Exploring potential of auger emitting radionuclides for targeted therapy

我提出的研究计划旨在对具有不同物理半衰期、俄歇电子发射能量和伴随发射的俄歇电子发射核素进行系统的体外评估，并结合不同的输送系统(将放射性核素放置在与DNA不同的位置)来探索俄歇发射核素用于靶向放射性核素治疗(TRT)的潜力。这项研究的目的是在单细胞水平上了解细胞核与俄歇电子的相互作用过程，并将有助于设计基于俄歇发射的放射性核素的有效放射性药物。这将涉及与理论计算并行的实验工作。此外，我们将比较从119Sb、125I、103mRh、67Ga、111In和197M+GHG到发射放射性核素的α(225Ac/213Bi)和β(177Lu)的俄歇电子的体外治疗效果，以可能结合几种发射类型进行靶向治疗。一些被提议的同位素(111In、67Ga和125I)是可以商业获得的，这使得我们可以立即开始体外实验。然而，在开始体外评估之前，一些最有希望的同位素(119Sb、103mRh和197Hg)将需要生产、放射化学和放射性标记的发展。我们将利用TRIUMF独特的设施和建立的合作网络来制作和研究TRT的拟议同位素保存库。我们将利用TRIUMF的回旋加速器，能量从13到500 MeV，从而能够生产所有拟议的俄歇候选者。研究候选人的放射化学处理将在TRIUMF的屏蔽烟囱和热室设施中进行。这项提议的另一个重要组成部分是多机构和多学科合作方面。螯合方面将与不列颠哥伦比亚大学(C.Orvig，Chemisry)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·贝纳德，放射学，分子肿瘤学)合作进行。该计划还包括几个国际合作：丹麦南方大学(H.Thisgaard)，美国康奈尔大学(J.Wilson)和荷兰伊拉斯谟MC(J.Nonnekens)，关于俄歇发射体候选者以及与β发射体和阿尔法发射体的比较；俄罗斯联合核研究所(D.Filosofov)，关于毒性效应的理论计算以及对推荐候选者的放射化学支持；美国威斯康星州大学(J.W.Engle)，关于生产、放射化学方面和拟议研究候选者的体外评价。通过建立TRIUMF先进的同位素生产能力，以及治疗性(α、β和俄歇)同位素生产方面的新兴努力，这项研究提案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 β- 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.