~(99m)TC-3P-RGD_2显像定量评价肿瘤整合素αvβ3表达及其应用的实验研究
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摘要
目的：探讨~(99m)Tc-HYNIC-PEG4-E[PEG4-c(RGDfk)]2(简称~(99m)Tc-3P-RGD_2)整合素α_vβ_3受体靶向U-SPECT-II/CT显像定量肿瘤整合素α_vβ_3受体表达水平及早期探测肿瘤复发转移灶进行准确的分期、分级，为新生血管治疗适应症的筛选、个体化治疗疗效早期预测、实时监测提供科学依据。
方法：本课题首先利用U-SPECT-II/CT考察了U-SPECT-CT融合显像对肿瘤体积（存活、坏死）及~(99m)Tc放射性活度精确定量的方法学，然后合成~(99m)Tc-3P-RGD_2，并以整合素α_vβ_3受体靶向的~(99m)Tc-3P-RGD_2在荷瘤鼠内生物学分布及免疫组化对肿瘤整合素α_vβ_3表达水平的定量数据为基础，构建裸鼠皮下移植瘤、肿瘤复发、肺及骨骼转移模型，探讨~(99m)Tc-3P-RGD_2肿瘤U-SPECT-II/CT显像定量肿瘤整合素α_vβ_3受体表达水平的可行性及对肿瘤复发、转移灶的早期探测，最后对整合素α_vβ_3高表达和低表达的肿瘤在抗新生血管治疗前及治疗过程中进行U-SPECT-CT显像,考察其对肿瘤抗血管疗效的治疗前预测和治疗过程中实时监测价值。
结果：基于U-SPECT-II/CT的U-SPECT-CT融合显像，结合microCT和microSPECT信息进行肿瘤感兴趣区勾画精确定量肿瘤体积（包括存活和坏死组织的单独体积测定），且U-SPECT-CT融合显像可有效定量~(99m)Tc放射性活度（R~2=0.9997，y=1.0885x+0.0618），偏倚性小。~(99m)Tc-3P-RGD_2前体可制备试剂盒，标记简单、方便，且荷瘤鼠体内理化特性好，肿瘤放射性摄取高且能稳定滞留一定时间，血、肝、肾等清除快。~(99m)Tc-3P-RGD_2尾静脉注射通过生物学分布实验和U-SPECT-CT显像分别定量肿瘤放射性摄取（%ID和%ID/g），与肿瘤体积变化趋势相似，其中脑胶质瘤内~(99m)Tc-3P-RGD_2放射性摄取（%ID）逐渐增加，通过二次方程曲线拟合（R~2均大于0.95），而在肿瘤重量小于1.0g时，肿瘤放射性摄取（%ID）与肿瘤大小（g）呈直线相关(R~2分别为0.8963和0.8929)。而肿瘤%ID/g随着肿瘤大小的增加而增加，在0.15-0.25g时达到峰值，随后由于肿瘤组织坏死逐渐降低，与免疫组化所示整合素αVβ3表达水平呈线性相关（R~2=0.8117），即~(99m)Tc-3P-RGD_2在脑胶质瘤内分布可有效反应肿瘤整合素αVβ3表达水平。整合素α_vβ_3作为乳腺癌细胞等肿瘤细胞及其新生血管内皮细胞表面高表达的粘附因子，可早期（长径为1.0mm）发现乳腺癌术后复发灶和肺、淋巴结、骨骼等多发转移灶，有效评价乳腺癌等恶性肿瘤的分期、分级，尤其是肺癌等微小转移灶（大于1mm）方面具有显著优势。~(99m)Tc-3P-RGD_2U-SPECT-CT显像通过定量肿瘤~(99m)Tc-3P-RGD_2摄取、整合素受体表达水平、密度，抗新生血管治疗疗效监测明显早于肿瘤体积的变化，治疗后第5天即表现出~(99m)Tc-3P-RGD_2放射性摄取差异（P<0.05），是抗新生血管治疗方案病人治疗前适应症筛选、疗效预测及早期评价的显像手段。
结论：U-SPECT-II/CT通过U-SPECT-CT融合显像可对肿瘤体积及~(99m)Tc放射性活度进行精确定量，~(99m)Tc-3P-RGD_2U-SPECT-CT显像可有效评价肿瘤整合素α_vβ_3受体表达水平，且通过对肿瘤复发、转移灶及时早期的探测和诊断，为肿瘤分期、分级及抗新生血管治疗适应症的筛选、个体化治疗剂量的确定、疗效早期预测、实时评价提供科学依据。
Aim To investigate the quantitive analysis of tumor integrinαvβ3expressionlevel by U-SPECT-CT imaging with integrinαvβ3targeting radiotracer~(99m)Tc-HYNIC-PEG4-E[PEG4-c(RGDfk)]2(~(99m)Tc-3P-RGD_2) and its potent use forearly detection of tumor regional recurrence, distant metastasis, grading. It may offergreat information for patient selection for anti-angiogensis therapy and therapeuticeffect monitoring. Methods U-SPECT-CT fusion imaging was used for exactdelineation of tumor volume, including functional and necrotic tissues, andquantification of~(99m)Tc radioactivity with the equipment of U-SPECT-II/CT. Weprepared the integrin αvβ3targeting radiotracer,~(99m)Tc-3P-RGD_2, and finishedSPECT-CT imaging and biodistribution studies at different time points aftersubcutaneous implantion of tumor cells in nude mice. And relationship wasestablished between tumor uptake(percentage of injected dose%ID and percentage ofinjected dose per gram,%ID/g) with tumor integrin αvβ3expression level. On thebasis of the establishment of the subcutaneous tumor xenograft model and tumorregional recurrence model and lung, bone metastasis model, we investigatedU-SPECT-II/CT imaging for the quantification of tumor integrin αvβ3expression leveland early detection of tumor recurrence and metastasis with radiotracer~(99m)Tc-3P-RGD_2. Different tumor models were established of different expressionlevel integrin αvβ3expression (U87MG glioma with high expression level anddifferentiated thyroid cancer low expression level of intergrinαvβ3).~(99m)Tc-3P-RGD_2U-SPECT-CT imaging was used to monitor the therapeutic effect of antiangiogenesis of tumors with different expression level of integrinα_vβ_3. Results: With anatomicaland function information, U-SPECT-CT fuion images was better for the delineationof tumor volume including functional and necrotic tissues. It was also found thatquantification of~(99m)Tc radioactivity could be done based on U-SPECT-CT imagingwith little bias. Linear relationship was found between radiocounts on U-SPECT-CTand its real radioactivity with R~2being0.9997. We prepared the kit for simple andconvenient radiolabeling of~(99m)Tc-3P-RGD_2. Biodistribution studies of~(99m)Tc-3P-RGD_2demonstrated that it was perfect with high tumor uptake and longretention time and rapid clearance for normal organs such as blood, liver and lung.Relationship between the tumor size (in cm3) and the tumor uptake (%/ID for totalradioactivity, and%ID/cm3for radioactivity density) determined by SPECT-CT andbiodistribution studies were established. They were similar to a great degree. Therelationship between the tumor volume and%ID of~(99m)Tc-3P-RGD_2was modeled asquadratic polynomial fitting curve (R~2>0.95for both SPECT-CT biodistributionstudies for tumors of0.01–2.0cm3. Linear relationship (R~2=0.8954forSPECT-CT data and0.8929for biodistribution data) between the tumor size and%IDof~(99m)Tc-3P-RGD_2when tumors were <1.0g or cm3. Tumor uptake (%ID/g) peakedwhen tumor size was0.15-0.25g or0.15-0.25cm3and decreased as tumor grewbecause of internal tumor necrosis. Linear relationship （R~2=0.8117）was foundbetween tumor uptake (%ID/g) and integrinα_vβ_3expression level determined byimmunostaining studies. In recurrent and metastatic tumor models,~(99m)Tc-3P-RGD_2U-SPECT-CT was definitely effective for early detection of tumor recurrence,micrometastasis in lung, bone and lymph nodes (with long diameter of1.0mm).Therapeutic effect of anti-angiogensis was better in tumors of high tumor uptake of~(99m)Tc-3P-RGD_2,in other words, high level integrin α_vβ_3expression, than tumor of lowlevel of uptake of~(99m)Tc-3P-RGD_2. And tumor uptake decrease was obvious on day5 after anti-angiogenesis, much earlier than tumor volume changes.
Conclusions: U-SPECT-CT fusion images can quantitively determine tumor volumeand tumor uptake of~(99m)Tc-3P-RGD_2with equipment of U-SPECT-II/CT. It caneffectively reflect tumor integrin α_vβ_3expression level and early detect tumorrecurrence and micrometastasis. Based on this,~(99m)Tc-3P-RGD_2U-SPECT-CTimaging was useful for tumor staging and grading and patient selection andtherapeutic effect prediction, dynamic monitoring of anti-angiogesis treatment。
方法：本课题首先利用U-SPECT-II/CT考察了U-SPECT-CT融合显像对肿瘤体积（存活、坏死）及~(99m)Tc放射性活度精确定量的方法学，然后合成~(99m)Tc-3P-RGD_2，并以整合素α_vβ_3受体靶向的~(99m)Tc-3P-RGD_2在荷瘤鼠内生物学分布及免疫组化对肿瘤整合素α_vβ_3表达水平的定量数据为基础，构建裸鼠皮下移植瘤、肿瘤复发、肺及骨骼转移模型，探讨~(99m)Tc-3P-RGD_2肿瘤U-SPECT-II/CT显像定量肿瘤整合素α_vβ_3受体表达水平的可行性及对肿瘤复发、转移灶的早期探测，最后对整合素α_vβ_3高表达和低表达的肿瘤在抗新生血管治疗前及治疗过程中进行U-SPECT-CT显像,考察其对肿瘤抗血管疗效的治疗前预测和治疗过程中实时监测价值。
结果：基于U-SPECT-II/CT的U-SPECT-CT融合显像，结合microCT和microSPECT信息进行肿瘤感兴趣区勾画精确定量肿瘤体积（包括存活和坏死组织的单独体积测定），且U-SPECT-CT融合显像可有效定量~(99m)Tc放射性活度（R~2=0.9997，y=1.0885x+0.0618），偏倚性小。~(99m)Tc-3P-RGD_2前体可制备试剂盒，标记简单、方便，且荷瘤鼠体内理化特性好，肿瘤放射性摄取高且能稳定滞留一定时间，血、肝、肾等清除快。~(99m)Tc-3P-RGD_2尾静脉注射通过生物学分布实验和U-SPECT-CT显像分别定量肿瘤放射性摄取（%ID和%ID/g），与肿瘤体积变化趋势相似，其中脑胶质瘤内~(99m)Tc-3P-RGD_2放射性摄取（%ID）逐渐增加，通过二次方程曲线拟合（R~2均大于0.95），而在肿瘤重量小于1.0g时，肿瘤放射性摄取（%ID）与肿瘤大小（g）呈直线相关(R~2分别为0.8963和0.8929)。而肿瘤%ID/g随着肿瘤大小的增加而增加，在0.15-0.25g时达到峰值，随后由于肿瘤组织坏死逐渐降低，与免疫组化所示整合素αVβ3表达水平呈线性相关（R~2=0.8117），即~(99m)Tc-3P-RGD_2在脑胶质瘤内分布可有效反应肿瘤整合素αVβ3表达水平。整合素α_vβ_3作为乳腺癌细胞等肿瘤细胞及其新生血管内皮细胞表面高表达的粘附因子，可早期（长径为1.0mm）发现乳腺癌术后复发灶和肺、淋巴结、骨骼等多发转移灶，有效评价乳腺癌等恶性肿瘤的分期、分级，尤其是肺癌等微小转移灶（大于1mm）方面具有显著优势。~(99m)Tc-3P-RGD_2U-SPECT-CT显像通过定量肿瘤~(99m)Tc-3P-RGD_2摄取、整合素受体表达水平、密度，抗新生血管治疗疗效监测明显早于肿瘤体积的变化，治疗后第5天即表现出~(99m)Tc-3P-RGD_2放射性摄取差异（P<0.05），是抗新生血管治疗方案病人治疗前适应症筛选、疗效预测及早期评价的显像手段。
结论：U-SPECT-II/CT通过U-SPECT-CT融合显像可对肿瘤体积及~(99m)Tc放射性活度进行精确定量，~(99m)Tc-3P-RGD_2U-SPECT-CT显像可有效评价肿瘤整合素α_vβ_3受体表达水平，且通过对肿瘤复发、转移灶及时早期的探测和诊断，为肿瘤分期、分级及抗新生血管治疗适应症的筛选、个体化治疗剂量的确定、疗效早期预测、实时评价提供科学依据。
Aim To investigate the quantitive analysis of tumor integrinαvβ3expressionlevel by U-SPECT-CT imaging with integrinαvβ3targeting radiotracer~(99m)Tc-HYNIC-PEG4-E[PEG4-c(RGDfk)]2(~(99m)Tc-3P-RGD_2) and its potent use forearly detection of tumor regional recurrence, distant metastasis, grading. It may offergreat information for patient selection for anti-angiogensis therapy and therapeuticeffect monitoring. Methods U-SPECT-CT fusion imaging was used for exactdelineation of tumor volume, including functional and necrotic tissues, andquantification of~(99m)Tc radioactivity with the equipment of U-SPECT-II/CT. Weprepared the integrin αvβ3targeting radiotracer,~(99m)Tc-3P-RGD_2, and finishedSPECT-CT imaging and biodistribution studies at different time points aftersubcutaneous implantion of tumor cells in nude mice. And relationship wasestablished between tumor uptake(percentage of injected dose%ID and percentage ofinjected dose per gram,%ID/g) with tumor integrin αvβ3expression level. On thebasis of the establishment of the subcutaneous tumor xenograft model and tumorregional recurrence model and lung, bone metastasis model, we investigatedU-SPECT-II/CT imaging for the quantification of tumor integrin αvβ3expression leveland early detection of tumor recurrence and metastasis with radiotracer~(99m)Tc-3P-RGD_2. Different tumor models were established of different expressionlevel integrin αvβ3expression (U87MG glioma with high expression level anddifferentiated thyroid cancer low expression level of intergrinαvβ3).~(99m)Tc-3P-RGD_2U-SPECT-CT imaging was used to monitor the therapeutic effect of antiangiogenesis of tumors with different expression level of integrinα_vβ_3. Results: With anatomicaland function information, U-SPECT-CT fuion images was better for the delineationof tumor volume including functional and necrotic tissues. It was also found thatquantification of~(99m)Tc radioactivity could be done based on U-SPECT-CT imagingwith little bias. Linear relationship was found between radiocounts on U-SPECT-CTand its real radioactivity with R~2being0.9997. We prepared the kit for simple andconvenient radiolabeling of~(99m)Tc-3P-RGD_2. Biodistribution studies of~(99m)Tc-3P-RGD_2demonstrated that it was perfect with high tumor uptake and longretention time and rapid clearance for normal organs such as blood, liver and lung.Relationship between the tumor size (in cm3) and the tumor uptake (%/ID for totalradioactivity, and%ID/cm3for radioactivity density) determined by SPECT-CT andbiodistribution studies were established. They were similar to a great degree. Therelationship between the tumor volume and%ID of~(99m)Tc-3P-RGD_2was modeled asquadratic polynomial fitting curve (R~2>0.95for both SPECT-CT biodistributionstudies for tumors of0.01–2.0cm3. Linear relationship (R~2=0.8954forSPECT-CT data and0.8929for biodistribution data) between the tumor size and%IDof~(99m)Tc-3P-RGD_2when tumors were <1.0g or cm3. Tumor uptake (%ID/g) peakedwhen tumor size was0.15-0.25g or0.15-0.25cm3and decreased as tumor grewbecause of internal tumor necrosis. Linear relationship （R~2=0.8117）was foundbetween tumor uptake (%ID/g) and integrinα_vβ_3expression level determined byimmunostaining studies. In recurrent and metastatic tumor models,~(99m)Tc-3P-RGD_2U-SPECT-CT was definitely effective for early detection of tumor recurrence,micrometastasis in lung, bone and lymph nodes (with long diameter of1.0mm).Therapeutic effect of anti-angiogensis was better in tumors of high tumor uptake of~(99m)Tc-3P-RGD_2,in other words, high level integrin α_vβ_3expression, than tumor of lowlevel of uptake of~(99m)Tc-3P-RGD_2. And tumor uptake decrease was obvious on day5 after anti-angiogenesis, much earlier than tumor volume changes.
Conclusions: U-SPECT-CT fusion images can quantitively determine tumor volumeand tumor uptake of~(99m)Tc-3P-RGD_2with equipment of U-SPECT-II/CT. It caneffectively reflect tumor integrin α_vβ_3expression level and early detect tumorrecurrence and micrometastasis. Based on this,~(99m)Tc-3P-RGD_2U-SPECT-CTimaging was useful for tumor staging and grading and patient selection andtherapeutic effect prediction, dynamic monitoring of anti-angiogesis treatment。
引文
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