A Triple Threat Against Ovarian Cancer: Os(II)‐Pt(IV)‐Ceritinib Conjugates for Photodynamic Therapy, Chemotherapy, and Immunogenic Cell Death Induction

IF 16.9 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Angewandte Chemie International Edition Pub Date : 2025-10-06 DOI:10.1002/anie.202518623

Marta Redrado, Sourav Acharya, Pierre Mesdom, Tomer Babu, James W. Southwell, Laiane S. Oliveira, Samia Hidalgo, Philippe Arnoux, Céline Frochot, Dan Gibson, Gilles Gasser

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引用次数: 0

Abstract

Metal‐based anticancer agents offer unique opportunities to integrate multiple therapeutic modalities within a single molecular framework. Herein, we present the first Osmium(II)‐Platinum(IV)‐Ceritinib conjugate (Os‐Pt‐Cer) that synergistically combines photodynamic therapy (PDT), chemotherapy, and immunotherapy via immunogenic cell death (ICD) induction. This heterobimetallic complex features a photoactive osmium(II) polypyridyl core, a platinum(IV) prodrug derived from oxaliplatin, and the kinase inhibitor ceritinib as an axial ligand. Upon deep‐red irradiation (λ = 740 nm), the conjugate exhibits potent antiproliferative activity in ovarian 2D cancer cells and 3D tumour spheroids, with IC50 values in the low nanomolar range. In addition, Os‐Pt‐Cer effectively inhibits cancer cell migration. Mechanistic studies reveal that the conjugate induces hallmarks of ICD, including calreticulin exposure, ATP release, HMGB1 secretion and phagocytosis. This multifunctional approach highlights the potential of osmium(II)‐platinum(IV) conjugates as promising candidates for overcoming resistance and immune evasion in high‐grade ovarian carcinoma.

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卵巢癌的三重威胁：Os（II）‐Pt（IV）‐Ceritinib偶联物用于光动力治疗、化疗和免疫原性细胞死亡诱导

基于金属的抗癌药物提供了在单一分子框架内整合多种治疗方式的独特机会。在这里，我们提出了第一个锇(II) -铂(IV) - Ceritinib偶联物（Os - Pt - Cer），它通过免疫原性细胞死亡（ICD）诱导协同结合光动力治疗（PDT）、化疗和免疫治疗。这种杂双金属配合物具有光活性锇（II）多吡啶核，从奥沙利铂衍生的铂（IV）前药和激酶抑制剂ceritinib作为轴向配体。在深红色照射（λ = 740 nm）下，该缀合物对卵巢2D癌细胞和3D肿瘤球体显示出强大的抗增殖活性，IC50值在低纳摩尔范围内。此外，Os‐Pt‐Cer还能有效抑制癌细胞的迁移。机制研究表明，该偶联物可诱导ICD的特征，包括钙网蛋白暴露、ATP释放、HMGB1分泌和吞噬。这种多功能方法强调了锇(II) -铂（IV）偶联物作为克服高级别卵巢癌耐药和免疫逃避的有希望的候选者的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Angewandte Chemie International Edition 化学-化学综合

CiteScore

26.60

自引率

6.60%

发文量

3549

审稿时长

1.5 months

期刊介绍： Angewandte Chemie, a journal of the German Chemical Society (GDCh), maintains a leading position among scholarly journals in general chemistry with an impressive Impact Factor of 16.6 (2022 Journal Citation Reports, Clarivate, 2023). Published weekly in a reader-friendly format, it features new articles almost every day. Established in 1887, Angewandte Chemie is a prominent chemistry journal, offering a dynamic blend of Review-type articles, Highlights, Communications, and Research Articles on a weekly basis, making it unique in the field.