顺铂和Sabutoclax配位自组装聚合物纳米粒子对肾癌细胞生长的抑制作用

Cisplatin and Sabutoclax Coordination Self-Assembled Polymer Nanopar-ticles Inhibit the Growth of Renal Crcinoma Cells

制备含顺铂和Sabutoclax(SA)的自组装聚合物纳米粒子,观察其对肾癌细胞生长的作用。顺铂和Sabutoclax经配位反应自组装形成纳米粒子,分别采用动态光散射和透射电镜测试粒径分布、稳定性和形态,X射线光电子能谱测定Fe^(3+)离子化学状态,HPLC检测体外释放。在肾癌细胞A498中,MTT法检测纳米粒子的细胞毒性,流式检测其细胞凋亡诱导作用,荷瘤小鼠模型观察纳米粒子的体内药效学。结果显示,顺铂和Sabutoclax经配位自组装形成粒径(50±2.6)nm左右的纳米粒子,该纳米粒子具有良好的稳定性、pH响应性和释放行为,易被A498细胞摄取,可显著抑制A498的增殖、诱导细胞凋亡,并可显著抑制小鼠体内肿瘤生长,同时对体重无明显影响,其对A498细胞的生长抑制、细胞凋亡诱导作用均强于顺铂、顺铂和Sabutoclax联合应用。该纳米粒子在体外及小鼠体内表现良好的肿瘤杀伤作用,且作用优于顺铂、顺铂和Sabutoclax联合应用。该纳米粒子可作为潜在的药物载体逆转顺铂耐药用于肾癌或其它恶性肿瘤的治疗。

To prepare cisplatin and sabutoclax-containing self-assembled Polymer nanoparticles,and observe its effect on the growth of renal carcinoma cells in vitro and in mice,cisplatin and sabutoclax were self-assembled into nanoparticles by coordination reaction.The particle size distribution,stability and morphology were respectively measured by dynamic light scattering(DLS)and transmission electron microscopy(TEM).The chemical states of Fe^(3+)ions were determined by X-ray photoelectron spectroscopy.HPLC was used to assess in vitro drug release of nanoparticles,and confocal microscope was used to observe its cellular uptake in A498 cells.Cytotoxicity and apoptosis in A498 cells were respectively detected by MTT assay and flow cytometry,and pharmacodynamics of nanoparticles was observed in tumor-bearing mice.Results showed that cisplatin and sabutoclax could self-assemble and form nanoparticles with particle size of about(50±2.6)nm by coordination reaction.The nanoparticles had good stability,pH response and release behavior,and were easy to be absorbed by A498 cells.It could significantly inhibit the proliferation and induce apoptosis of A498 cells.In tumor-bearing mice,the nanoparticles could significantly inhibit tumor growth,and had no significant effect on body weight.The growth inhibition and apoptosis induction of nanoparticles on A498 cells were both better than cisplatin or cisplatin combined with sabutoclax.In conclusion,the nanoparticle shown better tumor killing effect than cisplatin and cisplatin combined with sabutoclaxa,which could be further used as a potential drug carrier to reverse cisplatin resistance in the treatment of renal cancer or other malignant tumors.