Translational nanoconstructs for targeted tissue accumulation and guided surgery in cancer

该项目旨在为精确手术及其他领域（如治疗性药物输送）的纳米颗粒结构的发展提供革命性的进步。这将通过汇集杯芳烃化学、纳米化学、PET（正电子发射断层扫描）成像和外科成像方面的专家来实现。通过开发杯芳烃的化学性质，我们将优化凝集素受体的结合亲和力，并证明选择性靶向癌细胞。我们的初步研究表明，放射性标记的（18F）“点击”杯芳烃很容易获得，通过改进的HPLC纯化（通过guest掺入实现），可以实现体内生物分布，突出理想的（肾脏）清除率。采用杯芳烃为基础的支架的一个主要好处是进一步功能化的能力。考虑到这一点，使用标准协议（点击化学），杯芳烃将被进一步修改，增加一个NOTA基序。结合这种强结合基序将使我们能够开发这种新平台技术的放射性标记，具有最大的灵活性，即18F和68Ga放射性核素。将功能化杯芳烃支架固定在发光共轭聚合物纳米颗粒上，以增强其成像能力。然后将获得输送平台的生物分布和肿瘤摄取（PET成像），结果将反馈到合成程序中，以使我们能够优化结果。体外研究成功后，将评估体内肿瘤摄取；肿瘤和器官摄取将被量化，以评估生物分布和肿瘤靶向性。该项目的最后阶段将通过结合可定制的双相机头，探索将该技术用于体内光谱收集的机会。为了评估深度灵敏度和多模态制导，内窥镜伽马探针将用于多功能探针识别。这种结合的方法将适用于临床前成像，重点是高分辨率和信号质量。

This project aims to deliver transformative advances in the development of nanoparticle constructs for use in precision surgery and beyond (e.g. therapeutic drug delivery). This will be achieved by bringing together experts with complimentary expertise in calixarene chemistry, nanochemistry, PET (positron emission tomography) imaging and surgical imaging. By developing the chemistry of calixarenes, we will optimize the galectin receptor binding affinity and demonstrate selective cancer cell targeting. Our preliminary studies reveal that radiolabelled (18F) 'Clicked' calixarenes are readily accessible, with improved HPLC purification (achieved via guest incorporation), which enables in vivo bio-distribution, highlighting ideal (renal) clearance. A major benefit of employing a calixarene-based scaffold is the ability for further functionalization. With this in mind, using standard protocols (Click chemistry), the calixarene will be further modified with the addition of a NOTA motif. The incorporation of such a strongly binding motif will allow us to develop the radiolabelling of this new platform technology, with maximum flexibility i.e. with both 18F and 68Ga radionuclides. The functionalized calixarene scaffold will be immobilized on luminescent conjugated polymer nanoparticles to enhance the imaging capabilities. The biodistribution and tumour uptake of the delivery platform will then be accessed (PET imaging), and results will be fed back into the synthetic programme to allow us to optimize the results. Following successful in vitro studies, in vivo tumour uptake will be assessed; tumour and organ uptake will be quantified to assess biodistribution and tumour targeting. The final phase of the project will explore opportunities for using this technology for the collection of spectra in vivo, by combining with a customizable dual camera head. To evaluate depth sensitivity and multimodal guidance an endoscopic gamma probe will be used for multi-functional probe identification. Such a combined approach will be suitable for pre-clinical imaging with a focus on high resolution and signal quality.