Development, radiobiological assessment and dosimetry of radiopharmaceuticals emitting alpha and beta particles

发射α和β粒子的放射性药物的开发、放射生物学评估和剂量测定

• 批准号: 2740407
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2740407
• 关键词: Development; radiobiological; assessment; dosimetry; radiopharmaceuticals

Aim of the PhD Project:Cancer recurrence is often related to the inability to treat small metastases as well as resistance to current available therapies.To help overcome this issue, we will create new targeted molecular radionuclide therapeutics and imaging strategies in cancer using SPECT imaging and alpha/beta particle-emitting radionuclide lead-212.Project description:Key hypotheses are:Novel cancer-targeting radiopharmaceuticals incorporating radioactive lead are stable and specific for their targets. (WP1)Radiation cell and nuclear dose relate to toxicity by 212Pb-VMT-alpha-NET or other 212Pb-labelled radiopharmaceuticals in cancer cells. (WP2)Radiation dose determined from 203Pb-VMT-alpha-NET SPECT/CT imaging relates to tumour growth inhibition by 212Pb-VMT-alpha-NET (WP3)A biologically-informed in silico model can predict therapeutic efficacy of 212Pb-labelled radiopharmaceuticals (WP4).Background:Every two minutes, someone in the UK is diagnosed with cancer. While treatments are improving and cancer survival has doubled in the UK in the last 40 years, tumour resistance and metastasis remain significant challenges in cancer therapies. Neuroendocrine tumours (NETs) is the cancer type focussed on here. Once they metastasize, the 5-year survival rate drops to <30%, as they respond poorly to chemotherapies.Molecular radionuclide therapy (MRT) is an exciting new way to overcome therapy resistance in primary cancer cells and simultaneously target metastases. MRT employs radioactivity attached to antibodies or peptides, injected into the blood stream to specifically target and irradiate cancer cells spread throughout the body. The field has been driven by beta particle-emitters, but alpha particles provide the possibility to go from palliation to curative therapy.Despite their potential, a limited radionuclide supply and/or inconvenient or cumbersome radiochemistry for alpha particle-emitters such as 213Bi, 225Ac, 211At and 227Th, mean other avenues need to be explored. Equally, in-depth radiobiological studies need to be carried out (such as described here) to determine acceptable ratios of tumour:healthy tissue toxicity and accurate radiation dose limits to organs that are currently limiting the amount of activity that can be injected.212Pb is fast gaining attention in MRT to treat both large primary tumours and small metastases, due to the release of beta particles and short-lived daughter alpha particles as well as its physical half-life and ability to be generator-produced. Also, this radionuclide enables a theranostic approach as 203Pb can be imaged by single photon emission computed tomography (SPECT) allowing the location and amount of 203Pb delivered to be determined. This allows targeted calibration of 212Pb delivery to a tumour. Initial (pre-)clinical work has shown the potential of 212Pb-labeled radiopharmaceuticals in treating a range of cancers with little toxicity.Here, we will explore, optimise, and carry out radiobiological studies to maximise impact of a novel radionuclide therapy (212Pb-VMT-alpha-NET; produced by collaborator Viewpoint Molecular Targeting) for patients with neuroendocrine tumours as well as explore other cancer-targeting approaches. This will be achieved through MRT using not only somatostatin receptor-binding peptides (to target MRT to NETs), but also to other cancer-targeting moieties such as PSMA in prostate cancer, attached to radioactive alpha particle-emitter, 212Pb and to use the imaging equivalent (using 203Pb) to determine optimal delivery of 212Pb to cancer cells.

博士项目目标：癌症复发通常与无法治疗小转移以及对现有治疗方法的耐药性有关。为了帮助克服这一问题，我们将利用SPECT成像和α / β粒子发射放射性核素铅-212在癌症中创造新的靶向分子放射性核素治疗和成像策略。项目描述：主要假设是：含放射性铅的新型靶向癌症的放射性药物对其靶点是稳定和特异性的。（WP1）辐射细胞和核剂量与212Pb-VMT-alpha-NET或其他212pb标记的放射性药物对癌细胞的毒性有关。由203Pb-VMT-alpha-NET SPECT/CT成像确定的辐射剂量与212Pb-VMT-alpha-NET （WP3）对肿瘤生长的抑制有关。一个生物学知情的硅模型可以预测212pb标记的放射性药物（WP4）的治疗效果。背景：在英国，每两分钟就有一人被诊断出患有癌症。虽然在过去的40年里，英国的治疗方法不断改进，癌症存活率翻了一番，但肿瘤耐药性和转移仍然是癌症治疗的重大挑战。神经内分泌肿瘤（NETs）是这里重点讨论的癌症类型。一旦转移，5年生存率下降到<30%，因为他们对化疗的反应很差。分子放射性核素治疗（MRT）是一种令人兴奋的新方法，可以克服原发性癌细胞的治疗耐药，同时靶向转移。MRT利用附着在抗体或多肽上的放射性物质，将其注射到血液中，专门针对并照射扩散到全身的癌细胞。这个领域一直是由β粒子发射器驱动的，但α粒子提供了从缓解到治愈治疗的可能性。尽管它们具有潜力，但对于213Bi、225Ac、211At和227等α粒子发射器来说，放射性核素供应有限和/或不方便或繁琐的放射化学意味着需要探索其他途径。同样，需要进行深入的放射生物学研究（如此处所述），以确定可接受的肿瘤比例：健康组织毒性和对器官的准确辐射剂量限制，这些限制目前限制了可注射的活动性。212Pb由于释放β粒子和短暂的子α粒子，以及它的物理半衰期和生成能力，在MRT治疗中大的原发肿瘤和小的转移瘤中迅速获得关注。此外，这种放射性核素可以通过单光子发射计算机断层扫描（SPECT）成像203Pb，从而确定203Pb的位置和量，从而使治疗方法成为可能。这允许有针对性地校准212Pb输送到肿瘤。初步的（前）临床工作表明，212pb标记的放射性药物在治疗一系列癌症方面具有很小的毒性。在这里，我们将探索、优化和开展放射生物学研究，以最大限度地发挥新型放射性核素治疗（212Pb-VMT-alpha-NET；由合作者Viewpoint Molecular Targeting生产）对神经内分泌肿瘤患者的影响，并探索其他癌症靶向治疗方法。这将通过MRT来实现，不仅使用生长抑素受体结合肽（将MRT靶向NETs），还使用其他靶向癌症的部分，如前列腺癌中的PSMA，附着在放射性α粒子发射器212Pb上，并使用成像当量（使用203Pb）来确定212Pb向癌细胞的最佳递送。