Optimization Of Parameters For Tumor-targeting Of Radio-

无线电肿瘤靶向参数的优化

• 批准号: 7215864
• 负责人: Chang Hum Paik
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7215864
• 关键词: angiogenesis; biological transport; chemical conjugate; chemical property; clearance rate; laboratory mouse; macromolecule; neoplasm /cancer blood supply; neoplasm /cancer radiation therapy; pharmacokinetics; radiobiology; radiotracer; receptor binding; whole body irradiation effect

The overall purpose of this research was to improve the tumor targeting properties of radiolabeled biologicals by optimizing chemical parameters. This year we have investigated the methods of radiolabeling a peptidomimetic integrin alphaVbeta3 antagonist, 4-[2-(3,4,5,6-tetrahydro-pyrimidine-2-ylamino)ethyloxy]benzoyl-2-(S)-aminoethylsulfonyl-amino-beta-alanine (IA) with In-111 and Tc-99m(CO)3 for the assessment of tumor angiogenesis and receptor status in tumor. IA conjugated with an aminodiacetic acid and labeled with Tc-99m(CO)3, and IA conjugated with isothiocyanatobenzyl-DOTA and labeled with In-111 were tested for the receptor targeting properties in nude mice bearing receptor-positive tumor. The In-111 IA was excreted via the renal system whereas the Tc-99m IA was taken up rapidly by the hepatobiliary system that resulted in a lower Tc-99m IA concentration in blood. The In-111 IA accumulation in the receptor-positive tumor was greater than the Tc-99m IA. The tumor uptake of both In-111 IA and Tc-99m IA was blocked by co-administration of a molar excess amount of unlabeled IA, indicating that the tumor uptake was receptor mediated. However, the tumor to organ ratios did not improve much over time because the labeled IAs were not retained well in the tumor perhaps due to a low affinity to the receptor. This study helped us identify two parameters to improve: 1) the receptor-binding affinity needs to be improved. 2) whole-body clearance pharmacokinetics needs to be optimized by preventing rapid hepatobiliary clearance. To improve the receptor targeting properties, we are now investigating the use of macromolecules as universal carriers of IA and radioisotopes for cancer diagnosis and therapy.

本研究的总体目的是通过优化化学参数来提高放射性标记生物制剂的肿瘤靶向性。本研究采用In-111和Tc-99 m（CO）_3标记拟肽类整合素α V β_3拮抗剂4-[2-（3，4，5，6-四氢嘧啶-2-基氨基）乙氧基]苯甲酰基-2-（S）-氨基乙基磺酰基-氨基-β-丙氨酸（IA），以评价肿瘤血管生成和受体状态。分别用氨基二乙酸偶联、Tc-99 m（CO）3标记的IA和异硫氰酸苄DOTA偶联、In-111标记的IA在荷受体阳性肿瘤的裸鼠体内进行受体靶向性质的检测。In-111 IA通过肾脏系统排泄，而Tc-99 m IA被肝胆系统快速吸收，导致血液中Tc-99 m IA浓度较低。In-111 IA在受体阳性肿瘤中的蓄积大于Tc-99 m IA。In-111 IA和Tc-99 m IA的肿瘤摄取通过共施用摩尔过量的未标记IA而被阻断，表明肿瘤摄取是受体介导的。然而，随着时间的推移，肿瘤与器官的比率并没有得到太大改善，因为标记的IA在肿瘤中没有很好地保留，这可能是由于与受体的亲和力较低。这项研究帮助我们确定了两个需要改进的参数：1）受体结合亲和力需要改进。2)全身清除药代动力学需要通过防止快速肝胆清除来优化。为了提高受体靶向特性，我们现在正在研究使用大分子作为IA和放射性同位素的通用载体用于癌症诊断和治疗。