Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, P. R. China.
Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, 410078, P. R. China.
Angew Chem Int Ed Engl. 2022 Aug 1;61(31):e202203546. doi: 10.1002/anie.202203546. Epub 2022 Jun 21.
Recent progress in studying copper-dependent targets and pathways in the context of tumor treatment has provided new insights into therapeutic strategies of leveraging copper-dependent disease vulnerabilities and pharmacological manipulation of intratumor copper transportation to improve chemotherapy. Here, we developed reactive oxygen species (ROS)-sensitive nanoparticles loaded with copper chaperone inhibitor DC_AC50 and cisplatin(IV) prodrug. The released DC_AC50 can promote a remarkable accumulation of intracellular cisplatin and copper through inhibition of the Atox1-ATPase pathways, thereby enhancing the chemotherapeutic effect of cisplatin and inducing significant ROS generation. Excessive ROS then elicits intense endoplasmic reticulin (ER) stress which facilitates the immunogenic cell death (ICD) spurring a sustained immune response. Our study suggests that nanoparticle-mediated copper chaperone inhibition via DC_AC50 can restore the immunogenicity of tumor cells for enhanced chemotherapy and cancer immunotherapy.
近年来，在肿瘤治疗方面，对铜依赖性靶标和途径的研究取得了新的进展，为利用铜依赖性疾病脆弱性和对肿瘤内铜运输的药理学干预来改善化疗提供了新的治疗策略。在这里，我们开发了负载铜伴侣抑制剂 DC_AC50 和顺铂（IV）前药的活性氧（ROS）敏感纳米颗粒。释放的 DC_AC50 可以通过抑制 Atox1-ATPase 途径促进细胞内顺铂和铜的显著积累，从而增强顺铂的化疗效果并诱导大量 ROS 的产生。过量的 ROS 会引发强烈的内质网（ER）应激，促进免疫原性细胞死亡（ICD），刺激持续的免疫反应。我们的研究表明，通过 DC_AC50 介导的纳米颗粒抑制铜伴侣可以恢复肿瘤细胞的免疫原性，从而增强化疗和癌症免疫治疗效果。
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