高等学校化学学报 ›› 2010, Vol. 31 ›› Issue (10): 1999.

• 研究论文 • 上一篇    下一篇

叶酸受体靶向的人血清白蛋白-叶酸偶联物的制备、标记及生物性能评价

张亚东, 庞燕, 陆洁, 魏晓焱, 杨文江, 朱美霖   

  1. 北京师范大学化学学院,  放射性药物教育部重点实验室, 北京 100875
  • 收稿日期:2009-12-28 出版日期:2010-10-10 发布日期:2010-10-10
  • 通讯作者: 陆洁, 女, 博士, 讲师, 主要从事放射性药物化学研究. E-mail: ljie74@bnu.edu.cn
  • 基金资助:

    国家自然科学基金(批准号: 20701004)资助.

Preparation, Labeling and Biological Evaluation of Human Serum Albumin-folate Conjugate for Targeting Folate Receptor

ZHANG Ya-Dong, PANG Yan, LU Jie*, WEI Xiao-Yan, YANG Wen-Jiang, ZHU Mei-Lin   

  1. Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China
  • Received:2009-12-28 Online:2010-10-10 Published:2010-10-10
  • Contact: LU Jie. E-mail: ljie74@bnu.edu.cn
  • Supported by:

    国家自然科学基金(批准号: 20701004)资助.

摘要: 以人血清白蛋白为连接剂和药物载体, 制备了人血清白蛋白-叶酸偶联物(HSA-FA), 其偶联数n≈3. 以SnCl2·H2O作为还原剂, 采用直接标记法制备 99mTc-HSA-FA标记配合物, 其放射化学纯度大于90%. 体外细胞结合实验结果表明, 99mTc-HSA-FA能被叶酸受体高表达的KB细胞特异性摄取. 荷瘤S180小鼠体内生物分布的研究结果表明, 与 99mTc-HSA相比, 99mTc -HSA-FA在小鼠体内的生物分布发生明显变化, 其在肿瘤中的放射性浓集明显增加(t=12.03, P<0.05), 并表现出较高的摄取[(4.37±1.12)%ID/g at 1 h]和滞留[(3.40±0.69)%ID/g at 4 h]; 经注射过量稳定配体使 99mTc-HSA-FA受到抑制后, 其在肿瘤和肾中的摄取明显降低(t=24.17和17.87, P<0.05), 表明人血清白蛋白-叶酸偶联物对叶酸受体有特异性结合.

关键词: 叶酸受体, 叶酸-人血清白蛋白偶联物, 99mTc-HSA-FA, 生物分布

Abstract: The folate receptor is a useful target that has been exploited for tumor-specific drug delivery. In this study, Human serum albumin-folate conjugate(HSA-FA) was prepared with HSA as the linker and drug carrier. Coupling degree of the conjugate show that one molecule of HSA is loaded with about three folic acid molecules. The corresponding 99mTc-complex was successfully obtained by SnCl2·2H2O as reducing agent. The radiochemical purity of the product was above 90% by TLC and HPLC. The results of in vitro experiments show that the complex bound the KB tumor cells specifically. In vivo study of 99mTc-HSA-FA was performed in Kunming mice bearing S180 tumor. Compared with 99mTc-HSA, the biodistribution of 99mTc-HSA-FA was different and the tumor uptake was significantly increased(t=12.03, P<0.05). 99mTc-HSA-FA showed a high accumulation[(4.37±1.12)%ID/g at 1h] and good retention[(3.40±0.69)%ID/g at 4 h] in tumor. The ratios of tumor/blood and tumor/muscle increased with time and were 0.45 and 4.28 at 1 h post injection, and reached 0.76 and 5.00 at 4 h post injection, respectively. After blocking with the cold ligand, the uptakes of kidney and tumor were lower than the control(t=24.17 and 17.87, respectively, P<0.05). These results indicate the specific binding of HSA-FA to the folate receptor.

Key words: Folate receptor, Human serum albumin-folate conjugate, 99mTc-HSA-FA, Biodistribution

TrendMD: