前列腺癌特异性分子探针的构建及其活体MR成像实验研究
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摘要
目的:
1.培养人前列腺癌细胞系,建立前列腺癌荷瘤裸鼠模型,探讨PSCA在其中的表达及其意义;
2.应用纳米金磁微粒标记抗人PSCA单抗7F5,构建前列腺癌特异性MR分子探针7F5@GoldMag,检测其与前列腺癌细胞结合的特异性;
3.探讨7F5@GoldMag用于体外、体内MR显像的可行性及其在PCa特异性诊断中的价值和意义。
方法:
1.培养人前列腺癌细胞系LNCaP、PC-3和人肝癌细胞系SMMC-7721,建立荷瘤裸鼠模型,利用免疫组织化学,间接免疫荧光,免疫细胞化学,流式细胞术和western blotting等方法,检测PSCA在体外培养的前列腺癌细胞系及荷瘤裸鼠肿瘤中的表达。
2.将金磁微粒作为MR对比剂标记7F5,应用非共价键偶联方法构建前列腺癌特异性MR分子探针7F5@GoldMag,通过激光共聚焦显微镜观察,流式细胞术,透射电镜观察等方法,检测探针与前列腺癌细胞结合的特异性。
3.利用临床应用的3.0T磁共振扫描仪建立MR扫描序列,观察不同浓度的金磁微粒MR成像情况,探讨MR可分辨的最低浓度;研究探针用于特异性体外细胞成像的可行性;对荷瘤裸鼠经尾静脉注射7F5@GoldMag,分别在注射前、注射后6 h、12 h和24 h行MR扫描,观察其对肿瘤T2WI信号的影响,探讨其用于体内肿瘤MR成像的可行性。
结果:
1.人前列腺癌细胞系LNCaP、PC-3及人肝癌细胞系SMMC-7721呈单层贴壁生长;LNCaP细胞成瘤率12.5%(1/8);PC-3和SMMC-7721细胞成瘤率100%(8/8);免疫细胞化学染色、间接免疫荧光、Western-blot及流式细胞术检测结果证实LNCaP、PC-3细胞表达PSCA;SMMC-7721细胞不表达PSCA;荷瘤裸鼠组织的免疫组织化学染色证实了类似结果。
2.成功构建了前列腺癌特异性MR分子探针7F5@GoldMag;流式细胞术检测结果7F5@GoldMag与LNCaP及PC-3细胞结合率分别为85.2%和92.1%,而与SMMC-7721细胞结合率为4.2%,无关抗体@GoldMag组三种细胞均为阴性;激光共聚焦显微镜观察见LNCaP和PC-3细胞与7F5@GoldMag有特异性结合,红色荧光位于细胞膜,SMMC-7721细胞的胞膜未见红色荧光,无关抗体组各细胞系均为阴性;透射电镜观察LNCaP及PC-3靠近细胞膜可见多个直径约50nm的团块状致密电子密度颗粒聚集, SMMC-7721细胞表面未见致密电子密度颗粒,无关抗体@GoldMag组各细胞系均仅个别视野见少量致密电子密度颗粒,且距离细胞膜较远。
3. GoldMagTM-CS稀释至1:640与1%琼脂糖凝胶相比,T2WI序列信号强度差异有统计学意义;利用7F5@GoldMag标记不同细胞系行MR扫描结果提示, 7F5@GoldMag可显著降低LNCaP和PC-3细胞T2WI信号,而对SMMC-7721MR信号无显著影响。非特异抗体偶联的GoldMag对三种细胞MR信号均无显著影响。
4.荷瘤裸鼠MR显像结果,PC-3荷瘤裸鼠注射7F5@GoldMag 6 h、12 h和24 h后肿瘤组织T2WI信号强度较平扫显著降低(ANOVA,F=43.675,p=0.000);注射探针后12 h较6 h信号强度有进一步降低(p=0.001);注射后12 h和24 h肿瘤信号强度差异无统计学意义(p=0.145)。而SMMC-7721+7F5@GoldMag、PC-3+无关抗体@GoldMag和SMMC-7721+无关抗体@GoldMag组在平扫和注射造影剂后6 h、12 h和24 h肿瘤信号强度差异无统计学意义。
结论:
应用纳米金磁微粒与抗人PSCA单抗7F5偶联成功构建了前列腺癌特异性MR探针7F5@GoldMag,具有良好的理化性质和免疫活性,在3.0 T MR扫描仪检测对体外前列腺癌细胞及活体前列腺癌组织具有靶向性的增强效果,为下一步的临床实验打下了基础。
Objective:
1. To cultivate prostate cancer cell lines and to establish the nude mice model grafted with human PCa and to determine the expression of PSCA.
2. To construct the PSCA specific MR molecular probe 7F5@GoldMag, and to examine its biochemical characteristics.
3. To investigate the feasibility of in vitro and in vivo MRI of 7F5@GoldMag in PCa by using a clinical 3.0 T MR system.
Methods:
1. Prostate cancer cell lines were cultured and nude mice models were established. The expression of PSCA of prostate cancer cell lines and nude mice model was determined by using indirect immunofluorescence, immunocytochemistry, flow cytometry, western blotting and immunohistochemistry.
2. The PSCA specific MR molecular probe 7F5@GoldMag was constructed by conjugating anti-human PSCA mAb 7F5 with GoldMagTM-CS nanoparticles, and the coupling efficiency was calculated. The specific binding capability for 7F5@GoldMag to prostate cancer cells was detected by using laser confocal microscopy, transmission electron microscope and flow cytometry.
3. MR scan sequences were established by using a clinical 3.0 T MR scanner. GoldMagTM-CS nanoparticles solution in different concentration was scanned to ascertain the lowest concentration that can be detected by MR system. The feasibility of molecular imaging of PSCA specific MR probe 7F5@GoldMag in vitro and in vivo was investigated. After conventional scan, T2W images were obtained after the probe was injected into nude mice model through caudal vein 6 h, 12 h and 24 h later, respectively. Statistical analyses were performed to assess the statistical differences of tumor signal intensity using one-way ANOVA with SPSS 11.5 software package as parameters were normally distributed. p<0.05 was considered as statistically significant difference.
Results:
1. The LNCaP, PC-3 and SMMC-7721 cells were injected subcutaneously in nude mice and the tumor incidence rates were LNCaP 12.5% (1/8), PC-3 100% (8/8) and SMMC-7721 100% (8/8), respactively. The results of indirect immunofluorescence, immunocytochemistry, flow cytometry, western blotting and immunohistochemistry showed that PSCA had high level expression on the plasma membrane of LNCaP and PC-3 cells, while no positive findings on the plasma membrane of SMMC-7721 cells.
2. The PSCA specific MR molecular probe (7F5@GoldMag) was successfully constructed. The results of laser confocal microscopy, transmission electron microscope and flow cytometry proved that 7F5@GoldMag can specific bind with LNCaP and PC-3 cells.
3. The T2WI signal intensity of GoldMagTM-CS was significantly lower than that of agarose gel even if the former was diluted by 640 times. 7F5@GoldMag could specificly decrease T2WI signal intensity of LNCaP and PC-3 cells in vitro.
4. After the probe 7F5@GoldMag was injected into nude mice model through caudal vein 6 h, 12 h and 24 h later, T2WI signal intensity of PC-3 tumor was significantly lower than that of conventional scan (ANOVA, F=43.675, p=0.000). After the probe was injected 12 h later, the signal intensity showed further decrease than 6 h later (p=0.001). The tumor signal intensity showed no significant difference between 12 h and 24 h (p=0.145). While the signal intensity of control groups didn’t show significant difference after injection of 7F5@GoldMag and non-related IgG@GoldMag, respectively.
Conclusion:
1. The PSCA specific MR molecular probe (7F5@GoldMag) was successfully constructed by conjugating anti-human PSCA mAb 7F5 with GoldMagTM-CS nanoparticles. It could specificly bind with PSCA positive prostate cancer cells.
2. 7F5@GoldMag has target-directed enhancement effect in prostate cancer cell lines in vitro and in nude mice model grafted with PC-3 in vivo using a clinical 3.0 T MR scanner. It may therefore be a new noninvasive specific MR molecular probe in early-stage diagnosis of prostate carcinoma in the future.
1.培养人前列腺癌细胞系,建立前列腺癌荷瘤裸鼠模型,探讨PSCA在其中的表达及其意义;
2.应用纳米金磁微粒标记抗人PSCA单抗7F5,构建前列腺癌特异性MR分子探针7F5@GoldMag,检测其与前列腺癌细胞结合的特异性;
3.探讨7F5@GoldMag用于体外、体内MR显像的可行性及其在PCa特异性诊断中的价值和意义。
方法:
1.培养人前列腺癌细胞系LNCaP、PC-3和人肝癌细胞系SMMC-7721,建立荷瘤裸鼠模型,利用免疫组织化学,间接免疫荧光,免疫细胞化学,流式细胞术和western blotting等方法,检测PSCA在体外培养的前列腺癌细胞系及荷瘤裸鼠肿瘤中的表达。
2.将金磁微粒作为MR对比剂标记7F5,应用非共价键偶联方法构建前列腺癌特异性MR分子探针7F5@GoldMag,通过激光共聚焦显微镜观察,流式细胞术,透射电镜观察等方法,检测探针与前列腺癌细胞结合的特异性。
3.利用临床应用的3.0T磁共振扫描仪建立MR扫描序列,观察不同浓度的金磁微粒MR成像情况,探讨MR可分辨的最低浓度;研究探针用于特异性体外细胞成像的可行性;对荷瘤裸鼠经尾静脉注射7F5@GoldMag,分别在注射前、注射后6 h、12 h和24 h行MR扫描,观察其对肿瘤T2WI信号的影响,探讨其用于体内肿瘤MR成像的可行性。
结果:
1.人前列腺癌细胞系LNCaP、PC-3及人肝癌细胞系SMMC-7721呈单层贴壁生长;LNCaP细胞成瘤率12.5%(1/8);PC-3和SMMC-7721细胞成瘤率100%(8/8);免疫细胞化学染色、间接免疫荧光、Western-blot及流式细胞术检测结果证实LNCaP、PC-3细胞表达PSCA;SMMC-7721细胞不表达PSCA;荷瘤裸鼠组织的免疫组织化学染色证实了类似结果。
2.成功构建了前列腺癌特异性MR分子探针7F5@GoldMag;流式细胞术检测结果7F5@GoldMag与LNCaP及PC-3细胞结合率分别为85.2%和92.1%,而与SMMC-7721细胞结合率为4.2%,无关抗体@GoldMag组三种细胞均为阴性;激光共聚焦显微镜观察见LNCaP和PC-3细胞与7F5@GoldMag有特异性结合,红色荧光位于细胞膜,SMMC-7721细胞的胞膜未见红色荧光,无关抗体组各细胞系均为阴性;透射电镜观察LNCaP及PC-3靠近细胞膜可见多个直径约50nm的团块状致密电子密度颗粒聚集, SMMC-7721细胞表面未见致密电子密度颗粒,无关抗体@GoldMag组各细胞系均仅个别视野见少量致密电子密度颗粒,且距离细胞膜较远。
3. GoldMagTM-CS稀释至1:640与1%琼脂糖凝胶相比,T2WI序列信号强度差异有统计学意义;利用7F5@GoldMag标记不同细胞系行MR扫描结果提示, 7F5@GoldMag可显著降低LNCaP和PC-3细胞T2WI信号,而对SMMC-7721MR信号无显著影响。非特异抗体偶联的GoldMag对三种细胞MR信号均无显著影响。
4.荷瘤裸鼠MR显像结果,PC-3荷瘤裸鼠注射7F5@GoldMag 6 h、12 h和24 h后肿瘤组织T2WI信号强度较平扫显著降低(ANOVA,F=43.675,p=0.000);注射探针后12 h较6 h信号强度有进一步降低(p=0.001);注射后12 h和24 h肿瘤信号强度差异无统计学意义(p=0.145)。而SMMC-7721+7F5@GoldMag、PC-3+无关抗体@GoldMag和SMMC-7721+无关抗体@GoldMag组在平扫和注射造影剂后6 h、12 h和24 h肿瘤信号强度差异无统计学意义。
结论:
应用纳米金磁微粒与抗人PSCA单抗7F5偶联成功构建了前列腺癌特异性MR探针7F5@GoldMag,具有良好的理化性质和免疫活性,在3.0 T MR扫描仪检测对体外前列腺癌细胞及活体前列腺癌组织具有靶向性的增强效果,为下一步的临床实验打下了基础。
Objective:
1. To cultivate prostate cancer cell lines and to establish the nude mice model grafted with human PCa and to determine the expression of PSCA.
2. To construct the PSCA specific MR molecular probe 7F5@GoldMag, and to examine its biochemical characteristics.
3. To investigate the feasibility of in vitro and in vivo MRI of 7F5@GoldMag in PCa by using a clinical 3.0 T MR system.
Methods:
1. Prostate cancer cell lines were cultured and nude mice models were established. The expression of PSCA of prostate cancer cell lines and nude mice model was determined by using indirect immunofluorescence, immunocytochemistry, flow cytometry, western blotting and immunohistochemistry.
2. The PSCA specific MR molecular probe 7F5@GoldMag was constructed by conjugating anti-human PSCA mAb 7F5 with GoldMagTM-CS nanoparticles, and the coupling efficiency was calculated. The specific binding capability for 7F5@GoldMag to prostate cancer cells was detected by using laser confocal microscopy, transmission electron microscope and flow cytometry.
3. MR scan sequences were established by using a clinical 3.0 T MR scanner. GoldMagTM-CS nanoparticles solution in different concentration was scanned to ascertain the lowest concentration that can be detected by MR system. The feasibility of molecular imaging of PSCA specific MR probe 7F5@GoldMag in vitro and in vivo was investigated. After conventional scan, T2W images were obtained after the probe was injected into nude mice model through caudal vein 6 h, 12 h and 24 h later, respectively. Statistical analyses were performed to assess the statistical differences of tumor signal intensity using one-way ANOVA with SPSS 11.5 software package as parameters were normally distributed. p<0.05 was considered as statistically significant difference.
Results:
1. The LNCaP, PC-3 and SMMC-7721 cells were injected subcutaneously in nude mice and the tumor incidence rates were LNCaP 12.5% (1/8), PC-3 100% (8/8) and SMMC-7721 100% (8/8), respactively. The results of indirect immunofluorescence, immunocytochemistry, flow cytometry, western blotting and immunohistochemistry showed that PSCA had high level expression on the plasma membrane of LNCaP and PC-3 cells, while no positive findings on the plasma membrane of SMMC-7721 cells.
2. The PSCA specific MR molecular probe (7F5@GoldMag) was successfully constructed. The results of laser confocal microscopy, transmission electron microscope and flow cytometry proved that 7F5@GoldMag can specific bind with LNCaP and PC-3 cells.
3. The T2WI signal intensity of GoldMagTM-CS was significantly lower than that of agarose gel even if the former was diluted by 640 times. 7F5@GoldMag could specificly decrease T2WI signal intensity of LNCaP and PC-3 cells in vitro.
4. After the probe 7F5@GoldMag was injected into nude mice model through caudal vein 6 h, 12 h and 24 h later, T2WI signal intensity of PC-3 tumor was significantly lower than that of conventional scan (ANOVA, F=43.675, p=0.000). After the probe was injected 12 h later, the signal intensity showed further decrease than 6 h later (p=0.001). The tumor signal intensity showed no significant difference between 12 h and 24 h (p=0.145). While the signal intensity of control groups didn’t show significant difference after injection of 7F5@GoldMag and non-related IgG@GoldMag, respectively.
Conclusion:
1. The PSCA specific MR molecular probe (7F5@GoldMag) was successfully constructed by conjugating anti-human PSCA mAb 7F5 with GoldMagTM-CS nanoparticles. It could specificly bind with PSCA positive prostate cancer cells.
2. 7F5@GoldMag has target-directed enhancement effect in prostate cancer cell lines in vitro and in nude mice model grafted with PC-3 in vivo using a clinical 3.0 T MR scanner. It may therefore be a new noninvasive specific MR molecular probe in early-stage diagnosis of prostate carcinoma in the future.
引文
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