Immuno-chemotherapeutic Metal Complexes for Cancer Stem Cell-Directed Therapy

癌症是全球医疗保健面临的主要挑战之一，对社会产生重大影响。尽管癌症治疗取得了重大进展，但肿瘤复发的致命发生率仍然很常见。癌症复发与癌症干细胞（CSC）的存在密切相关，CSC是一种癌细胞亚群，可以逃避当前的治疗方案并激活肿瘤再生长和转移。目前还没有药物（单一或组合）可以去除任何组织类型的CSC。鉴定具有治疗潜力的化学试剂，包括用于癌症治疗的化学试剂，对于化学生物学和药物化学的研究具有高度重要性。传统上，有机分子在这一领域的研究中占主导地位，因此对含金属化合物的治疗特性知之甚少。关于无机化合物的免疫潜力的信息甚至更少。金属配合物提供的化学多样性为探索纯有机化合物无法实现的生物相关化学空间领域提供了平台。金属络合物的多功能性，其来自于金属、氧化态、氧化还原态、配体的数量和类型、配位几何结构、磁性和光学性质的选择，可以被利用来开发新的药剂，以克服包括癌症在内的疾病的直接挑战。该提案将联合收割机基础无机化学和免疫疗法相结合，以开发一体化免疫化疗金属络合物，以通过细胞毒性作用安全地和选择性地去除肿瘤细胞，并重新激活针对残留CSC的休眠免疫应答。具体而言，我们将开发铜（II）络合物，其可以通过活性氧（ROS）介导的内质网（ER）应激诱导CSC的免疫原性细胞死亡（ICD），从而充当抗CSC疫苗。该项目的结果可能最终导致新的策略，以实现延长的肿瘤缓解。这是一个高度多学科的项目，将在药物无机化学领域开辟新的方向，并将解决目前CSC指导的治疗方法的关键限制。

Cancer is one of the leading global healthcare challenges and has a high impact on society. Despite significant advancements in cancer care, fatal incidences of tumour recurrence are still common. Cancer relapse is strongly linked to the existence of cancer stem cells (CSCs), a sub-population of cancer cells that can evade current therapeutic regimens and activate tumour regrowth and metastasis. Currently there are no drugs (single or combinations) that can remove CSCs of any tissue type. The identification of chemical agents with therapeutic potential, including for cancer treatment, is of high importance for research in chemical biology and medicinal chemistry. Traditionally organic molecules have dominated research in this area, and thus relatively little is known about the therapeutic properties of metal-containing compounds. Even less information is known about the immunotherapeutic potential of inorganic compounds. The chemical diversity offered by metal complexes provides a platform to explore areas of biologically relevant chemical space that cannot be achieved by purely organic compounds. The versatility of metal complexes, which arises from the choice of metal, oxidation state, redox state, number and type of ligands, coordination geometry, magnetic and optical properties, can be harnessed to develop new agents to overcome immediate challenges in diseases including cancer. This proposal will combine fundamental inorganic chemistry and immunotherapy to develop all-in-one immuno-chemotherapeutic metal complexes to safely and selectively remove tumour cells through cytotoxic effects, and reactivate dormant immune response against residual CSCs. Specifically, we will develop copper(II) complexes that can induce immunogenic cell death (ICD) of CSCs by reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, hence acting as an anti-CSC vaccine. The outcomes of the project could ultimately lead to new strategies to achieve extended tumour remission. This is a highly multidisciplinary project that will forge new directions in medicinal inorganic chemistry, and will address key limitations in current CSC-directed therapeutic approaches.