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99Tcm-TP5-3 microSPECT/CT探测乳腺癌化疗后细胞凋亡的实验研究

99Tcm-TP5-3 microSPECT/CT for the early evaluation of response in mice bearing MDA-MB-231 breast carcinoma after a single dose of paclitaxel chemotherapy

摘要:

目的 合成新型凋亡显像剂99Tcm-半胱氨酸-膜联蛋白V(TP5-3),研究其在小鼠体内生物分布和药代动力学特点,探讨99Tcm-TP5-3 microSPECT/CT检测乳腺癌单次化疗后肿瘤早期细胞凋亡的可行性.方法 以直接还原法对TP5-3进行99Tcm标记,HPLC检测产物的标记率;进行正常小鼠体内99Tcm-TP5-3的生物分布及药代动力学研究.建立荷MDA-MB-231人乳腺癌裸鼠模型,取10只分为2组,化疗组单次腹腔内注射紫杉醇(每只40 mg/kg),对照组注射等体积生理盐水,48 h后由尾静脉注射37 MBq 99Tcm-TP5-3,进行microSPECT/CT图像采集,显像后立即处死、取材,比较2组肿瘤的放射性摄取(%ID/g)、T/NT(NT取肌肉);采用流式细胞术和病理学检测肿瘤凋亡细胞.采用单因素方差分析、两样本t检验和直线相关分析数据.结果 99Tcm-TP5-3标记率>95%,室温放置4h放化纯仍保持在(96.0±1.5)%,稳定性好.正常小鼠注射显像剂后30 min肾脏放射性摄取最高[(8.48±1.07) %ID/g],其他脏器分布较少;血液清除快,注射后4h血液放射性摄取[(2.07±0.35) %ID/g]较注射后5 min[(13.74±4.21) %ID/g]减少了85%(F=11.310,P<0.05);显像剂主要浓聚于肾、肝和胃,经肾脏排泄.化疗后99Tcm-TP5-3 microSPECT/CT显像示化疗组T/NT为4.21±0.06,对照组T/NT仅1.57±0.67(f=12.820,P<0.05);化疗后生物分布实验示,化疗组肿瘤放射性摄取明显高于对照组,分别为(4.82±0.54) %ID/g和(1.44±0.38) %ID/g(t=0.679,P<0.05).肿瘤放射性摄取与流式细胞仪测定的凋亡细胞百分比呈正相关(r=0.985,P<0.05).HE染色示化疗后肿瘤组织有大量凋亡细胞,而对照组仅有少量.结论 99Tcm-TP5-3标记方法简单,生物分布理想,具备优良的药代动力学特性;99Tcm-TP5-3 microSPECT/CT可用于早期检测荷乳腺癌裸鼠模型化疗后的肿瘤细胞凋亡水平.

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abstracts:

Objective To synthesize 99Tcm-TP5-3 and evaluate its biodistribution and kinetics as a molecular probe for the detection of apoptosis,and evaluate tumor apoptosis after a single dose of paclitaxel chemotherapy in MDA-MB-231 breast tumor model.Methods TP5-3 was labeled with 99Tcm directly,and analyzed with HPLC.The radioactivity in tissues was measured and expressed as %ID/g and T/NT (tumor/muscle).The mice bearing MDA-MB-231 breast tumor were divided into two groups:the treatment group which was given a single dose of paclitaxel (40 mg· kg-1,via tail vein),and the control group which was injected with the same volume of normal saline.After therapy,99Tcm-TP5-3 was injected via tail vein in both groups (100 μ1 for each mouse).MicroSPECT/CT was performed at 3 h postinjection.Radioactivity in different tissues was determined after imaging.Apoptotic cells were measured with flow cytometry.The morphological changes of the apoptotic cells were observed by light microscopies.One-way analysis of variance,two-sample t test and linear correlation analysis were used to analyze the data.Results The radiolabeling efficiency was > 95% and the radiochemical purity of 99Tcm-TP5-3 was (96.0± 1.5)% at room temperature for 4 h.The predominant uptake was found in the kidneys at 30 min postinjection ((8.48± 1.07) %ID/g),with rapid tracer clearance from the circulation.By comparison with activity at 5 min postinjection ((13.74± 4.21) %ID/g),85% of the initial activity reduced in blood at 4 h ((2.07±0.35) %ID/g; F=11.310,P< 0.05).99Tcm-TP5-3 was mainly accumulated in the kidneys,liver and stomach,and excreted via the kidneys.T/NT in the treated group was 4.21±0.06,which was significantly higher than that of the control group (1.57±0.67; t =12.820,P<0.05).The radioactivity of tumor tissue in the treatment group was much higher than that in the control group (4.82±0.54) %ID/g vs (1.44±0.38) %ID/g,t=0.679,P<0.05).The tumor uptake of 99Tcm-TP5-3 in the treatment group positively correlated well with the apoptotic cells (r =0.985,P<0.05).Histopathology further confirmed that a large number of apoptosis had occurred in the tumor after paclitaxel treatment.Conclusion 99Tcm-TP5-3 appears to have potential to be a useful molecular probe for imaging tumor cell apoptosis.

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