Exploring potential of auger emitting radionuclides for targeted therapy

我提出的研究计划旨在系统地体外评估具有不同物理半衰期的俄歇电子发射放射性核素，俄歇电子发射能量，以及与各种递送系统（将放射性核素放置在DNA的不同接近度）相结合的伴随发射，以探索俄歇发射放射性核素用于靶向放射性核素治疗（TRT）的潜力。本研究旨在了解细胞核与俄歇电子在单细胞水平上相互作用的过程，并将允许基于俄歇发射放射性核素设计有效的放射性药物。这将涉及与理论计算并行的实验工作。此外，我们将比较来自119Sb， 125I, 103mRh, 67Ga， 111In和197m+gHg的俄盖电子对α (225Ac/213Bi)和β (177Lu)发射放射性核素的体外治疗效果，以可能结合几种发射类型进行靶向治疗。一些建议的同位素（111In， 67Ga和125I）是市售的，这使我们能够立即开始体外实验。然而，一些最有希望的同位素（119Sb、103mRh和197Hg）在开始体外评估之前，将需要开发生产、放射化学和放射性标记。我们将利用TRIUMF的独特设施及其已建立的合作网络，为TRT生产和研究拟议的同位素曲目。我们将利用TRIUMF的回旋加速器，能量从13到500 MeV，能够生产所有拟议的俄歇候选体。研究候选人的放射化学处理将在TRIUMF的屏蔽通风柜和热室设施中进行。这一建议的另一个重要组成部分是多机构和多学科合作方面。螯合方面将与英属哥伦比亚大学（C. Orvig，化学）合作进行。体外评估和细胞实验将与不列颠哥伦比亚省癌症机构（F. Benard，放射学，分子肿瘤学）合作进行。该项目还包括一些国际合作：丹麦南方大学（H. Thisgaard），美国康奈尔大学（J. Wilson）和荷兰Erasmus MC （J. Nonnekens）对俄热发射候选体的体外评估以及与-发射体和α发射体的比较；俄罗斯联合核研究所（D. Filosofov）关于毒性效应的理论计算和对拟议候选物质放射化学的支持；威斯康星大学，美国（J.W. Engle）的生产，放射化学方面和拟议的研究候选物的体外评价。通过建立TRIUMF先进的同位素生产能力，以及在治疗（α -， β -和俄歇）同位素生产方面的新努力，该研究计划旨在巩固加拿大作为TRT卓越中心的地位。

My proposed research program aims at the systematic in vitro evaluation of Auger-electron emitting radionuclides with different physical half-lives, Auger electron emission energies, and accompanying emissions in combination with various delivery systems (placing radionuclides within different proximities to DNA) to explore the potential of Auger emitting radionuclides for targeted radionuclide therapy (TRT). This research aims to understand the processes of interaction of cell nuclei with Auger electrons on single cell level and will allow to design effective radiopharmaceuticals based on Auger-emitting radionuclides. This will involve experimental work in parallel with theoretical calculations. Further, we will compare the in vitro therapeutic efficacy of Auger electrons from 119Sb, 125I, 103mRh, 67Ga, 111In and 197m+gHg to alpha (225Ac/213Bi) and beta (177Lu) emitting radionuclides to possibly combine several emission types for targeted therapy. Some of the proposed isotopes (111In, 67Ga and 125I) are commercially available which allows us to start in vitro experiments immediately. However, some of the most promising isotopes (119Sb, 103mRh and 197Hg) will require development of production, radiochemistry and radiolabeling before starting in vitro evaluation. We will take advantage of TRIUMF's unique facilities and its established collaboration network to produce and study the proposed repertoire of isotopes for TRT. We will utilize TRIUMF's cyclotrons with energies from 13 to 500 MeV, enabling production of all proposed Auger candidates. Radiochemical processing of research candidates will be done in shielded fumehood and hot cell facilities at TRIUMF. Another crucial component of this proposal is the multi-institutional and multidisciplinary collaboration aspect. The chelation aspects will be performed in collaboration with the University of British Columbia (C. Orvig, Chemisry). In vitro evaluation and cell experiments will be performed in collaboration with the British Columbia Cancer Agency (F. Benard, Radiology, Molecular Oncology). This program also includes several international collaborations: Southern University of Denmark (H. Thisgaard), Cornell U., USA (J. Wilson) and Erasmus MC, The Netherlands (J. Nonnekens) on in vitro evaluation of Auger emitting candidates as well as comparison with - emitters and alpha emitters; Joint Institute for Nuclear Research, Russia (D. Filosofov) on theoretical calculation of toxicity effects and support on radiochemistry of proposed candidates; U. of Wisconsin, USA (J.W. Engle) on production, radiochemical aspects and in vitro evaluation of proposed research candidates. By building on TRIUMF's advanced isotope production capabilities, and emerging efforts in therapeutic (alpha-, beta- and Auger-) isotope production, this research proposal aims to solidify Canada as a center of excellence in TRT.