Optimization Of Parameters For Tumor-targeting Of Radio-

无线电肿瘤靶向参数的优化

• 批准号: 7332117
• 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/7332117
• 关键词: Optimization; Parameters; Tumor; targeting; Radio

The overall purpose of this research was to improve the tumor targeting properties of radiolabeled biologicals by optimizing chemical parameters. For the past one year, we have synthesized a second generation radiolabeled peptidomimetic antagonist (IA) with a high affinity for ava3 receptor by conjugating the amino terminus of 4-[2-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)-ethyloxy]benzoyl-2-(S)-[N-(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonylamino-a-alanine hydrochloride (IAC), a hydrophobic carbamate derivative of the first generation IA, with 2-p-isothiocyanatobenzyl-DOTA and labeled with 111In.. We have demonstrated that this 111In-IAC with a higher affinity to the receptor accumulated in the receptor-positive tumor (xenografted in nude mice) with a higher peak tumor uptake value and was retained in the tumor for a much longer duration than that of the first generation IA with a lower affinity while clearing rapidly from the whole-body via the renal excretion. We have also synthesized oligomeric forms of the first generation IA by conjugating IA to monoclonal antibody (MoAb). The receptor-binding affinity increased proportionally to the level of IA molecules conjugated per MoAb. The fluorescence microscopic analysis showed that fluorescein labeled MoAb-IA10 outlined neovasculatures but not tumor cells at 4 and 21 hr post injection. The neovasculatures outlined with FITC-MoAb-IA10 were superimposed with blood vessels outlined with rhodamine-lectin. This fluorescence microscopic analysis supports the hypothesis that the 111In labeled MoAb-IA10 in tumors was localized on the neovasculatures via binding to ava3 receptors, but not on tumor cells.

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品的肿瘤靶向性。在过去的一年里，我们通过将第一代IA的疏水氨基甲酸酯衍生物4-[2-（3,4,5,6-四氢嘧啶-2-氨基氨基）-乙基]苯甲酰-2-(S)-[N-（3-氨基-新戊基-1-氨基氨基）]-氨基乙基磺酰基氨基-a-丙氨酸盐酸盐（IAC）的氨基端与2-对异硫氰酸酯酶- dota偶联，并标记为111In，合成了对ava3受体具有高亲和力的第二代放射性标记拟肽拮抗剂（IA）。我们已经证明，这种对受体具有更高亲和力的111In-IAC在受体阳性肿瘤（移植到裸鼠身上）中积累，具有更高的峰值肿瘤摄取值，并且在肿瘤中保留的时间比第一代具有较低亲和力的IA长得多，同时通过肾脏排泄迅速从全身清除。我们还通过偶联IA与单克隆抗体（MoAb）合成了第一代IA的低聚形式。受体结合亲和度随着每个MoAb结合的IA分子的水平成比例地增加。荧光显微镜分析显示，在注射后4和21小时，荧光素标记的MoAb-IA10勾勒出了新生血管，但没有肿瘤细胞。FITC-MoAb-IA10标记的新生血管与罗丹明-凝集素标记的血管重叠。荧光显微镜分析支持了111In标记的肿瘤中MoAb-IA10通过与ava3受体结合定位于新生血管，而不是肿瘤细胞的假设。