期刊
ACS APPLIED MATERIALS & INTERFACES
卷 11, 期 29, 页码 25740-25749出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.9b08115
关键词
hypoxic; azoreductase; metal-organic frameworks; chemoresistance; cancer therapy
资金
- National Natural Science Foundation of China [21775037, 21735001, 21573063]
- Hunan Natural Science Foundation [2018JJ3032]
- Shenzhen Science and Technology Innovation Committee [JCYJ20170306141630229]
The insufficient oxygen supply may cause hypoxia in a solid tumor, which can lead to drug resistance and unsatisfactory chemotherapy effect. To address this issue, a new nanodrug has been developed with azoreductase-responsive functional metal-organic frameworks (AMOFs), where chemotherapeutic drugs were encapsulated in the AMOFs and small interfering RNAs (siRNAs) were absorbed on the surface of AMOFs. The siRNA was designed to contain hypoxia-inducible factor (HIF)-1 alpha against RX-0047, which can induce significant downregulation of HIF-1 alpha protein. The azobenzene units within the frameworks of AMOFs could be reduced to amines by the highly expressed azoreductase under the oxygen-deficient environment, which results in azoreductase-responsive release of the encapsulated drugs and siRNAs under the hypoxic condition. Therefore, once the drug-loaded AMOF entered the hypoxic cancer cells, the azoreductase-responsive release of siRNA could decrease the efflux of chemotherapeutic drugs via inhibiting the expressions of HIF-1 alpha, multidrug resistance gene 1, and P-glycoprotein. This nanodrug can thus efficiently break hypoxia-induced chemoresistance and result in high-efficient cancer therapy in hypoxic tumors. As far as we know, this is the first attempt to construct an AMOF-based nanodrug with hypoxic harvesting behaviors. This proof-of-concept research provides a simple strategy for the construction of hypoxic-responsive AMOFs and also offers a unique on-command drug delivery platform, which can effectively break hypoxia-induced chemoresistance.
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