Inorganic nanoparticles for radiolabelling with 223Ra / 212Pb, for multimodal imaging and therapy in cancer.

PhD项目的目标：开发生产用于双模式治疗和光学成像探针的223 RaS量子点（QD）纳米颗粒和212 PbS量子点的方法。开发专门针对223 Ra和212 Pb的配体，允许使用微波合成技术在不同温度下成核量子点。整合靶向癌症中表达的表面受体，如前列腺癌的PSMA和高级别胶质瘤（HGG）中的uPAR。α和β发射量子点体外和体内治疗效果的验证项目描述：该项目旨在开发利用纳米颗粒平台将α（和β）粒子发射放射性核素治疗靶向癌细胞的新方法。量子点将是选择的纳米颗粒，因为它们可以使用微波合成以简单的方式合成，并以简单的一锅法用靶向肽/抗体官能化。然后，α发射纳米颗粒也将是荧光的，从而提供成像的选择，其中治疗性颗粒是通过近红外成像。该项目将重点关注镭-223和铅-212，因为它们是有前途的放射性核素治疗剂，可以制成223 RaS或212 PbS量子点。含有发射α粒子的放射性核素的药物已被确定为晚期转移性癌症的有希望的治疗方法，并且在该领域存在重大的研究和商业兴趣。第一个为临床使用而开发的α发射药物是镭-223二氯化物，已证明对患者有益。镭-223二氯化物是一种用于晚期前列腺癌患者的许可产品，已扩散到骨骼，自2016年以来一直在NHS中使用。自那时以来的发展现在使得能够使用α粒子发射放射性核素来治疗原发性癌症。在这些药物中，放射性核素必须附着在靶向分子上，这样它才能特异性地传递到癌细胞。这需要放射性核素与靶向分子牢固且稳定地结合。由于镭具有独特的化学性质（低电荷与离子半径比导致弱静电金属-配体相互作用），因此螯合化学的使用受到限制。为了克服这一点，我们将从简单的源元素/分子中生产纳米颗粒，这些源元素/分子被调整为优先与镭-223结合，然后以简单的一锅法用靶向基团官能化纳米颗粒的表面。这里研究的放射性核素212 Pb由于其增加的可用性、合适的半衰期以及将其连接到肿瘤靶向化合物的几种选择而作为替代α-发射体受到关注。此外，它还有望通过释放B和A粒子来治疗大型原发性肿瘤和小型转移瘤。212 Pb也是由发生器产生的，使得按需洗脱成为可能。最初的（前）临床工作已经显示了212 Pb标记的放射性药物在治疗癌症中的潜力，然而，其他提高癌细胞中212 Pb摄取的方法是一个值得探索的有趣途径。我们将在2种癌症模型中验证这些223 RaS/212 PbS治疗性QD的靶向。首先，前列腺癌模型将用于将QD与临床中的治疗性α/β对应物进行比较。其次，还将探索高级别胶质瘤（HGG）模型，其中放射治疗的使用仅限于靶向较低的放射治疗，如伽玛刀或质子束。

Aim of the PhD Project: To develop methodology to produce 223RaS Quantum dot (QD) nanoparticles and 212PbS QDs for dual modal therapeutic and optical imaging probe. Develop ligands specifically tuned for 223Ra and 212Pb that allow for nucleation of QDs at different temperatures using microwave synthesis techniques. Incorporate targeting for surface receptors expressed in cancer such as PSMA for prostate cancer and uPAR in high grade glioma (HGG) Validation of therapeutic efficacy in vitro and in vivo of alpha and beta-emitting QDs.Project description:This project sets out to develop new methods of targeting alpha (and beta) particle-emitting radionuclide therapies to cancer cells utilising nanoparticle platforms. Quantum dots will be the nanoparticle of choice as they can be synthesised in a facile manner using microwave synthesis and functionalised with targeting peptides/antibodies in a simple one-pot manner. The alpha-emitting-nanoparticles will then also be fluorescent giving the option of imaging where the therapeutic particle is by near-infrared imaging. This project will focus on radium-223 and lead-212, as they are promising radionuclide therapeutics and can be made into 223RaS or 212PbS quantum dots. Drugs containing alpha-particle-emitting radionuclides have been identified as promising treatments for late-stage metastatic cancer and there is significant research and commercial interest in this area. The first alpha-emitting pharmaceutical developed for clinical use, with proven patient benefit was radium-223 dichloride. Radium-223 dichloride is a licenced product for patients with late-stage prostate cancer which has spread to their bones and has been in use in the NHS since 2016. Developments since then now enable the use of alpha-particle-emitting radionuclides to treat primary types of cancer. In these drugs, the radionuclide must be attached to a targeting molecule so it can be specifically delivered to the cancer cells. This requires the radionuclide to be strongly and stably bound to the targeting molecule. As radium has unique chemical properties (low charge-to-ionic radius ratio causing weak electrostatic metal-ligand interactions) the use of chelation chemistry is limited. To overcome this, we will produce nanoparticles from simple source elements/molecules that are tuned to bind to radium-223 preferentially and then functionalise the surface of the nanoparticle with a targeting group in a facile one-pot manner. 212Pb, the radionuclide studied here, is gaining attention as an alternative a-emitter due to its increasing availability, suitable half-life, and several options with which to attach it to tumour-targeting compounds. Also, it holds promise to treat both large primary tumours and small metastases through its release of b and a particles. 212Pb is also generator-produced, making on-demand elution possible. Initial (pre)clinical work has shown the potential of 212Pb-labeled radiopharmaceuticals in treating cancers, however other methods with which to enhance 212Pb uptake in cancer cells are an interesting avenue to explore. We will validate the targeting of these 223RaS/212PbS therapeutic QDs in 2 cancer models. Firstly, prostate cancer models will be used to compare the QDs to the therapeutic alpha/beta counterparts that are in the clinic. Secondly high-grade glioma (HGG) models, where the use of radiotherapy is limited to less targeted radiotherapy such as gamma knife or proton beam, will also be explored.