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开发以及对癌症进行全身放射治疗的策略。该核心是这些分子的开发和翻译的核心，并支持所有项目：(1) 制备新构建的分子作为放射性结合物，用于开发研究、体外分析、小鼠体内研究和测试初步药物批次，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，以缀合和放射性标记选定的构建体作为具有优化产量、稳定性和可重复质量的放射性药物； (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； (4) 根据 RUC、IRB、FDA 和辐射保存记录 利用监管机构。在当前资助期间，该核心开发了简化程序，使用第三个项目中开发的大环肽连接螯合剂，用 Y-90 放射性标记单克隆抗体，具有高产率和放射性药物质量。该核心制备的用于第一个和第二个项目临床研究的 Lym-1 和 m170 DOTA 肽药物，通过出色的肿瘤靶向性和降低肝脏辐射剂量，证实了小鼠肝脏放射性清除率的增强。新资助期内该核心的提案包括转让每个项目生产的分子制剂的化学成分 允许进行额外的药物开发、螯合缀合、PEG 批量合成、SHAL 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、高产量程序，以最大限度地减少费用和辐射暴露。第三个项目的组合文库中用于“按需”切割的 DOTA 螯合接头、第一个项目的 DOTA-SHAL 和第二个项目的 DOTA-(scFv)4 PEG 正在非肿瘤小鼠中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物级生产、纯化、结合、质量控制、储存和放射性标记的方法以及最终小鼠和患者批次（和剂量）释放标准。

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.