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目的制备叶酸受体靶向的~(68)Ga-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-赖氨酸-叶酸(~(68)Ga-DOTA-lysFA),用小动物正电子发射计算机体层摄影术(microPET)-CT动态显像考察其间质给药后体内药代动力学。方法合成~(68)Ga-DOTA-lys-FA,考察其理化特性。用人卵巢癌细胞(SKOV3)和人肺癌细胞(A549)测定受体结合实验。荷人卵巢癌细胞裸鼠模型33只,雌性,体质量18~20 g,鼠龄8~10周;瘤体直径0.6~0.8 cm;荷人肺癌细胞裸鼠模型4只,雌性,体质量18~20 g,鼠龄8~10周。通过尾静脉注射~(68)Ga-DOTA-lys-FA后不同时间点处死荷瘤鼠,解剖分离重要脏器称质量和用γ计数仪进行放射性测定,分析其体内生物学分布。抽签法随机分为~(68)Ga-DOTA-lys-FA尾静脉注射组(Ⅳ组)、肿瘤间质注射组(IT组),荷人肺癌细胞模型(A549)作为阴性对照组(ITC组),在给药后不同时间点行microPET-CT显像,勾画肿瘤及脏器感兴趣区并计算其放射性摄取(%ID和%ID/cm~3),对比分析~(68)Ga-DOTA-lys-FA给药后不同时间体内生物学分布。结果 ~(68)Ga-DOTA-lys-FA标记率为(97.80±2.11)%。3 h内体外稳定性好,尾静脉注射后microPET-CT获得的60 min肿瘤/肺部放射性摄取比值为5.36±1.03,明显高于生物学分布结果 (4.13±1.25,t=4.97,P=0.001)。基于microPET-CT定量,IT组60 min、180 min肿瘤放射摄取量分别为(125.60±18.40)%ID/cm~3、(91.80±14.50)%ID/cm~3,明显高于ITC组[(42.30±11.46)%ID/cm~3、(12.82±3.86)%ID/cm~3](P<0.001、0.001),也明显高于IV组。结论 ~(68)Ga-DOTAlys-FA microPET-CT动态显像可更有效评价其体内生物学分布,瘤内注射可明显增加其瘤内生物半减期,为治疗性核素标记叶酸靶向治疗提供数据支持。
OBJECTIVE To prepare folate receptor-targeted (68) Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate-lysine-folate ) Ga-DOTA-lysFA) was used to investigate the in vivo pharmacokinetics of its interstitial drug delivery using small animal positron emission computed tomography (microPET) -CT dynamic imaging. Methods ~ (68) Ga-DOTA-lys-FA was synthesized and its physical and chemical properties were investigated. Receptor binding experiments were performed on human ovarian cancer cells (SKOV3) and human lung cancer cells (A549). Twenty-three nude mice bearing human ovarian cancer cells were female, body weight was 18-20 g, mice were 8-10 weeks old, tumors were 0.6-0.8 cm in diameter, and 4 nude mice bearing lung cancer cells were female. Body mass 18 ~ 20 g, 8 to 10 weeks old. Tumor-bearing mice were sacrificed at different time points after injection of ~ (68) Ga-DOTA-lys-FA into the caudal vein. The quality of vital organs was dissected and radioactivity was measured by gamma counter. The biological distribution in vivo was analyzed. The lottery method was randomly divided into (68) Ga-DOTA-lys-FA tail vein injection group (IV group), tumor interstitial injection group (IT group) and human lung cancer cell model (A549) ). The micro-PET imaging was performed at different time points after administration. The tumor and visceral regions of interest were plotted and their radioactivity uptake was calculated (% ID and% ID / cm ~ 3). The comparative analysis of 68 Ga-DOTA Biodistribution of -s-FA at different times after administration. Results The ~ (68) Ga-DOTA-lys-FA labeling rate was (97.80 ± 2.11)%. The in vivo and in vitro stability was good within 3 h. The radioactivity uptake rate of micro-PET-CT at 60 min after tail vein injection was 5.36 ± 1.03, which was significantly higher than the results of biodistribution (4.13 ± 1.25, t = 4.97, P = 0.001 ). On the basis of microPET-CT quantification, the radioactivity uptake of IT group was (125.60 ± 18.40)% ID / cm ~ 3 at 60 min and 180 min (91.80 ± 14.50)% ID / cm ~ 42.30 ± 11.46)% ID / cm ~ 3, (12.82 ± 3.86)% ID / cm ~ 3] (P <0.001,0.001) Conclusion The dynamic imaging of ~ (68) Ga-DOTAlys-FA microPET-CT can be used to evaluate the in vivo biological distribution more effectively. The intratumoral injection can significantly increase the biological half-life of tumor, Provide data support.