Core--Radiopharmaceutical Development

该计划的总体目标是放射性同位素载体分子的转化发展和向癌症提供全身放射治疗的策略。该核心对于这些分子的开发和翻译至关重要，并支持所有项目：（1）制备新构建的分子作为放射缀合物，用于发育研究、体外分析、体内小鼠研究以及测试初步药物批次并准备IND文件用于未来的临床研究;（2）将化学从项目转化为标准方法，以结合和放射性标记所选择的构建体作为放射性药物，具有优化的产率、稳定性和可再现的质量;（3）根据体外质量控制、动力学和小鼠耐受性的严格评估，确保药物开发试剂的稳定性和质量;以及（4）根据RUC、IRB、FDA和辐射标准保存记录 使用监管机构。在本资助期内，该核心开发了简化的程序，使用第三个项目中开发的大环肽连接螯合剂，以高产率和放射性药物质量用Y-90放射性标记单克隆抗体。在小鼠中观察到的增强的放射性肝脏清除率通过在第一和第二项目中使用该核心制备的Lym-1和m170 DOTA肽药物的优异的肿瘤靶向和降低对肝脏的辐射剂量得到证实。在新的资助期内，该核心项目的提案包括每个项目生产的分子制剂的化学转移 允许额外的药物开发、螯合物缀合、PEG批次合成、SHAL q.c.，放射性金属标记的优化，以及确保体外和体内稳定性的研究。这包括为所有三个项目的临床前研究准备放射性药物，使用已经开发的简化的高产程序，以最大限度地减少费用和辐射暴露。来自第三个项目中的组合文库的用于“按需”切割的DOTA螯合物接头、来自第一个项目的DOTA-SHAL和来自第二个项目的DOTA-（scFv）4PEG正在进行体外评价和在非肿瘤小鼠中的研究，以评估稳定性和耐受性。该核心将继续开发这些新型放射性药物的药用级生产、纯化、结合、质量控制、储存和放射性标记方法以及最终小鼠和患者批次（和剂量）放行标准。

The overall goal of this program is the translational development of radioisotope carrier molecules and strategies to deliver systemic radiotherapy to cancer. This core is central to the development and the translation of these molecules and supports all of the projects: (1) preparing newly constructed molecules as radioconjugates for developmental studies, in vitro analysis, in vivo mouse studies and testing preliminary pharmaceutical lots and preparing IND documents for future clinical studies; (2) translating chemistry from the projects to standard methods to conjugate and radiolabel selected constructs as radiopharmaceuticals with optimized yields, stability, and reproducible quality; (3) assuring stability and quality of reagents for pharmaceutical development based on rigorous evaluation of vitro quality controls, kinetics and tolerance in mice; and (4) maintaining records in accordance with RUC, IRB, FDA and radiation use regulatory agencies. During the current funded period, this core developed simplified procedures to radiolabel MAbs with Y-90 with high yields and radiopharmaceutical quality using macrocyclic peptide linker chelating agents developed in the third project. Enhanced hepatic clearance of radioactivity seen in mice was substantiated by the excellent tumor targeting and decrease radiation dose to liver with Lym-1 and m170 DOTA-peptide pharmaceuticals prepared by this core for clinical studies in the first and second projects. The proposal for this core for the new grant period includes transfer of chemistry of molecular agents produced by each project to allow additional pharmaceutical development, chelate conjugation, PEG lot syntheses, SHALs q.c., optimization of radiometal labeling, and studies to assure stability in vitro and in vivo. This includes preparing radiopharmaceuticals for all three projects preclinical studies, using simplified, high yield procedures already developed to minimize expense and radiation exposure. DOTA chelate linkers for "on demand" cleavage from the combinatorial libraries in the third project, DOTA-SHALs from the first project, and DOTA-(scFv)4 PEG from the second project are undergoing in vitro evaluation and studies in non tumored mice to assess stability and tolerance. This core will continue to develop the methods for pharmaceutical grade production, purification, conjugation, quality control, storage and radiolabeling and final mouse and patient lot (and dose) release criteria for these novel radiopharmaceuticals.