Novel chemistry to improve the biostability of organo-astatine bonds in alpha-emitting radiopharmaceutical therapeutics

提高α发射放射性药物治疗中有机砹键生物稳定性的新型化学方法

• 批准号: 10286099
• 负责人: Mehran Makvandi
• 金额: $ 32.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286099
• 关键词: Address; Astatine; Basic Science; Biologic Development; Biological; Biological Assay; Blood; Boron; Carbon; Cells; Chemicals; Chemistry; Clinical; DNA; Daughter; Development; Dissociation; Drug Kinetics; Drug Targeting; Elements; Ensure; Half-Life; Halogens; Human; Human body; Hydrolysis; In Vitro; Isotopes; Journals; Kidney; Liver; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Methods; Modeling; Mus; Normal tissue morphology; Oncogenes; Oncoproteins; Organ; Outpatients; Patients; Pharmaceutical Preparations; Pharmacology; Positioning Attribute; Production; Property; Prosthesis; Proteins; Publishing; Radiation; Radiochemistry; Radioimmunoconjugate; Radioisotopes; Radiopharmaceuticals; Resistance; Route; Scientist; Shipping; Solid Neoplasm; System; Technology; Testing; Therapeutic; Time; Toxic effect; Translating; Travel; Treatment Efficacy; analog; base; cancer cell; cancer therapy; cancer type; chemical property; chemical stability; clinical translation; dehalogenation; design; halogenation; high reward; high risk; immune checkpoint blockade; improved; in vivo; inhibitor/antagonist; method development; nanobodies; news; novel; novel strategies; particle; physical property; prevent; response; scaffold; small molecule; tumor; uptake; virtual; virtual library

Abstract/Summary Of the few -emitting radionuclides that exist, astatine-211 (211At) is one of the most promising -emitting radionuclides, because its physical and chemical properties are perfectly matched for -emitting radiopharmaceutical therapeutics (-RPTs) used for treatment of otherwise incurable tumors. However, the in vivo release of 211At from pharmacological targeting constructs diminishes therapeutic efficacy while increasing toxicity to normal tissues, and is the single biggest obstacle for realizing the true potential of 211At--RPTs. This proposal directly addresses the critical unmet need to develop novel chemistry for improving organo-astatine bond stability to prevent its release in vivo. The carbon-halogen bond strength is inversely related with halogen size, and as the largest halogen, the bond strength of carbon-astatine (C-At) is the weakest, which makes it more vulnerable to oxidative dehalogenation in vivo. Currently, most 211At-conjugation methods use C-At bonds and as a result have poor biostability. Alternatively, using boron-astatine (B-At) bonds, which are stronger than C-At bonds, is an effective strategy to improve the in vivo stability of 211At--RPTs. Therefore, we propose to investigate previously unexplored boron hetero-atom ring systems that are uniquely well-suited as pharmacons to develop biologically stable 211At--RPTs. These ring systems have established halogenation chemistry adaptable for astatine-substitution at boron or carbon positions in ring systems, each providing unique properties for enhancing stability and enable orthogonal routes for 211At-radioastatination. In this proposal we will systematically interrogate the chemistry of astato-substituted boron-heterocycles to develop new methods for 211At-radioastatination and translate basic science discoveries to application ready technology by demonstrating “proof of concept” with a biologically stable small molecule 211At--RPT.

摘要/总结 在现有的少数 α 发射放射性核素中，砹 211 (211At) 是最有前途的 α 发射放射性核素之一 放射性核素，因为其物理和化学性质与发射 α 的物质完全匹配 用于治疗无法治愈的肿瘤的放射性药物疗法（α-RPT）。 药理学靶向结构体内释放 211At 会降低治疗效果，同时增加 对正常组织的毒性，是实现 211At-α-RPT 真正潜力的最大障碍。 该提案直接解决了开发新型化学物质以改善有机砹的关键未满足需求 键稳定性，防止其在体内释放 碳-卤键强度与卤素成反比。 碳砹（C-At）作为最大的卤素，其键合强度最弱，这使得 目前，大多数 211At 缀合方法都使用 C-At 键。 因此生物稳定性较差，或者使用比砹更强的硼-砹 (B-At) 键。 C-At键是提高211At-α-RPTs体内稳定性的有效策略。 研究以前未探索过的硼杂原子环系统，这些系统非常适合作为药物 开发生物稳定的 211At-α-RPT 这些环系统已经建立了卤化化学。 适用于环系统中硼或碳位置的砹取代，每个都提供独特的 增强稳定性并实现 211At 放射性抑制的正交路线的特性。 将系统地研究阿斯塔托取代的硼杂环的化学性质以开发新方法 211At-放射性抑制并将基础科学发现转化为应用技术 用生物稳定的小分子 211At-α-RPT 展示“概念验证”。