Azoreductase-Responsive Metal-Organic Framework-Based Nanodrug for Enhanced Cancer Therapy via Breaking Hypoxia-induced Chemoresistance.

Abstract

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)-1α against RX-0047, which can induce significant downregulation of HIF-1α 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-1α, 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.

• Authors: Caixia Huang, Wenlong Tan, Jing Zheng, Cong Zhu, Jia Huo, Ronghua Yang
• Journal: ACS applied materials & interfaces (ACS Appl Mater Interfaces) Vol. 11 Issue 29 Pg. 25740-25749 (Jul 24 2019) ISSN: 1944-8252 [Electronic] United States
• PMID: 31251022 (Publication Type: Journal Article)

Chemical References

• Delayed-Action Preparations
• Drug Carriers
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Neoplasm Proteins
• Oligonucleotides
• RX 0047
• NADH, NADPH Oxidoreductases
• Nitroreductases
• azoreductase

Topics

• Animals
• Cell Hypoxia (drug effects, genetics)
• Delayed-Action Preparations (chemistry, pharmacokinetics, pharmacology)
• Drug Carriers (chemistry, pharmacokinetics, pharmacology)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Female
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, genetics, metabolism)
• MCF-7 Cells
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• NADH, NADPH Oxidoreductases (genetics, metabolism)
• Nanostructures (chemistry, therapeutic use)
• Neoplasm Proteins (genetics, metabolism)
• Neoplasms, Experimental (drug therapy, genetics, metabolism, pathology)
• Nitroreductases
• Oligonucleotides (chemistry, pharmacology)
• Xenograft Model Antitumor Assays