纳米金属有机骨架颗粒Hf-TCPP NMOFs用于肝癌CT成像的研究

Hafnium-Tetra (4-carboxyphenyl) porphine nanoscale metal-organic frameworks (Hf-TCPP NMOFs) for Computed tomography of Liver Cancer

目的:探索纳米金属有机骨架颗粒Hf-TCPP NMOFs用于肝癌CT成像的可行性。方法:应用微波辅助溶剂热技术制备纳米金属有机骨架颗粒Hf-TCPP NMOFs。通过人源HepG2细胞噻唑蓝(MTT)实验及BALB/c小鼠体内毒性试验验证Hf-TCPP NMOFs生物安全性。应用鼠源肝癌细胞Walk 256建立SD大鼠原位肝癌模型,通过原位肝癌CT成像探讨纳米金属有机骨架药物Hf-TCPP NMOFs用于肝癌CT造影剂的可行性及成像效果。组间比较采用t检验。结果:Hf-TCPP NMOFs粒径约120 nm,呈单分散的球形。细胞MTT试验表示超过80%HepG2细胞存活。通过注射3个不同药物浓度(10、20、40 mg/kg、对照组)药物后,检测小鼠不同时间点的血液生化指标。即使在最高浓度40 mg/kg时,第7天实验组与对照组比较,差异无统计学意义(WBC:8.14±0.23比8.17±0.26,t=-0.335,P>0.05;RBC:8.95±0.63比8.75±0.26,t=0.734,P>0.05;PLT:8.13±0.58比8.28±0.46,t=-0.617,P>0.05;LYM:2.21±0.28比2.24±0.15,t=-0.426,P>0.05;ALT:43.71±3.54比44.17±4.14,t=-0.531,P>0.05;AST:193.41±7.21比199.59±8.24,t=-1.032,P>0.05;CRE:35.13±2.72比36.86±3.19,t=-0.933,P>0.05;TBILI:0.97±0.15比0.99±0.16,t=-0.275,P>0.05;BUN:7.59±0.71比7.67±0.34,t=-0.251,P>0.05);第14天以下指标实验组与对照组比较差异无统计学意义(WBC:8.22±0.26比8.17±0.26,t=1.894,P>0.05;RBC:8.63±0.24比8.75±0.26,t=-0.517,P>0.05;PLT:8.14±0.48比8.28±0.46,t=-0.739,P>0.05;LYM:2.31±0.21比2.24±0.15,t=-0.926,P>0.05;ALT:44.54±6.65比44.17±4.14,t=0.236,P>0.05;TBILI:1.02±0.10比0.99±0.16,t=0.234,P>0.05;BUN:7.57±0.21比7.67±0.34,t=-0.317,P>0.05)。体重变化曲线显示注射不同浓度的小鼠体重随时间体重变化与对照组比较,虽然有所波动,但总体变化不大。重要器官(心、肝、脾、肺、肾)的组织病理学显示未见药物对脏器的损伤。SD大鼠原位肝癌模型体内CT成像效果表明Hf-TCPP NMOFs除了除具备较长的体内循环时间外,其在肝癌组织中表现出更佳的靶向聚集以及成像清晰度。结论:纳米金属有机骨架颗粒Hf-TCPP NMOFs对肝癌具有良好的CT成像效果。

Objective Exploring the feasibility of Hafnium-Tetra(4-carboxyphenyl)porphine nanoscale metal-organic frameworks(Hf-TCPP NMOFs)for Computed tomography of liver cancer.Methods In this experiment,Hf-TCPP NMOFs were prepared by microwave-assisted solvothermal technique,and the biosafety of Hf-TCPP NMOFs was verified by MTT assay in human-derived HepG2 cells and in vivo toxicity test in BALB/c mice.We applied murine-derived hepatocellular carcinoma cells Walk 256 to establish an in situ hepatocellular carcinoma model in SD rats,andthen explored the feasibility and imaging effects of nanoscale metal-organic frameworks Hf-TCPP NMOFs for hepatocellular carcinoma CT contrast agent by in situ hepatocellular carcinoma CT imaging.Comparisonbetween groups was performed by t test.Results Hf-TCPP NMOFs have a particle size of about 120 nm and are monodisperse spherical in shape.The cell MTT test indicates that more than 80%of HepG2 cells are viable.After injecting three different drug concentrations(10,20,40 mg/kg,control group),the blood biochemical indexes of mice at different time points were detected.Even at the highest concentration of 40 mg/kg,there was no significant difference between the experimental group and the control group on day 7(WBC:8.14±0.23 vs.8.17±0.26,t=-0.335,P>0.05;RBC:8.95±0.63 vs.8.75±0.26,t=0.734,P>0.05;PLT:8.13±0.58 vs.8.28±0.46,t=-0.617,P>0.05;LYM:2.21±0.28 vs.2.24±0.15,t=-0.426,P>0.05;ALT:43.71±3.54 vs.44.17±4.14,t=-0.531,P>0.05;AST:193.41±7.21 vs.199.59±8.24,t=-1.032,P>0.05;CRE:35.13±2.72 vs.36.86±3.19,t=-0.933,P>0.05;TBILI:0.97±0.15 vs.0.99±0.16,t=-0.275,P>0.05;BUN:7.59±0.71 vs.7.67±0.34,t=-0.251,P>0.05);hematological analysis also showed no significant difference between the experimental group and the control groupon day 14 even at the highest concentration,and the difference was not statistically significant(WBC:8.22±0.26 vs.8.17±0.26,t=1.894,P>0.05;RBC:8.63±0.24 vs.8.75±0.26,t=-0.517,P>0.05;PLT:8.14±0.48 vs.8.28±0.46,t=-0.739,P>0.05;LYM:2.31±0.21 vs.2.24±0.15,t=-0.926,P>0.05;ALT:44.54±6.65 vs.44.17±4.14,t=0.236,P>0.05;TBILI:1.02±0.10 vs.0.99±0.16,t=0.234,P>0.05;BUN:7.57±0.21 vs.7.67±0.34,t=-0.317,P>0.05).The body weight change curve shows that the weight change of mice injected with different concentrations over time compared to the control group,although fluctuating,the overall change is not large.Histopathology of vital organs(heart,liver,spleen,lungs,kidneys)shows no drug-inflicted organ damage.In vivo CT imaging in SD rat in situ hepatocellular carcinoma model exhibited better target aggregation and imaging clarity in liver cancer tissues,in addition to longer in vivo circulation time.Conclusion Nanometallic organic backbone particles Hf-TCPP NMOFs have excellent CT imaging effect on liver cancer.