Parameters For Tumor-targeting Of Radio-biologicals

放射生物制剂肿瘤靶向参数

• 批准号: 6675308
• 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/6675308
• 关键词: biological transport; chemical conjugate; chemical kinetics; chemical models; chemical reaction; clearance rate; laboratory mouse; neoplasm /cancer radiation therapy; polymers; radiation sensitivity; radiobiology; radiotracer; whole body irradiation effect

The overall purpose was to improve the tumor targeting properties of radiolabeled biologicals by optimizing chemical parameters. This years research was centered on 2 projects. The first project was to modify a spherical polymer, generation 3 PAMAM dendrimer (G3, MW 6909) and use it as a universal carrier of radiolabels and biological molecules. Using 3-[I-125]iodobenzoate and norbiotinamidosuccinate as model molecules, we have optimized the conjugation level of these molecules to G3 and improved the whole-body clearance kinetics in mice by blocking the non-specific uptake of G3 to liver and kidney upon neutralization of the highly positive-charged G3 by succinylation. We further improved the clearance kinetics of the radiolabel by inserting a metabolizable linker, triglycine between the label and G3 to a level that can be useful for a therapy approach. This approach can be applied to synthesize At-211 labeled G3-biotin for an alpha emitter-therapy of cancer that is pretargeted with antibody-streptavidin. The second project was to label Annexin V (AV) with I-125, In-111, Y-86, and Tc-99m for the detection of apoptosis to monitor the progress of cancer therapy. Among these, Tc-99m and Y-86 labeled AV were of particular interest because of their ideal imaging properties.

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。今年的研究集中在两个项目上。第一个项目是修改球形聚合物，第三代 PAMAM 树枝状聚合物（G3，MW 6909），并将其用作放射性标记和生物分子的通用载体。使用 3-[I-125]碘苯甲酸酯和降生物胺琥珀酸酯作为模型分子，我们优化了这些分子与 G3 的缀合水平，并通过琥珀酰化中和高正电荷 G3 后阻断 G3 到肝脏和肾脏的非特异性摄取，从而改善了小鼠的全身清除动力学。我们通过在标记和 G3 之间插入可代谢连接体三甘氨酸，进一步改善了放射性标记的清除动力学，使其达到可用于治疗方法的水平。该方法可用于合成 At-211 标记的 G3 生物素，用于用抗体链霉亲和素预靶向的癌症 α 发射体疗法。第二个项目是用I-125、In-111、Y-86和Tc-99m标记Annexin V（AV），用于检测细胞凋亡，以监测癌症治疗的进展。其中，Tc-99m 和 Y-86 标记的​​ AV 由于其理想的成像特性而受到特别关注。