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

该NSERC提案的目标是通过引入用于治疗和诊断应用的放射性示踪剂开发的新策略，丰富当前氟-18 （18F）标记化学物质的组合。我们提出了一些新的成像剂发现技术，围绕放射化学技术发展的纲领性主题。所有项目部分的共同目标是在核医学和标记化学中寻找新的治疗平台，以增强目前使用正电子发射断层扫描（PET）的成像技术组合。在第一部分中，我们将开发用于引入简化双重标记方案的构建块（BBs），结合使用诊断核素18F或治疗核素（例如177Lu）标记肿瘤靶向化合物（例如肽或抗体（ABs））的可能性。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，另一种用于放射治疗，同时减少了临床转化的监管工作。这些BBs由一种氟化硅受体（SiFA：一种硅基BB，用于18F的介绍）集成到一种用于放射性金属结合的螯合剂结构中。这种双标记BB可以很容易地附着在任何一种肽或蛋白质结构上，作为标记标签。在项目第二部分，我们将开发一种新的18F放射性标记方法，该方法基于silsesquioxan 18F-笼的形成，为肿瘤诊断应用提供18F标记的肽八聚体放射性示踪剂。通过多重亲和力的累积强度和个体肽/受体结合相互作用的协同结合，我们将引入具有改善肿瘤结合和组织保留的新化合物。18F离子作为结构模板，通过氟硅亲和相互作用选择性地促进了硅氧烷的化学形成。这种“氟化物笼化”或“f -点击笼化”的化学反应产生了具有极高摩尔活性的18f标记化合物。在第3部分，我们将开发具有SiFA功能的治疗性聚合物纳米颗粒（PNPs），用于易于18f放射性标记，以利用放射性标记纳米颗粒在癌症成像和治疗中的优势。为了使用我们的PNP作为同时进行PET成像和治疗放射性核素递送的治疗平台，我们开始化学定位PNP内部的SiFA片段，并计划用放射性金属螯合剂（例如DOTA）修饰PNP表面。不同大小的PNPs将被合成，并被不同的螯合剂和内部SiFA单元装饰，利用增强的渗透性和保留效应来靶向肿瘤。

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.