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

用于癌症干细胞定向治疗的免疫化疗金属配合物

• 批准号: EP/S005544/1
• 负责人: Kogularamanan Suntharalingam
• 金额: $ 27.74万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FS005544%2F1
• 关键词: Immuno; chemotherapeutic; Metal; Complexes; Cancer

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.

癌症是全球主要的医疗保健挑战之一，对社会具有重大影响。尽管癌症治疗取得了显着进步，但肿瘤复发的致命率仍然很常见。癌症复发与癌症干细胞（CSC）的存在密切相关，癌症干细胞是癌细胞的一个亚群，可以逃避当前的治疗方案并激活肿瘤的再生和转移。目前没有药物（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（包括癌症治疗）的化学制剂对于化学生物学和药物化学的研究非常重要。传统上有机分子主导了这一领域的研究，因此人们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治疗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一个平台。金属配合物的多功能性源于金属的选择、氧化态、氧化还原态、配体的数量和类型、配位几何形状、磁性和光学特性，可以用来开发新的药物来克服包括癌症在内的疾病的直接挑战。该提案将结合基础无机化学和免疫疗法，开发一体化免疫化疗金属复合物，通过细胞毒性作用安全、选择性地去除肿瘤细胞，并重新激活针对残留CSC的休眠免疫反应。具体来说，我们将开发铜（II）复合物，它可以通过活性氧（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。该项目的成果最终可能会产生实现延长肿瘤缓解的新策略。这是一个高度多学科的项目，将开创药物无机化学的新方向，并将解决当前 CSC 导向治疗方法的关键局限性。

项目成果

Breast Cancer Stem Cell Active Copper(II) Complexes with Naphthol Schiff Base and Polypyridyl Ligands

• DOI: 10.3390/inorganics9010005
• 发表时间: 2021-01-01
• 期刊: INORGANICS
• 影响因子: 2.9
• 作者: Northcote-Smith, Joshua;Johnson, Alice;Suntharalingam, Kogularamanan
• 通讯作者: Suntharalingam, Kogularamanan

Breast Cancer Stem Cell Potency of Nickel(II)-Polypyridyl Complexes Containing Non-steroidal Anti-inflammatory Drugs.

• DOI: 10.1002/chem.202001578
• 发表时间: 2020-11-02
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Feld CJ;Johnson A;Xiao Z;Suntharalingam K
• 通讯作者: Suntharalingam K

The anti-breast cancer stem cell properties of gold(i)-non-steroidal anti-inflammatory drug complexes.

• DOI: 10.1039/d2sc04707a
• 发表时间: 2023-01-18
• 期刊: Chemical science
• 影响因子: 8.4

The Anti-Breast Cancer Stem Cell Potency of Copper(I)-Non-Steroidal Anti-Inflammatory Drug Complexes.

• DOI: 10.3390/molecules28176401
• 发表时间: 2023-09-01
• 期刊: MOLECULES
• 影响因子: 4.6
• 作者: Johnson, Alice;Feng, Xiao;Singh, Kuldip;Ortu, Fabrizio;Suntharalingam, Kogularamanan
• 通讯作者: Suntharalingam, Kogularamanan

Immunogenic Cell Death of Breast Cancer Stem Cells Induced by an Endoplasmic Reticulum-Targeting Copper(II) Complex.

• DOI: 10.1002/cbic.202000553
• 发表时间: 2020-12-11
• 期刊: Chembiochem : a European journal of chemical biology
• 作者: Kaur P;Johnson A;Northcote-Smith J;Lu C;Suntharalingam K
• 通讯作者: Suntharalingam K