Silicon-18F and Metal Chelator Radio-Chemistries for Theranostic Applications

用于治疗诊断应用的硅 18F 和金属螯合剂放射化学

• 批准号: RGPIN-2019-04481
• 负责人: Schirrmacher, Ralf
• 金额: $ 3.5万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=689726
• 关键词: Silicon; 18F; Metal; Chelator; Radio

This NSERC proposal's goal is to enrich the current portfolio of fluorine-18 (18F) labeling*chemistries by introducing new strategies for radiotracer development for*theranostic and diagnostic applications. We propose a number of novel techniques for imaging*agent discovery, coalescing around the programmatic theme of radiochemical*technology development. The common goal of all program parts is finding new*theranostic platforms in nuclear medicine and labeling chemistries to enhance the*current portfolio of imaging technologies using Positron Emission Tomography (PET).***In program part 1, we will develop*building blocks (BBs) for introducing simplified dual labeling protocols,*combining the possibility to label a tumor targeting compound (e.g. peptides or*antibodies (ABs)) with either the diagnostic nuclide 18F or with a*therapeutic nuclide (e.g. 177Lu). This strategy omits the necessity*to clinically validate two different compounds, one for diagnostic imaging and*a second for endo-radiotherapy and concomitantly reduce the regulatory effort*for clinical translation. These BBs consist of a Silicon-Fluoride-Acceptor*(SiFA: a silicon-based BB for 18F introduction)*integrated into a chelator structure for radiometal binding. This dual labeling*BB can be easily attached to any kind of peptide or protein structure to serve*as a labeling tag. ***In program part 2, we will develop*a novel 18F-radiolabeling method based on the formation of silsesquioxan 18F- cages providing 18F-labeled peptide*octamer radiotracers for oncologic diagnostic applications. Through accumulated strength*of multiple affinities and cooperative binding of individual peptide/receptor*binding interactions, we will introduce novel compounds with improved tumor*binding and tissue retention. The 18F- ion acts as a*structural template selectively facilitating the chemical formation of the*silsesquioxan through fluoride silicon affinity interaction. This*“fluoride-caging” or “F-click to cage” chemistry yields 18F-labeled*compounds of exceptionally high molar activities. ***In program part 3, we will develop theranostic polymeric nanoparticles (PNPs) with the SiFA*functionality for easy 18F-radiolabeling to take advantage of*radiolabeled nanoparticles in cancer imaging and therapy. To use our PNPs as a theranostic platform*for simultaneous PET imaging and therapeutic radionuclide delivery, we started*to chemically locate the SiFA moiety inside the PNPs and plan to modify the PNP*surface with radiometal chelators (e.g. DOTA). Different sizes of PNPs will be synthesized and decorated*with different chelators as well as an internal SiFA unit exploiting the Enhanced Permeability and Retention Effect for tumor targeting.**

该 NSERC 提案的目标是通过引入用于治疗诊断和诊断应用的放射性示踪剂开发的新策略来丰富当前的氟 18 (18F) 标记*化学产品组合。我们提出了许多用于成像*剂发现的新技术，围绕放射化学*技术开发的主题。所有计划部分的共同目标是在核医学和标记化学中寻找新的*治疗诊断平台，以增强*当前使用正电子发射断层扫描（PET）的成像技术组合。***在计划第1部分中，我们将开发*构建块（BB）以引入简化的双标记协议，*结合标记肿瘤靶向化合物（例如肽或*抗体）的可能性 (ABs)) 与诊断核素 18F 或 a*治疗核素（例如 177Lu）。该策略省略了临床验证两种不同化合物的必要性，一种用于诊断成像，*另一种用于腔内放射治疗，同时减少了临床转化的监管工作*。这些 BB 由硅氟化物受体*（SiFA：用于引入 18F 的硅基 BB）*组成，集成到用于放射性金属结合的螯合剂结构中。这种双标记 *BB 可以轻松附着到任何类型的肽或蛋白质结构上，以充当标记标签。 ***在计划第 2 部分中，我们将开发*一种基于倍半硅氧烷 18F 笼形成的新型 18F 放射性标记方法，为肿瘤诊断应用提供 18F 标记肽*八聚体放射性示踪剂。通过多重亲和力的累积强度*和单个肽/受体*结合相互作用的协同结合，我们将推出具有改善的肿瘤*结合和组织保留的新型化合物。 18F-离子充当*结构模板，通过氟硅亲和相互作用选择性地促进*倍半硅氧烷的化学形成。这种*“氟化物笼”或“F-点击笼”化学产生具有极高摩尔活性的 18F 标记*化合物。 ***在计划第 3 部分中，我们将开发具有 SiFA* 功能的治疗诊断聚合物纳米颗粒 (PNP)，可轻松进行 18F 放射性标记，以在癌症成像和治疗中利用*放射性标记纳米颗粒。为了使用我们的 PNP 作为同步 PET 成像和治疗性放射性核素输送的治疗诊断平台*，我们开始*以化学方式将 SiFA 部分定位在 PNP 内部，并计划用放射性金属螯合剂（例如 DOTA）修饰 PNP* 表面。将合成不同尺寸的 PNP，并用不同的螯合剂以及内部 SiFA 单元进行装饰*，利用增强的渗透性和保留效应来实现肿瘤靶向。 **