cancer PDX model,targeted accumulation of Cy7.5 labeled NP@Pt(Ⅳ)at tumor tissue could be observed.After the treatment,the tumor volume of mice in NP@Pt(Ⅳ)group was(130±98)mm3,which was significantly lower than those in control group[(1 349±161)mm3,P＜0.001]and cisplatin group[(715±293)mm3,P=0.026].The tumor weight of mice in NP@Pt(Ⅳ))group was(0.17±0.09)g,which was significantly lower than those in control group[(1.55±0.11)g,P＜0.001]and cisplatin group[(0.82±0.38)g,P=0.029].The areas of tumor necrosis and apoptosis in mice treated with NP@Pt(Ⅳ))were higher than those in mice treated with cisplatin.Immunohistochemical staining revealed that there were low expressions of Ki-67 at tumor tissues of mice treated with NP@Pt(Ⅳ))compared with cisplatin.The change in body weight of mice in NP@Pt(Ⅳ))group was not significantly different from that of the control group[(18.56±2.04)g vs.(20.87± 0.79)g,P=0.063].Moreover,the major organs of the heart,liver,spleen,lung,and kidney were also normal by HE staining.Conclusion Redox-responsive NP@Pt(Ⅳ)),produced in this study can enhance the accumulation of cisplatin in ovarian cancer cells and improve the efficacy of ovarian cancer chemotherapy.
万方数据
维普
