目的 探讨放射性核素凋亡显像剂18F-ML-10无创监测多柔比星诱发心脏毒性的可行性。方法 36只KM小鼠随机分为对照组、低剂量(15 mg/kg)多柔比星模型组和高剂量(20 mg/kg)多柔比星模型组,每组12只。对照组腹腔注射生理盐水,多柔比星模型组腹腔注射一定剂量的多柔比星,48 h后进行小动物超声检测左室射血分数 (left ventricular ejection fraction, LVEF),以及放射性显像剂18F-ML-10与18F-FDG在小鼠体内的生物分布并测定每克组织放射性摄取值(%ID/g),处死的小鼠取出心脏进行caspase 3免疫组化检测心肌细胞的凋亡情况。结果 超声结果显示低剂量组[LVEF=(59.49±5.32)%]与高剂量组LVEF=(52.41±6.47)%小鼠左室射血分数明显低于对照组LVEF=(70.58±5.06)%,18F-FDG在低剂量组(%ID/g=21.67±3.69)与高剂量组(%ID/g=15.58±1.92)的摄取也明显低于对照组(%ID/g=36.18±3.65),而凋亡显像剂18F-ML-10在低剂量组(%ID/g=0.50±0.11)与高剂量组(%ID/g=1.100.55)的摄取明显明显高于对照组(%ID/g=0.02±0.02),差异均有统计学意义(P<0.05),caspase 3免疫组化显示模型组心肌细胞发生明显凋亡,与18F-ML-10在心脏的摄取相一致。结论 心肌细胞的凋亡是多柔比星诱导心脏毒性的重要途径,特异性凋亡显像剂18F-ML-10用于多柔比星诱发心肌细胞凋亡的毒性监测具有较好的应用前景。
Abstract
Objective To investigate the feasibility of noninvasive monitoring of doxorubicin-induced cardiotoxicity by radionuclide apoptosis imaging agent 18F-ML-10.Methods Thirty-six KM mice were randomly and equally divided into control group, low dose (15 mg / kg) model group and high dose (20 mg/kg) model group. The mice in control group were injected with normal saline. Doxorubicin was injected into model group at some dose. After 48 hours, mice were subjected to cardiac ultrasonography and the biodistribution of 18F-FDG and 18F-ML-10 was determined with gamma counting. The mice were sacrificed to remove the heart for caspase 3 immunohistochemical detection of myocardial cell apoptosis.Results The left ventricular ejection fraction was significantly lower in low dose group (LVEF=59.49±5.32%) and high dose group (LVEF=52.41±6.47%) than that in control group (LVEF=70.58±5.06%), but the uptake of 18F-FDG in low dose group (%ID/g=0.50±0.11) and high dose group (%ID/g=15.58±1.92) was significantly lower than that in control group (%ID/g=36.18±3.65).The uptake of apoptotic imaging agent 18F-ML-10 in low dose group (%ID/g=0.50±0.11) and high dose group(%ID/g=1.10±0.55)was significantly higher than that in control group (%ID/g=0.02±0.02) (P<0.05). Caspase 3 immunohistochemistry showed obvious apoptosis of myocardial cells in model group, which was consistent with the uptake of 18F-ML-10 in the heart.Conclusions Apoptosis is an important pathway for doxorubicin-induced cardiotoxicity. 18F-ML-10 may contribute to the detection of doxorubicin-induced myocardial apoptosis.
关键词
多柔比星 /
心脏毒性 /
凋亡 /
18F-ML-10
Key words
doxorubicin /
cardiotoxicity /
apoptosis /
18F-ML-10
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基金
天津市自然科学基金资助项目(13JCYBJC22000),武警后勤学院附属医院种子基金资助项目(FYQ201601)
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