核素标记多肽K237在肺癌分子显像和靶向治疗中的实验研究
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摘要
第一部分99Tcm_K237的制备及其小鼠体内分布
目的：探索99Tcm标记多肽K237的方法,研究标记物的稳定性及其小鼠体内的代谢分布情况。
方法：采用99Tcm直接标记多肽K237。探索不同标记条件下产物的标记率、放化纯、体外稳定性及其生物学活性改变。正常小鼠尾静脉注射99Tcm-K237(2.96 MBq,O.1 m1)后30 min和1、2、4、8及24 h后处死,取血液及主要脏器,称重并测量放射性,测定其每克组织百分注射剂量率(%ID/g)。将99Tcm-K237(5.55 MBq,0.1 m1)经荷人肺癌A549裸鼠尾静脉注射,于注射后1、2、3、5及8 h显像。
结果：本实验条件下得到99Tcm-K237的标记率和放化纯均>95%,其与人脐静脉内皮细胞(HUVEC)的最高特异性结合率为40.36%。99Tcm_K237在生理盐水和正常人血清中放置24 h后,其放化纯分别为(89.1±1.4)%和(88.3±1.1)%,二者差异无统计学意义(t=1.56,P>0.05)。静脉注射99Tcm_K237后24 h内,小鼠血液放射性清除迅速,放射性主要聚集在肾脏并经其清除,其它组织器官的放射性随时间逐渐降低。99Tcm-K237荷人肺癌A549裸鼠显像示肿瘤组织摄取高,不同时间的肿瘤／对侧正常组织放射性计数比值(T/NT)最高可达3.97±0.31。
结论：99Tcm-K237易于制备,标记率高,体内外稳定性好,具有较理想且符合实际的动物体内动力学表现,可望成为一种新的靶向性肿瘤血管生成显像剂。
第二部分131I-K237的制备及其在荷人肺癌裸鼠中的生物分布
目的：探索131I标记多肽K237的方法,研究标记物131I-K237的稳定性及其荷人肺癌A549裸鼠体内的生物学分布。
方法：采用Iodogen法131I标记多肽K237,人奇静脉内皮细胞(HUVEC)增值抑制试验和竞争抑制试验检测131I-K237的生物活性。将131I-K237经荷人肺癌A549裸鼠尾静脉注射后于不同时间处死,取肿瘤及主要脏器,测定各组织中每克组织的放射性百分注射剂量率(%ID/g)。
结果：本实验条件下得制备的131I-K237标记率为(60.16±1.21)%,经分离纯化后其放化纯为(96.87±0.82)%。分别在生理盐水和正常人血清中放置24 h后,131I-K237的放化纯仍>90%。HUVEC增值抑制试验显示不同浓度下131I-K237与未标记K237的抑制率均无明显差别(P>0.05)。131I-K237经荷瘤裸鼠尾静脉注射后,血液中放射性清除迅速,肾脏相对高摄取。给药后肿瘤/对侧相应部位肌肉组织的放射性比值(T/N)随时间延长而逐渐升高,12 h达到最高为4.3 1,24 h仍有4.19。
结论：131I-K237易于制备,具有较理想的动物体内动力学和对肿瘤的高亲和性,是一具有潜在的新型靶向性肿瘤血管生成显像和治疗药物。
第三部分131I标记K237靶向治疗荷人肺癌裸鼠的实验研究
目的：观察多肽K237及131I标记K237(131I-K237)对荷人肺癌A549裸鼠肿瘤靶向和放射性核素双重治疗的疗效。
方法：25只实验鼠建立荷人肺癌A549瘤裸鼠模型后,随机分成5组,分别为对照组(生理盐水)、131I组(11.1 MBq131I)、K237组(40μg)、131I-K237静脉组(含K237 40μg,1 1.1 MBq131I),以上各组均经裸鼠尾静脉给药,及131I-K237瘤体内注射组(含K237 40μg,11.1 MBq13’I)。各实验鼠均于15天后再次给药,剂量与第一次相同,定期测量肿瘤体积。实验至第31天处死小鼠,比较肿瘤的体积,计算抑瘤率,并通过生物化学、免疫组织化学及病理组织学等方法检测131I-K237对肿瘤生长的抑制作用及其对正常组织器官的放射毒副作用,检测CD34在各组肿瘤组织中的表达。两样本均数比较行成组设计t检验,多组均数比较用单因素方差分析。
结果：治疗结束时,13I-K237静脉和瘤体内注射组、K237组及131I组的抑瘤率分别为75.01%、78.99%、31.15%、12.61%。131I-K237静脉和瘤体内注射组肿瘤平均体积较小,与生理盐水对照组、K237组和131I组比较,差异均有统计学意义(P<0.01)。病理检查显示131I-K237治疗组和K237组肿瘤细胞发生明显坏死；未发现肝、肾和血液的辐射损伤效应。
结论：131I-K237对荷人肺癌裸鼠移植瘤的生长具有明显的抑制作用,未发现明显的毒副作用。
Part 1 Study on preparation of 99Tcm-K237 and it's biodistribution in mice
Objective A novel peptide K237, which was isolated from a phage-displayed peptide library, can inhibit tumor growth and metastasis by blocking the binding of vascular endothelial growth factor(VEGF) to it's KDR receptor.The aim of this study was to explore the method of the radiolabeling of peptides K237 with 99Tcm and investigate the stability of 99Tcm-K237 and its distribution in mice.
Methods Peptide K237 was labeled directly with 99Tcm. The labeling rate, the radiochemic purity, the in vitro stability and the biologic activity of Tcm-K237 were studied under various conditions.99Tcm-K237 was injected through tail vein of normal mice with 2.96 MBq in a volume of 0.1 ml. Those mice were killed at different stages after injection and their blood and other major organs were taken out, then the radioactivity count of these organs were measured to investigate the biodistribution. 99Tcm-K237 of 0.1 ml 5.55 MBq was injected into the tail vein of tumor bearing nude mice, then imaged at 1、2、3、5 and 8 h.
Results Under the conditions of SnCl2·2H2O 100μg, K237 100μg, pH value 6.0, reaction time 10～30 min and reaction temperature 4～37℃, the labeling rate and the radiochemic purity of 99Tcm-K237 were more than 95%. The specific binding efficiency of 99Tcm-K237 with human umbilical vein endothelial cell (HUVEC) was 40.36%. After 99Tcm-K237 was placed in physiologic saline and in blood serum, the radiochemic purity was respectively (89.1±1.4)% and (88.3±1.1)% at 24 h, while there was no significant difference between the two groups(t=1.56, P>0.05). In the first 24 h postinjection, the biodistribution in mice showed rapid blood and renal clearance with gradually excreted in other organs or tissues including heart, liver, lungs, stomach and muscle, most of the radioactivity was observed in renal. In imaging, the uptake ratios of tumor to background (T/B) at 1、2、3、5 and 8 h were 1.25±0.11、3.13±0.26、3.97±0.31、1.34±0.29 and 1.18±0.25, respectively.
Conclusion 99Tcm-K237, which is an easily prepared and labeled compound with high labeling rate and stability, will be a potential tumor imaging agent.
Part 2 Study on preparation of 131I-K237 and it's biodistribution in nude mice bearing human lung cancer
Objective To explore the method of the radiolabeling of peptide K237 with 131I and investigate the stability of 131I-K237 and its distribution in nude mice bearing human lung cancer.
Methods Iodogen method was used for 131I labeling K237. The bioactivity of 131I-K237 was tested by HUVEC proliferation inhibitory assay and the affinity of 131I-K237 was examined by competition binding studies.131I-K237 was injected through tail vein of nude mice with 2.96 MBq in a volume of 0.1 ml to investigate the biodistribution. Those mice were killed at different stages after injection and their blood and other major organs were taken out, then the radioactivity counts of these organs were measured to investigate the biodistribution.
Results The labeling rate of 131I-K237 was 60.16%, radiochemical purity was above 95%. The inhibition rate of HUVEC proliferation had no significant difference between radiolabeled K237 and unlabeled K237(P>0.05). After 131I-K237 was placed in physiologic saline and in blood serum, the radiochemic purity was>95%,respectively. The ratios of tumor to muscle(T/N) were 2.12、2.32、2.51、2.70、3.03、4.31and 4.19 at 30min、1 h、2 h、4 h、8 h、12 h and 24 h, respectively.
Conclusion 131I-K237, which is an easily prepared and labeled compound with high labeling rate and stability, will be a potential targeting tumor imaging and treating agent.
Part 3 Experimental study on targeting therapy in nude mice bearing human lung cancer with 131I-K237
Objective To investigate the targeted therapeutic efficiency of 131I radiolabeled peptide K237 (131I-K237) on nude mice bearing human lung cance.
Methods Human lung cancer xenografts with positive KDR expression were established in nude mice. All 25 mice models were divided into five groups randomly, including physiologic saline group, 131I-K237 group intravenously,131I-K237 group intratumorally, K237 group and 131I group. Thirty-one days after infusion, the tumor growth inhibition rate was calculated.The inhibited effect and the radiation breakdown of 131I-K.237 on nude mice were determined by biochemical, immunohistochemical and pathohistology methods.
Results Tthe inhibition rate of HUVEC proliferation had no significant difference between radiolabeled K237 and unlabeled K237(t=1.67, P> 0.05). The growth of transplanted lung cancer was inhibited by 75.01%, 78.99%,31.15% and 12.61% at groups treated with 131I-K237 intravenously, 131I-K237 intratumorally, K237 and 131I, respectively. The average tumor volume of the 131I-K237 trial groups less than that of the control, K237 and 131I group (P<0.01). Irreversible destruction of tumor cells in 131I-K237 trial groups and K237 group was found under light and electron microscope. There was no effect of radiation breakdown on liver, kidney, spleen and blood-cell in nude mice.
Conclusion 131I-K237 can effectively inhibit the growth of tumor in nude mice bearing human lung cancer, with little obvious side effects.
目的：探索99Tcm标记多肽K237的方法,研究标记物的稳定性及其小鼠体内的代谢分布情况。
方法：采用99Tcm直接标记多肽K237。探索不同标记条件下产物的标记率、放化纯、体外稳定性及其生物学活性改变。正常小鼠尾静脉注射99Tcm-K237(2.96 MBq,O.1 m1)后30 min和1、2、4、8及24 h后处死,取血液及主要脏器,称重并测量放射性,测定其每克组织百分注射剂量率(%ID/g)。将99Tcm-K237(5.55 MBq,0.1 m1)经荷人肺癌A549裸鼠尾静脉注射,于注射后1、2、3、5及8 h显像。
结果：本实验条件下得到99Tcm-K237的标记率和放化纯均>95%,其与人脐静脉内皮细胞(HUVEC)的最高特异性结合率为40.36%。99Tcm_K237在生理盐水和正常人血清中放置24 h后,其放化纯分别为(89.1±1.4)%和(88.3±1.1)%,二者差异无统计学意义(t=1.56,P>0.05)。静脉注射99Tcm_K237后24 h内,小鼠血液放射性清除迅速,放射性主要聚集在肾脏并经其清除,其它组织器官的放射性随时间逐渐降低。99Tcm-K237荷人肺癌A549裸鼠显像示肿瘤组织摄取高,不同时间的肿瘤／对侧正常组织放射性计数比值(T/NT)最高可达3.97±0.31。
结论：99Tcm-K237易于制备,标记率高,体内外稳定性好,具有较理想且符合实际的动物体内动力学表现,可望成为一种新的靶向性肿瘤血管生成显像剂。
第二部分131I-K237的制备及其在荷人肺癌裸鼠中的生物分布
目的：探索131I标记多肽K237的方法,研究标记物131I-K237的稳定性及其荷人肺癌A549裸鼠体内的生物学分布。
方法：采用Iodogen法131I标记多肽K237,人奇静脉内皮细胞(HUVEC)增值抑制试验和竞争抑制试验检测131I-K237的生物活性。将131I-K237经荷人肺癌A549裸鼠尾静脉注射后于不同时间处死,取肿瘤及主要脏器,测定各组织中每克组织的放射性百分注射剂量率(%ID/g)。
结果：本实验条件下得制备的131I-K237标记率为(60.16±1.21)%,经分离纯化后其放化纯为(96.87±0.82)%。分别在生理盐水和正常人血清中放置24 h后,131I-K237的放化纯仍>90%。HUVEC增值抑制试验显示不同浓度下131I-K237与未标记K237的抑制率均无明显差别(P>0.05)。131I-K237经荷瘤裸鼠尾静脉注射后,血液中放射性清除迅速,肾脏相对高摄取。给药后肿瘤/对侧相应部位肌肉组织的放射性比值(T/N)随时间延长而逐渐升高,12 h达到最高为4.3 1,24 h仍有4.19。
结论：131I-K237易于制备,具有较理想的动物体内动力学和对肿瘤的高亲和性,是一具有潜在的新型靶向性肿瘤血管生成显像和治疗药物。
第三部分131I标记K237靶向治疗荷人肺癌裸鼠的实验研究
目的：观察多肽K237及131I标记K237(131I-K237)对荷人肺癌A549裸鼠肿瘤靶向和放射性核素双重治疗的疗效。
方法：25只实验鼠建立荷人肺癌A549瘤裸鼠模型后,随机分成5组,分别为对照组(生理盐水)、131I组(11.1 MBq131I)、K237组(40μg)、131I-K237静脉组(含K237 40μg,1 1.1 MBq131I),以上各组均经裸鼠尾静脉给药,及131I-K237瘤体内注射组(含K237 40μg,11.1 MBq13’I)。各实验鼠均于15天后再次给药,剂量与第一次相同,定期测量肿瘤体积。实验至第31天处死小鼠,比较肿瘤的体积,计算抑瘤率,并通过生物化学、免疫组织化学及病理组织学等方法检测131I-K237对肿瘤生长的抑制作用及其对正常组织器官的放射毒副作用,检测CD34在各组肿瘤组织中的表达。两样本均数比较行成组设计t检验,多组均数比较用单因素方差分析。
结果：治疗结束时,13I-K237静脉和瘤体内注射组、K237组及131I组的抑瘤率分别为75.01%、78.99%、31.15%、12.61%。131I-K237静脉和瘤体内注射组肿瘤平均体积较小,与生理盐水对照组、K237组和131I组比较,差异均有统计学意义(P<0.01)。病理检查显示131I-K237治疗组和K237组肿瘤细胞发生明显坏死；未发现肝、肾和血液的辐射损伤效应。
结论：131I-K237对荷人肺癌裸鼠移植瘤的生长具有明显的抑制作用,未发现明显的毒副作用。
Part 1 Study on preparation of 99Tcm-K237 and it's biodistribution in mice
Objective A novel peptide K237, which was isolated from a phage-displayed peptide library, can inhibit tumor growth and metastasis by blocking the binding of vascular endothelial growth factor(VEGF) to it's KDR receptor.The aim of this study was to explore the method of the radiolabeling of peptides K237 with 99Tcm and investigate the stability of 99Tcm-K237 and its distribution in mice.
Methods Peptide K237 was labeled directly with 99Tcm. The labeling rate, the radiochemic purity, the in vitro stability and the biologic activity of Tcm-K237 were studied under various conditions.99Tcm-K237 was injected through tail vein of normal mice with 2.96 MBq in a volume of 0.1 ml. Those mice were killed at different stages after injection and their blood and other major organs were taken out, then the radioactivity count of these organs were measured to investigate the biodistribution. 99Tcm-K237 of 0.1 ml 5.55 MBq was injected into the tail vein of tumor bearing nude mice, then imaged at 1、2、3、5 and 8 h.
Results Under the conditions of SnCl2·2H2O 100μg, K237 100μg, pH value 6.0, reaction time 10～30 min and reaction temperature 4～37℃, the labeling rate and the radiochemic purity of 99Tcm-K237 were more than 95%. The specific binding efficiency of 99Tcm-K237 with human umbilical vein endothelial cell (HUVEC) was 40.36%. After 99Tcm-K237 was placed in physiologic saline and in blood serum, the radiochemic purity was respectively (89.1±1.4)% and (88.3±1.1)% at 24 h, while there was no significant difference between the two groups(t=1.56, P>0.05). In the first 24 h postinjection, the biodistribution in mice showed rapid blood and renal clearance with gradually excreted in other organs or tissues including heart, liver, lungs, stomach and muscle, most of the radioactivity was observed in renal. In imaging, the uptake ratios of tumor to background (T/B) at 1、2、3、5 and 8 h were 1.25±0.11、3.13±0.26、3.97±0.31、1.34±0.29 and 1.18±0.25, respectively.
Conclusion 99Tcm-K237, which is an easily prepared and labeled compound with high labeling rate and stability, will be a potential tumor imaging agent.
Part 2 Study on preparation of 131I-K237 and it's biodistribution in nude mice bearing human lung cancer
Objective To explore the method of the radiolabeling of peptide K237 with 131I and investigate the stability of 131I-K237 and its distribution in nude mice bearing human lung cancer.
Methods Iodogen method was used for 131I labeling K237. The bioactivity of 131I-K237 was tested by HUVEC proliferation inhibitory assay and the affinity of 131I-K237 was examined by competition binding studies.131I-K237 was injected through tail vein of nude mice with 2.96 MBq in a volume of 0.1 ml to investigate the biodistribution. Those mice were killed at different stages after injection and their blood and other major organs were taken out, then the radioactivity counts of these organs were measured to investigate the biodistribution.
Results The labeling rate of 131I-K237 was 60.16%, radiochemical purity was above 95%. The inhibition rate of HUVEC proliferation had no significant difference between radiolabeled K237 and unlabeled K237(P>0.05). After 131I-K237 was placed in physiologic saline and in blood serum, the radiochemic purity was>95%,respectively. The ratios of tumor to muscle(T/N) were 2.12、2.32、2.51、2.70、3.03、4.31and 4.19 at 30min、1 h、2 h、4 h、8 h、12 h and 24 h, respectively.
Conclusion 131I-K237, which is an easily prepared and labeled compound with high labeling rate and stability, will be a potential targeting tumor imaging and treating agent.
Part 3 Experimental study on targeting therapy in nude mice bearing human lung cancer with 131I-K237
Objective To investigate the targeted therapeutic efficiency of 131I radiolabeled peptide K237 (131I-K237) on nude mice bearing human lung cance.
Methods Human lung cancer xenografts with positive KDR expression were established in nude mice. All 25 mice models were divided into five groups randomly, including physiologic saline group, 131I-K237 group intravenously,131I-K237 group intratumorally, K237 group and 131I group. Thirty-one days after infusion, the tumor growth inhibition rate was calculated.The inhibited effect and the radiation breakdown of 131I-K.237 on nude mice were determined by biochemical, immunohistochemical and pathohistology methods.
Results Tthe inhibition rate of HUVEC proliferation had no significant difference between radiolabeled K237 and unlabeled K237(t=1.67, P> 0.05). The growth of transplanted lung cancer was inhibited by 75.01%, 78.99%,31.15% and 12.61% at groups treated with 131I-K237 intravenously, 131I-K237 intratumorally, K237 and 131I, respectively. The average tumor volume of the 131I-K237 trial groups less than that of the control, K237 and 131I group (P<0.01). Irreversible destruction of tumor cells in 131I-K237 trial groups and K237 group was found under light and electron microscope. There was no effect of radiation breakdown on liver, kidney, spleen and blood-cell in nude mice.
Conclusion 131I-K237 can effectively inhibit the growth of tumor in nude mice bearing human lung cancer, with little obvious side effects.
引文
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