Molecularly engineered iron-catalysed cancer nanomedicine

癌症免疫疗法正在彻底改变癌症治疗。然而，目前使用单克隆抗体（mAb）靶向免疫检查点阻断的免疫治疗药物仅使相对小部分的癌症患者受益，并且治疗极其昂贵。纳米技术、化学科学方法和先进的生物材料将在开发更有效的免疫治疗方法中发挥关键作用，从而帮助更多的患者。其中一个有希望的领域是开发免疫检查点的小分子抑制剂，但这些努力仍处于早期阶段。靶向程序性细胞死亡-1/程序性细胞死亡配体1信号通路的基于mAb的免疫检查点抑制剂在临床试验中特别有效。然而，将药物特异性递送至肿瘤微环境（TME）并调节免疫抑制性TME以改善对治疗的反应是非常具有挑战性的。纳米材料非常适合克服这些挑战，因为它们可以被合理地设计为药物递送载体并引发额外的抗肿瘤反应。该博士项目将利用一种多功能平台技术，将氧化铁纳米颗粒封装在磷脂胶束（mIONP）中，从而能够有效地在体外和体内将抗癌药物递送到肿瘤细胞中。该构建体提供成像和磁性特征以定位、引导和研究细胞特异性和生物分布以及治疗反应。在这种结构中，铁含量和酶样性质也提供了内在的癌症治疗。博士项目旨在开发新的分子工具（小分子和铁纳米结构材料），生物正交催化和生物缀合协议，以创建一个创新的化学免疫球蛋白载铁脂质纳米颗粒。该构建体将具有针对PD-1/PD-L1通路的免疫检查点阻断的化学编程特征，具有克服TME中的免疫抑制并触发铁催化的癌细胞死亡的潜力。最终，我们的目标是创建一个纳米医学平台，显着改善目前的免疫疗法和化学免疫疗法，并有潜力转化为临床实践。

Cancer immunotherapy is revolutionizing cancer treatment. However, the current immunotherapy drugs, which target immune checkpoint blockade using monoclonal antibodies (mAb), only benefit a relatively small fraction of cancer patients, and the treatments are extremely expensive. Nanotechnology, chemical science approaches and advanced biomaterials will play a critical role in the development of more effective immunotherapy treatments that can help more patients. One of the promising areas is in the development of small-molecule inhibitors of immune checkpoints but these efforts are still in early stages. mAb-based immune checkpoint inhibitors targeted to the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Signalling Pathway have been particularly effective in clinical trials. However, specific delivery of the drugs to the tumour microenvironment (TME) and modulating the immunosuppressive TME to improve the response to the therapy is very challenging. Nanomaterials are uniquely suited to overcome these challenges as they can be rationally designed to act as drug delivery vehicle and to trigger additional anti-tumour responses. This PhD project will harness a versatile platform technology that encapsulating iron oxide nanoparticles inside phospholipid micelles (mIONPs) enables effective in vitro and in vivo delivery of the anti-cancer drugs to the tumour cells. The construct provides imaging and magnetic features to locate, guide and study cellular specificity and biodistribution and therapeutic responses. In this construct intrinsic cancer therapy is also provided by its iron content and enzyme-like properties.The PhD project seeks to develop new molecular tools (small-molecules and iron nanostructured materials), bioorthogonal catalysis and bioconjugation protocols to create an innovative chemoimmunotherapeutic iron-loaded lipid nanoparticle. The construct will have chemically programmed features for immune checkpoint blockade targeting the PD-1/PD-L1 pathway, with the potential to overcome immune-suppression in the TME and to trigger iron-catalysed cancer cell death. Ultimately, the goal is creating a nanomedicine platform that significantly improves current immunotherapy and chemoimmunotherapy, and with potential for translation into clinical practice.