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; 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/摘要 在存在的少数发射放射线中，Astatine-211（211AT）是最有希望的发射之一 放射线，因为其物理和化学特性与发射完美匹配 用于治疗原本无法治愈的肿瘤的放射性药物治疗（-RPTS）。但是，in 从药物靶向构建体中释放211AT的体内释放降低了治疗效率的同时提高了治疗效率 对正常组织的毒性，并且是实现211AT-rpts真正潜力的最大障碍。这 提案直接解决了开发新的化学以改善有机生髓丁的关键需求 键稳定性以防止其在体内释放。碳释放键强度与卤素成反比 大小，作为最大的卤素，碳 - 庄严（C-AT）的键强度是最弱的，这使得它 在体内更容易受到氧化脱卤的影响。目前，大多数211at结合方法都使用C-AT键 因此，使用硼 - astatine（b-at）键，其强度比 C-AT键是提高211AT-RPT体内稳定性的有效策略。因此，我们建议 研究以前出乎意料的硼杂音原子环系统，非常适合作为药物 开发生物学稳定的211AT--rpts。这些环系统已经建立了卤化化学 适用于在硼或环系统中的碳位置的Astaine-sublebibledsitution的适应 增强稳定性和启用正交路线的特性，以实现211at-降级。在这个建议中，我们 将系统地询问astato取代的硼 - 盐旋转的化学反应以开发新方法 对于211AT估计，并将基础科学发现转化为应用准备技术 用生物学稳定的小分子211at--rpt展示“概念证明”。