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

用于使用 223Ra / 212Pb 进行放射性标记的无机纳米粒子，用于癌症的多模式成像和治疗。

• 批准号: 2740858
• 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-2740858
• 关键词: Inorganic; nanoparticles; radiolabelling; 223Ra; 212Pb

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.

博士项目目标：开发用于双模治疗和光学成像探针的223RaS量子点纳米粒子和212PbS量子点纳米粒子的制备方法。利用微波合成技术，开发专门针对223Ra和212Pb的配体，使量子点在不同温度下成核。结合靶向癌症表面受体，如前列腺癌的PSMA和高级别胶质瘤（HGG）的uPAR。验证α和β发射量子点的体外和体内治疗效果。项目描述：该项目旨在开发利用纳米粒子平台靶向α（和β）粒子发射放射性核素治疗癌细胞的新方法。量子点将成为纳米粒子的首选，因为它们可以用微波合成的简单方式合成，并以简单的一锅方式与靶向肽/抗体功能化。发射α的纳米粒子也将是荧光的，从而可以选择在治疗粒子所在的位置通过近红外成像进行成像。该项目将重点研究镭-223和铅-212，因为它们是有前途的放射性核素治疗药物，可以制成223RaS或212PbS量子点。含有α粒子释放放射性核素的药物已被确定为治疗晚期转移性癌症的有希望的治疗方法，并且在这一领域有重要的研究和商业兴趣。第一种用于临床使用的α -发射药物是镭-223二氯化物，经证实对患者有益。镭-223二氯化物是一种许可产品，用于治疗已经扩散到骨骼的晚期前列腺癌患者，自2016年以来一直在NHS中使用。自那时以来的发展现在使使用释放α粒子的放射性核素治疗原发性癌症成为可能。在这些药物中，放射性核素必须附着在一个目标分子上，这样它才能被特异性地输送到癌细胞中。这就要求放射性核素与靶分子紧密稳定地结合在一起。由于镭具有独特的化学性质（低电荷-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。为了克服这个问题，我们将从简单的源元素/分子中生产纳米粒子，这些元素/分子被调整为优先与镭-223结合，然后用简单的一锅方式将纳米粒子的表面与靶向基团功能化。本文所研究的放射性核素212Pb作为一种可替代的a-发射器正受到越来越多的关注，因为它的可用性越来越高，半衰期合适，并且有几种选择可以将其附着在肿瘤靶向化合物上。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性肿瘤。212Pb也是由发生器产生的，可以按需洗脱。初步（预）临床工作已经显示了212Pb标记的放射性药物在治疗癌症方面的潜力，然而，其他增强癌细胞对212Pb摄取的方法是一个值得探索的有趣途径。我们将在两种癌症模型中验证这些223RaS/212PbS治疗性量子点的靶向性。首先，前列腺癌模型将用于比较量子点与临床治疗中的α / β对应物。其次，还将探索高级别胶质瘤（HGG）模型，其中放疗的使用仅限于较少靶向放疗，如伽玛刀或质子束。