One-step, site-specific labelling of His-tagged proteins with technetium-99m and rhenium-188 for cancer imaging and therapy

本博士项目的目的：本项目将联合收割机新的过渡金属化学与蛋白质工程相结合，生产和临床前（体外，体内）评价一对放射性治疗药物，可以快速和简单地用锝-99 m和锝-188标记，用于癌症的分子成像和靶向放射性核素治疗。项目描述/背景：从20世纪90年代到现在，核医学已经从基于未知结构的Tc-99 m络合物（Tc-99 m-bisphosphonates，DMSA，DTPA等）的功能成像放射性药物发展到现在，在临床上已经有了很大的发展。以及几乎不了解的摄取机制，进入了分子成像的新时代。特别是，使用生物分子（主要是肽和蛋白质）作为分子靶向载体已成为这一时期分子成像的支柱。用正电子发射放射性核素如Ga-68和F-18放射性标记这些分子用于PET成像的化学方法在过去20年中一直是研究和开发的主要焦点（包括在King's开发的特别有效的螯合剂化学方法，使用我们专有的三（羟基吡啶酮）（THP）螯合剂）。然而，自2000年以来，它们的Tc-99 m标记方法的平行开发几乎完全被忽视。然而，尽管PET的增长，Tc-99 m放射性药物的开发仍然是一个高度优先的几个原因。PET扫描仪和为PET提供放射性示踪剂比使用Tc-99 m的SPECT更昂贵且更不广泛。在可预见的未来，发达国家和中低收入国家都可能继续依赖Tc-99 m。最近Mo-99生产的危机导致Tc-99 m短缺，促使各国和工业界开发新的生产方法，并实施Mo-99和Tc-99 m的新生产设施。与此同时，商业SPECT扫描仪设计的改进也在继续，导致更好的定量、分辨率和灵敏度以及真正的动态SPECT。因此，现在有一个未满足的需求，开发新的化学与SPECT（Tc-99 m）1分子成像的新时代，并与化学靶向放射性核素治疗（Re-188）2。主要未满足的需求是方法，使敏感的生物分子的放射性标记简单，有效，和要求不高的基础设施，如自动化合成设备。否则，临床应用就不会有进展。为了使新一代的放射性示踪剂对于医学界及其患者（包括中低收入国家的患者）容易获得且经济，理想的放射性标记将采用类似于20世纪70年代开发的基于试剂盒的Tc-99 m化学的程序，包括简单的操作，如将Tc-99 m发生器添加到含有所需还原剂和其它成分的试剂盒小瓶中。应避免纯化和其他额外步骤。目前生物分子99 mTc/188 Re标记的化学不符合这些要求。同样的原理也适用于开发用放射性核素标记生物分子的方法，以用于靶向放射性核素治疗。满足这一未满足的需求将使我们能够更直接地满足临床上对广泛可用的标记蛋白质的未满足的需求，以用于临床上的癌症和其他疾病的成像。

Aim of the PhD Project:The project will combine new transition metal chemistry with protein engineering to produce and evaluate preclinically (in vitro, in vivo) a theranostic pair of radiopharmaceuticals, that can be labelled quickly and simply with technetium-99m and rhenium-188, for molecular imaging and targeted radionuclide therapy of cancer.Project Description / Background:From the 1990s to the present time, nuclear medicine has moved from the functional imaging radiopharmaceuticals based on Tc-99m complexes of unknown structure (Tc-99m-bisphosphonates, DMSA, DTPA etc.) and barely understood mechanism of uptake, into a new era of molecular imaging. In particular, the use of biomolecules (mainly peptides and proteins) as molecular targeting vectors has become the mainstay of molecular imaging during this period. Chemistry for radiolabelling such molecules with positron emitting radionuclides such as Ga-68 and F-18 for PET imaging has been a major focus of research and development in the last 20 years (including particularly efficient chelator chemistry developed at King's, using our proprietary tris(hydroxypyridinone) (THP) chelators). However, the parallel development of Tc-99m-labelling methods for them has been almost entirely neglected since 2000. Yet, despite the growth of PET, Tc-99m radiopharmaceutical development remains a high priority for several reasons. PET scanners, and the provision of radiotracers for PET, are more costly and less widely available than for SPECT with Tc-99m. Both developed countries and low-to-middle income countries are likely to continue to depend on Tc-99m for the foreseeable future. The recent crises in Mo-99 production, leading to shortages of Tc-99m, have galvanised nations and industry into development of new production methods and implementation of new production facilities for Mo-99 and Tc-99m. At the same time, improvements in commercial SPECT scanner design have continued, leading to better quantification, resolution and sensitivity as well as truly dynamic SPECT. There is therefore now an unmet need to develop new chemistry for this new age of molecular imaging with SPECT (Tc-99m)1 and to partner it with chemistry for targeted radionuclide therapy (Re-188)2.The major unmet need is methodology to make radiolabelling of sensitive biomolecules simple, efficient, and undemanding in terms of infrastructure such as automated synthesis equipment. Without this, clinical application will not progress. To make the new generation of radiotracers readily accessible and economic to the medical community and its patients, including those in lower and middle income countries, the ideal radiolabelling would employ a procedure similar to the well-established kit-based Tc-99m chemistry developed in the 1970s, involving operations as simple as adding Tc-99m generator eluate to a kit vial containing the required reducing agents and other ingredients. Purification and other additional steps should be avoided. These requirements are not met by current chemistry for biomolecular 99mTc/188Re labelling. The same principles apply to the development of methods for radiolabelling biomolecules with radionuclides for targeted radionuclide therapy.Meeting this unmet need will enable us to meet the more directly clinical unmet need for widely available labelled proteins for imaging cancer and other diseases in the clinic.