CM-101: Type I Collagen-targeted MR Imaging Probe for Detection of Liver Fibrosis.
CM-101: Type I Collagen-targeted MR Imaging Probe for Detection of Liver Fibrosis.
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DOI：
10.1148/radiol.2017170595
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发表时间：
2018-05
期刊：
影响因子：
19.7
通讯作者：
Caravan P
中科院分区：
文献类型：
--
作者：
Farrar CT;Gale EM;Kennan R;Ramsay I;Masia R;Arora G;Looby K;Wei L;Kalpathy-Cramer J;Bunzel MM;Zhang C;Zhu Y;Akiyama TE;Klimas M;Pinto S;Diyabalanage H;Tanabe KK;Humblet V;Fuchs BC;Caravan P
评估新型I型胶原靶向MR探针CM-101的生物分布、代谢和药代动力学，并评估其在动物模型中量化肝纤维化的能力。用质谱仪测定CM-101在大鼠体内的生物分布、药代动力学和稳定性。胆管结扎(BDL)组和假手术组大鼠于术后19d用1.5T临床MRI扫描仪进行成像。小鼠接受四氯化碳(CCl4)或赋形剂治疗，每周2次，持续10周，并在基线和最后一次CCl4治疗后1周在7.0Tesla临床前MRI扫描仪上进行成像。分别于注射10μm ol/kg CM-10 1前后对动物进行图像分析。用注射CM-101后肝脏和肌肉组织的对比噪声比(Δ)的变化来量化肝纤维化。肝组织行天狼星红染色和羟脯氨酸含量分析。研究动物护理机构小组委员会批准了所有活体程序。CM-101在大鼠体内清除快(t1/2=6.8±2.4分钟)，以肾排出为主。组织中Gd含量在注射CM-101后24小时较低(<；3.9±0.6%ID/g)，14天(<；0.33±12%ID/g)降低10倍，在骨中的蓄积可忽略不计(分别为0.07±0.02%ID/g和0.010±0.004%ID/g)。与假手术组(5.7±4.2)和四氯化碳处理组小鼠(18.3±6.5)相比，Δ组大鼠(13.6±3.2)显著升高(p<；0.001)。在大鼠肝纤维化模型和小鼠肝纤维化模型中，CM-101显示了快速的血液清除和全身消除，可以忽略Gd在骨骼或组织中的积聚，并且可以很好地检测到纤维化。
To evaluate the biodistribution, metabolism, and pharmacokinetics of a new type I collagen targeted MR probe, CM-101, and asses its ability to quantify liver fibrosis in animal models. Biodistribution, pharmacokinetics and stability of CM-101 in rats were measured by mass spectrometry. Bile duct ligated (BDL) and sham rats were imaged 19 days post procedure using a 1.5-Tesla clinical MRI scanner. Mice were treated with carbon tetrachloride (CCl4) or vehicle 2 times/week for 10 weeks and were imaged on a 7.0-Tesla preclinical MRI scanner at baseline and 1 week following the last CCl4 treatment. Animals were imaged before and after injection of 10 μmol/kg CM-101. Changes in contrast-to-noise ratio (ΔCNR) between liver and muscle tissue following CM-101 injection were used to quantify liver fibrosis. Liver tissue was analyzed for Sirius Red staining and hydroxyproline content. The institutional subcommittee for research animal care approved all in vivo procedures. CM-101 demonstrated rapid blood clearance (t1/2=6.8±2.4 min) and predominately renal elimination in rats. Biodistribution showed low tissue Gd levels at 24-hours (<3.9±0.6 %ID/g) and 10-fold lower levels at 14 days (<0.33±12 %ID/g) after CM-101 injection with negligible accumulation in bone (0.07±0.02 and 0.010±0.004 %ID/g at 1 and 14 days, respectively). ΔCNR was significantly (p<0.001) higher in BDL (13.6±3.2) rats compared to sham (5.7±4.2) rats and in the CCl4 treated mice (18.3±6.5) compared to baseline values (5.2±1.0). CM-101 demonstrated fast blood clearance and whole body elimination, negligible accumulation of Gd in bone or tissue, and robust detection of fibrosis in rat BDL and mouse CCl4 models of liver fibrosis.
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