RGD-USPIO纳米粒构建及其在肿瘤MRI诊断中应用
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摘要
第一部分新生血管靶向氧化铁纳米粒的构建及核磁共振成像诊断中的动物研究
目的:制备具有肿瘤新生血管靶向的超顺磁性造影剂;体外细胞实验检测cRGD-USPIO与细胞的结合能力并初步探讨其在肿瘤MR成像中的应用。
方法:化学共沉淀一步法制备超小型超顺磁性氧化铁纳米粒,采用化学交联法将含有RGD序列的环形短肽(cRGD)与USPIO共价结合制备具有肿瘤新生血管靶向的超顺磁性氧化铁纳米粒;光学显微镜、透射电镜对所制备的肿瘤新生血管靶向纳米粒行形态学观察和核心粒径大小的检测;采用激光散射粒度分析仪测定USPIO和cRGD-USPIO的粒径分布;振动样品磁强计检测比饱和磁化强度;采用邻二氮菲法检测cRGD-USPIO中铁含量。培养人肺腺癌A549细胞及人脐静脉内皮细胞(HUVECs),并将cRGD-USPIO和USPIO分别与A549细胞和人脐静脉内皮细胞孵育24h,24h后采用普鲁士兰染色法检测cRGD-USPIO和USPIO与人肺腺癌A549细胞及人脐静脉内皮细胞的特异性结合能力;在体内试验中,建立A549裸鼠移植瘤模型,先行平扫,然后分别尾静脉注射USPIO和cRGD-USPIO,24h后行MRI检测并收集信号强度,与USPIO对比,评价cRGD-USPIO对肿瘤MRI信号增强作用。
结果:制备获得cRGD-USPIO纳米粒,其核心纳米粒径为5nm～10nm,cRGD-USPIO平均粒径为(43.97±10.1)nm,饱和磁化强度为59.94 emu/g,其铁的含量为22.88mg/ml。细胞结合实验结果提示与USPIO组比较,cRGD-USPIO组阳性染色明显增强。动物体内MRI诊断结果显示,USPIO组信号强度降低值为315.76±69.85,cRGD-USPIO组的信号强度降低值为792.17±116.51,约是USPIO组信号强度降低值的2.5倍,肿瘤信号强度明显降低(P﹤0.01)
结论:成功制备了cRGD-USPIO纳米粒,该纳米粒具有良好的理化性质;构建的靶向超顺磁性氧化铁纳米粒与A549细胞、人脐静脉内皮细胞的结合率为100%;裸鼠体内试验提示构建的靶向超顺磁性氧化铁纳米粒可成为一种新型有助于肿瘤早期诊断特异性的MRI阴性造影剂。
第二部分cRGD-USPIO纳米粒的急性、亚急性毒理实验
目的:研究实验制备的cRGD-USPIO纳米粒的毒性
方法:昆明小鼠30只,分为3组,分别尾静脉注入生理盐水,低剂量的cRGD-USPIO和高剂量的cRGD-USPIO,观察外部器官、皮毛的变化、活动量、进食量、体重等变化;2周后,从眼球后静脉丛取血测定红细胞(RBC)总数、白细胞(WBC)总数、血红蛋白(HGB)、血小板(Plt)、和测定血清生化指标谷丙转氨酶(ALT)、谷草转氨酶(AST)、总胆红素(TBIL)、尿素(UREA)、尿酸(UA)、肌酐(CREA)的含量,然后各组随机处死5只,处死后计算各器官的脏器指数,并做病理切片行HE染色和普鲁士蓝染色。
结果:本实验采用最大给药量的方法,在受试小鼠的急性毒性试验中,未见有小鼠死亡,发现高剂量组在给药后有暂时的少动现象,而其他剂量组均正常,1周后各剂量组小鼠的外部器官、皮毛、活动量、进食量等均正常;2周后从眼球后静脉丛取血测血常规,发现低剂量组和高剂量组与对照组相比无明显差异;血清主要生化指标结果显示,各组指标没有统计学上的差异;各实验组的小鼠体重没有明显的差异,各组的脏器指数也没有统计学意义;各组小鼠脏器标本的病理切片HE染色中可见,小鼠肝、脾、肾、心、肺细胞均无水肿、变性、坏死等改变;在组织的普鲁士兰染色中,我们可以清楚的看到在高剂量组除在肺组织内较少见到蓝染的铁外,其他组织内均可见到蓝色铁。
结论:小鼠对实验制备的新生血管靶向超顺磁性氧化铁造影剂经尾静脉注射时,LD50>570mgFe/Kg,远高于临床所需用量(0.56-0.84mgFe/Kg),且主要脏器的病理检查,血液学检测亦未见明显改变,表明其急性及亚急性毒性很低。
Part I: Construction and evaluation of RGD-USPIO nanoparticles for tumor MR imaging.
Objective: To develop tumor angiogenesis targeted superparamagnetic MR contrast agent,to investigate the cRGD-USPIO binding ability to cells and its application in tumor MR molecular imaging.
Method: Ultra-small superparamagnetic iron oxide (USPIO) nanoparticles were prepared by one step chemical co-precipitation method. Tumor angiogenesis targeted superparamagnetic nanoparticles were prepared by covalently conjugating cyclic RGD(c-RGD) containing peptide sequence RGD to USPIO. We used optical microscopy and transmission electron microscopy to observe the nanoparticles’morphology and detect the size of the core of particles. USPIO and cRGD-USPIO particles size distribution were analyzed by laser scattering analyzer. Iron content in cRGD-USPIO was detected by phenanthroline assay. Human lung adenocarcinoma cell line A549 and human umbilical vein endothelial cells (HUVECs) were cultured. cRGD-USPIO and USPIO were incubated with A549 cells and HUVECs respectively for 24h, after 24h ,Prussian blue staining was performed to detect the specific binding ability of cRGD-USPIO to A549 cells and to HUVECs. In vitro, we established A549 xenograft models in nude mice. The nude mice were scanned first. Then USPIO and cRGD-USPIO were intravenously injected to nude mice. After 24h MRI was applied to detect and gather the signal strength. By comparing with USPIO, cRGD-USPIO enhancement to MR signal in diagnosing tumors was evaluated.
Result: We successfully developed cRGD-USPIO nanoparticles. The core diameter varies from 5 to 10 nm. The mean diameter of cRGD-USPIO is 43.97±10.1nm. The quality saturation magnetic intensity is 59.94 emu/g and the iron content is 22.88mg/ml.Cell binding ability experiments suggested that compared with the USPIO group, cRGD-USPIO group significantly increased the positive staining. MRI diagnosis in animals showed that reduce the signal strength of USPIO group was 315.76±69.85 and reduce the signal strength of cRGD-USPIO group was 792.17±116.51 which is 2.5 times more than that of USPIO group, compared with the USPIO group, tumor signal was significantly decreased in the cRGD-USPIO group (P <0.01).
Conclusion: cRGD-USPIO nanoparticles were successfully prepared. These nanoparticles maintain stable phyiscal and chemical properties. cRGD-USPIO and bound with A549 cells and HUVECs 100% respectively. The cRGD-USPIO nanoparticles we developed could be a novel specific MR negative contrast agent in early tumors diagnosis.
Part II: Acute and subacute toxicity test for tumor angiogenesis targeted iron oxide nanoparticles.
Objective: To evaluate the toxicity of cRGD-USPIO
Method: 30 Kunmming mice were randomly divided into 3 groups. The mice in one group were injected with saline through tail vein. The second group was injected with low dose of cRGD-USPIO and the third group with high dose of cRGD-USPIO. After injection, external organs, skin changes, activity, food intake, body weight changes were observed. After 2 weeks, retrobulbar venous plexus blood was taken and RBC、WBC、total hemoglobin(HGB) and platelets(Plt) were counted. Automatic Analyzer 7600-110 biochemical analyzer was used to detect ALT、AST、TBIL、UREA、UA、CREA. Then the mice were sacrificed. The organ index was calculated and HE and Prussian blue staining were performed.
Result: In our study, Mice were administered with maximum dose. In acute toxicity test, there was no death. We observed that mice in high-dose group had a temporary short time of less activity, while mice in other groups were normal. After 1 week, external organs, skin fur, activity and food intake were normal in all groups. After 2 weeks, retrobulbar venous plexus blood was taken for regular blood test. We observed that there was no significant difference among the three groups. Results of biochemical indicator suggest that there were no significant difference too; there was no difference of weight changes in all groups. HE staining was visible in mice biopsy samples of each group. No edema, degeneration and necrosis were observed in the liver、spleen、kidney、heart and lung cells of mice in each group. In Prussian blue staining, we can clearly observer blue staining of iron in all tissues except the lung of mice in high-dose group.
Conclusion: The LD50 of mice injected intravenously with superparamagnetic iron oxide contrast agent > 570mgFe/Kg, much higher than the amount of clinical practice (0.56-0.84mgFe/Kg). We performed pathological and blood test. No change was significantly observed. Our study suggests that cRGD-USPIO is of low toxicity.
目的:制备具有肿瘤新生血管靶向的超顺磁性造影剂;体外细胞实验检测cRGD-USPIO与细胞的结合能力并初步探讨其在肿瘤MR成像中的应用。
方法:化学共沉淀一步法制备超小型超顺磁性氧化铁纳米粒,采用化学交联法将含有RGD序列的环形短肽(cRGD)与USPIO共价结合制备具有肿瘤新生血管靶向的超顺磁性氧化铁纳米粒;光学显微镜、透射电镜对所制备的肿瘤新生血管靶向纳米粒行形态学观察和核心粒径大小的检测;采用激光散射粒度分析仪测定USPIO和cRGD-USPIO的粒径分布;振动样品磁强计检测比饱和磁化强度;采用邻二氮菲法检测cRGD-USPIO中铁含量。培养人肺腺癌A549细胞及人脐静脉内皮细胞(HUVECs),并将cRGD-USPIO和USPIO分别与A549细胞和人脐静脉内皮细胞孵育24h,24h后采用普鲁士兰染色法检测cRGD-USPIO和USPIO与人肺腺癌A549细胞及人脐静脉内皮细胞的特异性结合能力;在体内试验中,建立A549裸鼠移植瘤模型,先行平扫,然后分别尾静脉注射USPIO和cRGD-USPIO,24h后行MRI检测并收集信号强度,与USPIO对比,评价cRGD-USPIO对肿瘤MRI信号增强作用。
结果:制备获得cRGD-USPIO纳米粒,其核心纳米粒径为5nm～10nm,cRGD-USPIO平均粒径为(43.97±10.1)nm,饱和磁化强度为59.94 emu/g,其铁的含量为22.88mg/ml。细胞结合实验结果提示与USPIO组比较,cRGD-USPIO组阳性染色明显增强。动物体内MRI诊断结果显示,USPIO组信号强度降低值为315.76±69.85,cRGD-USPIO组的信号强度降低值为792.17±116.51,约是USPIO组信号强度降低值的2.5倍,肿瘤信号强度明显降低(P﹤0.01)
结论:成功制备了cRGD-USPIO纳米粒,该纳米粒具有良好的理化性质;构建的靶向超顺磁性氧化铁纳米粒与A549细胞、人脐静脉内皮细胞的结合率为100%;裸鼠体内试验提示构建的靶向超顺磁性氧化铁纳米粒可成为一种新型有助于肿瘤早期诊断特异性的MRI阴性造影剂。
第二部分cRGD-USPIO纳米粒的急性、亚急性毒理实验
目的:研究实验制备的cRGD-USPIO纳米粒的毒性
方法:昆明小鼠30只,分为3组,分别尾静脉注入生理盐水,低剂量的cRGD-USPIO和高剂量的cRGD-USPIO,观察外部器官、皮毛的变化、活动量、进食量、体重等变化;2周后,从眼球后静脉丛取血测定红细胞(RBC)总数、白细胞(WBC)总数、血红蛋白(HGB)、血小板(Plt)、和测定血清生化指标谷丙转氨酶(ALT)、谷草转氨酶(AST)、总胆红素(TBIL)、尿素(UREA)、尿酸(UA)、肌酐(CREA)的含量,然后各组随机处死5只,处死后计算各器官的脏器指数,并做病理切片行HE染色和普鲁士蓝染色。
结果:本实验采用最大给药量的方法,在受试小鼠的急性毒性试验中,未见有小鼠死亡,发现高剂量组在给药后有暂时的少动现象,而其他剂量组均正常,1周后各剂量组小鼠的外部器官、皮毛、活动量、进食量等均正常;2周后从眼球后静脉丛取血测血常规,发现低剂量组和高剂量组与对照组相比无明显差异;血清主要生化指标结果显示,各组指标没有统计学上的差异;各实验组的小鼠体重没有明显的差异,各组的脏器指数也没有统计学意义;各组小鼠脏器标本的病理切片HE染色中可见,小鼠肝、脾、肾、心、肺细胞均无水肿、变性、坏死等改变;在组织的普鲁士兰染色中,我们可以清楚的看到在高剂量组除在肺组织内较少见到蓝染的铁外,其他组织内均可见到蓝色铁。
结论:小鼠对实验制备的新生血管靶向超顺磁性氧化铁造影剂经尾静脉注射时,LD50>570mgFe/Kg,远高于临床所需用量(0.56-0.84mgFe/Kg),且主要脏器的病理检查,血液学检测亦未见明显改变,表明其急性及亚急性毒性很低。
Part I: Construction and evaluation of RGD-USPIO nanoparticles for tumor MR imaging.
Objective: To develop tumor angiogenesis targeted superparamagnetic MR contrast agent,to investigate the cRGD-USPIO binding ability to cells and its application in tumor MR molecular imaging.
Method: Ultra-small superparamagnetic iron oxide (USPIO) nanoparticles were prepared by one step chemical co-precipitation method. Tumor angiogenesis targeted superparamagnetic nanoparticles were prepared by covalently conjugating cyclic RGD(c-RGD) containing peptide sequence RGD to USPIO. We used optical microscopy and transmission electron microscopy to observe the nanoparticles’morphology and detect the size of the core of particles. USPIO and cRGD-USPIO particles size distribution were analyzed by laser scattering analyzer. Iron content in cRGD-USPIO was detected by phenanthroline assay. Human lung adenocarcinoma cell line A549 and human umbilical vein endothelial cells (HUVECs) were cultured. cRGD-USPIO and USPIO were incubated with A549 cells and HUVECs respectively for 24h, after 24h ,Prussian blue staining was performed to detect the specific binding ability of cRGD-USPIO to A549 cells and to HUVECs. In vitro, we established A549 xenograft models in nude mice. The nude mice were scanned first. Then USPIO and cRGD-USPIO were intravenously injected to nude mice. After 24h MRI was applied to detect and gather the signal strength. By comparing with USPIO, cRGD-USPIO enhancement to MR signal in diagnosing tumors was evaluated.
Result: We successfully developed cRGD-USPIO nanoparticles. The core diameter varies from 5 to 10 nm. The mean diameter of cRGD-USPIO is 43.97±10.1nm. The quality saturation magnetic intensity is 59.94 emu/g and the iron content is 22.88mg/ml.Cell binding ability experiments suggested that compared with the USPIO group, cRGD-USPIO group significantly increased the positive staining. MRI diagnosis in animals showed that reduce the signal strength of USPIO group was 315.76±69.85 and reduce the signal strength of cRGD-USPIO group was 792.17±116.51 which is 2.5 times more than that of USPIO group, compared with the USPIO group, tumor signal was significantly decreased in the cRGD-USPIO group (P <0.01).
Conclusion: cRGD-USPIO nanoparticles were successfully prepared. These nanoparticles maintain stable phyiscal and chemical properties. cRGD-USPIO and bound with A549 cells and HUVECs 100% respectively. The cRGD-USPIO nanoparticles we developed could be a novel specific MR negative contrast agent in early tumors diagnosis.
Part II: Acute and subacute toxicity test for tumor angiogenesis targeted iron oxide nanoparticles.
Objective: To evaluate the toxicity of cRGD-USPIO
Method: 30 Kunmming mice were randomly divided into 3 groups. The mice in one group were injected with saline through tail vein. The second group was injected with low dose of cRGD-USPIO and the third group with high dose of cRGD-USPIO. After injection, external organs, skin changes, activity, food intake, body weight changes were observed. After 2 weeks, retrobulbar venous plexus blood was taken and RBC、WBC、total hemoglobin(HGB) and platelets(Plt) were counted. Automatic Analyzer 7600-110 biochemical analyzer was used to detect ALT、AST、TBIL、UREA、UA、CREA. Then the mice were sacrificed. The organ index was calculated and HE and Prussian blue staining were performed.
Result: In our study, Mice were administered with maximum dose. In acute toxicity test, there was no death. We observed that mice in high-dose group had a temporary short time of less activity, while mice in other groups were normal. After 1 week, external organs, skin fur, activity and food intake were normal in all groups. After 2 weeks, retrobulbar venous plexus blood was taken for regular blood test. We observed that there was no significant difference among the three groups. Results of biochemical indicator suggest that there were no significant difference too; there was no difference of weight changes in all groups. HE staining was visible in mice biopsy samples of each group. No edema, degeneration and necrosis were observed in the liver、spleen、kidney、heart and lung cells of mice in each group. In Prussian blue staining, we can clearly observer blue staining of iron in all tissues except the lung of mice in high-dose group.
Conclusion: The LD50 of mice injected intravenously with superparamagnetic iron oxide contrast agent > 570mgFe/Kg, much higher than the amount of clinical practice (0.56-0.84mgFe/Kg). We performed pathological and blood test. No change was significantly observed. Our study suggests that cRGD-USPIO is of low toxicity.
引文
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[1] Gupta H, Weissleder R. Targeted Contrast Agents in MR Imaging [J].MR Clin North Am.1996, 4(1):171-176.
[2] Herschman HR. Molecular Imaging: Looking at Problems, Seeing Solutions [J].Scienee.2003, 302(5645):605-608.
[3] Lu Y, Low PS. Folate-mediated delivery of macromolecular anticancer therapeutic agents [J].Adv Drag Deliv Rev.2002, 54(5):675-693.
[4] Choi H, Choi SR, Zhou R, et al. Iron oxide nanoparticles as magnetic resonance contrast agent for tumor imaging via folate receptor-targeted delivery [J]. Acad Radol.2004, 11(9):996-1004.
[5] Leamon CP, Low PS. Folate-mediated targeting: from diagnostics to drug and gene delivery [J].Drug Discov Today.2001, 6(1):44-51.
[6] Hong G,Yuan R,Liang B,et al. Folate-functionalized polymeric micelle as hepatic carcinoma-targeted, MRI-ultrasensitive delivery system of antitumor drugs [J].Biomed Microdevices.2008, 10(5):693-700.
[7]龚金兰,汪森明,胡喜钢等.肿瘤靶向性药物载体叶酸一壳聚糖微球的制备及特性研究.2008,28(12):2183-2186。
[8]刘洪玲,李军.肿瘤靶向PEI包覆磁性纳米凝胶的光化学制备及征.2008,29(8):1703-1706。
[9] Choi H, Choi SR, Zhou R, et al. Iron oxide nanoparticles as magnetic resonance contrast agent for tumor imaging via folate receptor-targeted delivery [J]. Acad Radiol. 2004, 11(9):996-1004.
[10] Zitzmann S, Ehemann V, Schwab M, et al. Arginine-glycine-aspartic acid (RGD)-peptide binds to both tumor and tumor-endothelial cells in vivo[J]. Cancer Res.2002, 62(18):5139-5143.
[11] Winter PM, Morawski AM, Caruthers SD, et al. Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta3-integrin-targeted nanoparticles[J]. Circulation. 2003, 108(18):2270-2274.
[12] Harris TD, Kslogeropoulous S, Nguyen T, et al. Design, synthesis, and evaluation of radiolabeled integrin alpha v beta 3 receptor antagonists for tumor imaging and radiotherapy [J]. Cancer Biother Radiopharm. 2003, 18(4):627-641.
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