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Exploiting the acquired vulnerability of cisplatin-resistant tumors with a hypoxia-amplifying DNA repair–inhibiting (HYDRI) nanomedicine

Various cancers treated with cisplatin almost invariably develop drug resistance that is frequently caused by substantial DNA repair. We searched for acquired vulnerabilities of cisplatin-resistant cancers to identify undiscovered therapy. We herein found that cisplatin resistance of cancer cells co...

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Detalles Bibliográficos
Autores principales: Chen, Jing, Wang, Xue, Yuan, Yuan, Chen, Haoting, Zhang, Lingpu, Xiao, Haihua, Chen, Jingqi, Zhao, Yongxiang, Chang, Jin, Guo, Weisheng, Liang, Xing-Jie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997498/
https://www.ncbi.nlm.nih.gov/pubmed/33771859
http://dx.doi.org/10.1126/sciadv.abc5267
Descripción
Sumario:Various cancers treated with cisplatin almost invariably develop drug resistance that is frequently caused by substantial DNA repair. We searched for acquired vulnerabilities of cisplatin-resistant cancers to identify undiscovered therapy. We herein found that cisplatin resistance of cancer cells comes at a fitness cost of increased intracellular hypoxia. Then, we conceived an inspired strategy to combat the tumor drug resistance by exploiting the increased intracellular hypoxia that occurs as the cells develop drug resistance. Here, we constructed a hypoxia-amplifying DNA repair–inhibiting liposomal nanomedicine (denoted as HYDRI NM), which is formulated from a platinum(IV) prodrug as a building block and payloads of glucose oxidase (GOx) and hypoxia-activatable tirapazamine (TPZ). In studies on clinically relevant models, including patient-derived organoids and patient-derived xenograft tumors, the HYDRI NM is able to effectively suppress the growth of cisplatin-resistant tumors. Thus, this study provides clinical proof of concept for the therapy identified here.