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

PHD项目的目的：该项目将新的过渡金属化学与蛋白质工程相结合，在临床前(体外、体内)生产和评价一对放射性药物，这种药物可以快速、简单地用~(99m)Tm和~(188)Re标记，用于分子成像和肿瘤的靶向放射性治疗。项目描述/背景：从20世纪90年代到现在，核医学已经从基于结构未知的~(99)T-~(99)M络合物(~(99)T-~(99)M-双膦酸盐、DMSA、DTPA等)发展到现在的功能显像性放射性药物。几乎不了解摄取的机制，进入了分子成像的新时代。特别是，利用生物分子(主要是多肽和蛋白质)作为分子靶向载体已经成为这一时期分子成像的主流。用发射正电子的放射性核素(如Ga-68和F-18)标记此类分子用于PET成像的化学一直是过去20年来研究和开发的主要焦点(包括King‘s公司开发的特别高效的螯合剂化学，使用我们的专利三(羟基吡啶酮)(THP)螯合剂)。然而，自2000年以来，与之平行发展的~(99m)Tc标记方法几乎完全被忽视。然而，尽管PET的增长，出于几个原因，Tc-99m放射性药物的开发仍然是一个高度优先的问题。PET扫描仪和为PET提供的放射性示踪剂，比使用Tc-99m的SPECT成本更高，可获得的范围更小。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于~(99)Cs。最近钼-99生产方面的危机导致了氚-99m的短缺，促使各国和工业界开发新的生产方法，并实施新的钼-99和氚-99m生产设施。与此同时，商业SPECT扫描仪的设计不断改进，带来了更好的量化、分辨率和灵敏度，以及真正的动态SPECT。因此，现在有一个尚未得到满足的需求，即利用SPECT(Tc-99m)1为这个新的分子成像时代开发新的化学，并将其与用于靶向放射性核素治疗的化学相结合(Re-188)2。尚未得到满足的主要需求是使敏感生物分子的放射性标记变得简单、高效和对基础设施(如自动合成设备)要求不高的方法。没有这一点，临床应用就不会取得进展。为了使医学界及其患者，包括中低收入国家的患者容易获得和经济地使用新一代放射性示踪剂，理想的放射性标记应采用类似于1970年代开发的成熟的基于试剂盒的Tc-99m化学试剂盒的程序，操作简单，只需将Tc-99m发生器洗脱液加入装有所需还原剂和其他成分的试剂盒中即可。应避免提纯和其他额外步骤。生物分子99mTc/188Re标记的现有化学方法不能满足这些要求。同样的原则也适用于开发放射性核素标记生物分子的方法，用于靶向放射性核素治疗。满足这一未得到满足的需求将使我们能够更直接地满足临床上对广泛用于癌症和其他疾病成像的标记蛋白的需求。

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.