Core--Radiopharmaceutical Development

该计划的总体目标是放射性同位素载体分子的翻译开发和为癌症提供系统放射治疗的策略。这个核心对这些分子的开发和翻译至关重要，并支持所有的项目：(1)制备新构建的分子作为放射性结合物，用于发育研究、体外分析、小鼠体内研究和初步药物批次测试，并为未来的临床研究准备IND文件；(2)将化学从项目转化为标准方法，以连接和标记选定的结构作为放射性药物，具有最佳的产量、稳定性和可重复的质量；(3)基于对体外质量控制、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和辐射保持记录 使用监管机构。在当前资助期间，该核心开发了使用第三个项目中开发的大环肽连接物螯合剂以高产率和放射性药物质量标记Y-90的放射性标记单抗的简化程序。在第一个和第二个项目的临床研究中，该核心制备的Lym-1和m170 DOTA多肽药物具有出色的肿瘤靶向性，并减少了对肝脏的辐射剂量，从而增强了小鼠对肝脏的放射性清除。这一核心在新的赠款期间的提议包括每个项目生产的分子制剂的化学转让。 为了进行更多的药物开发、螯合结合、聚乙二醇批量合成、SHALs的质量控制、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、高产量的程序，将费用和辐射暴露降至最低。第三个项目的组合文库中用于“按需”切割的DOTA螯合连接体、第一个项目中的DOTA-SHALs和第二个项目中的DOTA-(ScFv)4聚乙二醇正在非肿瘤小鼠身上进行体外评估和研究，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、连接、质量控制、储存和放射性标记以及最终小鼠和患者批次(和剂量)释放标准的方法。

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.