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

PHD项目的目的：癌症复发通常与无法治疗微小转移以及对现有治疗方法的耐药性有关。为了帮助克服这个问题，我们将使用SPECT成像和α/β粒子发射放射性核素铅-212来创建新的癌症靶向分子放射性核素疗法和成像策略。项目描述：主要假设是：含有放射性铅的新型癌症靶向放射性药物是稳定的，并且针对其靶点具有特异性。(WP1)辐射细胞和核剂量与~(212)Pb-VMT-α-Net或其他~(212)Pb标记的放射性药物对癌细胞的毒性有关。(WP2)由~(203)Pb-VMT-α-Net SPECT/CT成像确定的辐射剂量与~(212)Pb-VMT-α-Net(WP3)对肿瘤生长的抑制有关。在过去的40年里，虽然英国的治疗方法正在改进，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中的重大挑战。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年存活率下降到30%，因为它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，可以克服原发癌细胞的治疗阻力，同时靶向转移。MRT使用附着在抗体或多肽上的放射性，注入血液中，以特定的靶向和照射扩散到全身的癌细胞。这一领域一直由β粒子发射体驱动，但阿尔法粒子提供了从缓解到治愈的可能性。尽管它们的潜力有限，但放射性核素供应有限，和/或对阿尔法粒子发射体如~(213)Bi、~(225)Ac、~(211)At和~(227)Th进行放射化学不便或繁琐，这意味着需要探索其他途径。同样，还需要进行深入的放射生物学研究(如本文所述)，以确定可接受的肿瘤比率：健康的组织毒性和对目前限制可注入活动量的器官的准确辐射剂量限值。由于β粒子和短命的子α粒子的释放以及物理半衰期和发电机产生的能力，212Pb在MRT中迅速获得关注，用于治疗大的原发肿瘤和小的转移瘤。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)对203Pb进行成像，从而实现了治疗方法，从而可以确定203Pb的位置和数量。这使得可以对肿瘤的~(212)Pb输送进行靶向校准。初步的(前期)临床工作表明，~(212)Pb标记的放射性药物在治疗一系列毒性很小的癌症方面具有潜力。在这里，我们将探索、优化和开展放射生物学研究，以最大限度地提高新型放射性核素疗法(~(212)Pb-VMT-α-Net；由合作伙伴视点分子靶向技术生产)对神经内分泌肿瘤患者的影响，并探索其他癌症靶向方法。这将通过MRT实现，不仅使用生长抑素受体结合肽(靶向MRT to Net)，而且还针对其他癌症靶向部分，如前列腺癌中的PSMA，连接到放射性α粒子发射体212Pb，并使用成像当量(使用203Pb)来确定212Pb向癌细胞的最佳输送。

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.