Parameters For Tumor-targeting Of Radio-biologicals

放射生物制剂肿瘤靶向参数

• 批准号: 7005951
• 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/7005951
• 关键词: biological transport; chemical conjugate; chemical kinetics; chemical models; chemical property; chemical reaction; chemical synthesis; clearance rate; laboratory mouse; neoplasm /cancer radiation therapy; physical separation; polymers; radiation sensitivity; radiobiology; radiotracer; whole body irradiation effect

The overall purpose of our research was to improve the tumor targeting properties of radiolabeled biologicals by optimizing chemical parameters. This year we developed a semi-automated 3-column system to purify a positron emitter, Y-86 because it is a better surrogate radionuclide than In-111 currently in use to estimate dosimetry of Y-90-labeled therapeutic radiopharmaceuticals. This purification system involved the passage of Cyclotron produced Y-86 samples through a Sr-selective Sr-Spec column, a Y-selective RE-Spec column and finally a cation-exchange Aminex A5 column connected in series. This method enabled us to decontaminate Sr by 250,000 times with >80% recovery of Y-86. We also investigated a new Tc-99m chemistry involving [Tc-99m (OH)3(CO)3]+ with Tc-99m (I) oxidation state to label biological molecules under mild conditions. The three water molecules of this complex are labile and can be substituted by a molecule with two or three coordination sites to form a stable ellipsoidal Tc-99m complex. We optimized the chemical condition to label norbiotinamido-DTPA, -benzylDTPA, -EDTA and ?succinimidoethylamino-(bis-ethylamine) with Tc-99m at 45?C and investigated the relationship between the polarity of the Tc-99m products and in vivo clearance kinetics. The biodistribution study in mice indicates that this approach is promising where further optimization of the polarity would produce a Tc-99m labeled biotin that rapidly accumulates in tumors with pretargeted antibody-streptavidin and is excreted via the renal system.

我们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品的肿瘤靶向特性。今年，我们开发了一种半自动 3 柱系统来纯化正电子发射体 Y-86，因为它是比目前用于估计 Y-90 标记治疗放射性药物剂量测定的 In-111 更好的替代放射性核素。该纯化系统涉及回旋加速器产生的 Y-86 样品通过 Sr 选择性 Sr-Spec 柱、Y 选择性 RE-Spec 柱，最后通过串联连接的阳离子交换 Aminex A5 柱。这种方法使我们能够将 Sr 净化 250,000 次，Y-86 回收率 >80%。我们还研究了一种新的 Tc-99m 化学反应，涉及具有 Tc-99m (I) 氧化态的 [Tc-99m (OH)3(CO)3]+ 在温和条件下标记生物分子。该复合物的三个水分子是不稳定的，可以被具有两个或三个配位点的分子取代，形成稳定的椭圆形Tc-99m复合物。我们优化了在 45℃ 下用 Tc-99m 标记去甲生物酰胺-DTPA、-苄基DTPA、-EDTA 和琥珀酰亚胺乙氨基-（双乙胺）的化学条件，并研究了 Tc-99m 产物的极性与体内清除动力学之间的关系。小鼠体内的生物分布研究表明，这种方法很有前景，进一步优化极性将产生 Tc-99m 标记的生物素，该生物素可通过预先靶向的抗体链霉亲和素在肿瘤中快速积累，并通过肾脏系统排泄。