期刊
ACS APPLIED MATERIALS & INTERFACES
卷 13, 期 48, 页码 56972-56987出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.1c18053
关键词
triple-negative breast cancer; glycolysis; small-interfering RNA; metal-organic frameworks; magnetic resonance imaging
资金
- Guangdong Basic and Applied Basic Research Foundation [2019A1515011722, 2020A1515010825]
- National Natural Science Foundation of China [22104159, 22174164, 21904146, U1801681]
- Key Areas Research and Development Program of Guangdong [2019B020235001]
- Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme
TNBC is typically associated with poor prognosis due to its only partial response to chemotherapy and lack of clinically established targeted therapies coupled with an aggressive disease course. In this study, a novel nanomedicine was developed to target PKM2 enzyme in TNBC cells, inhibiting tumor glycolysis and achieving anticancer effects.
Triple-negative breast cancer (TNBC) is typically associated with poor prognosis due to its only partial response to chemotherapy and lack of clinically established targeted therapies coupled with an aggressive disease course. Aerobic glycolysis is a hallmark of reprogrammed metabolic activity in cancer cells, which can be repressed by small-interfering RNA (siRNA). However, the lack of effective carriers to deliver vulnerable siRNA restricts the clinical potentials of glycolysis-based gene therapy for TNBC. Herein, we develop a tumor-targeted, biomimetic manganese dioxide (MnO2)-shrouded metal-organic framework (MOF) based nanomedicine to deliver siRNA against pyruvate kinase muscle isozyme M2 (siPKM2), wherein PKM2 is a rate-limiting enzyme in glycolysis, to inhibit the reprogrammed glycolysis of TNBC. This MOF-based genetic nanomedicine shows excellent monodispersity and stability and protects siPKM2 against degradation by nucleases. The nanomedicine not only substantially blocks the glycolytic pathway but also improves intracellular hypoxia in TNBC cells, with a resultant O-2-enhanced anticancer effect. In the mice orthotopic TNBC model, the nanomedicine shows a remarkable therapeutic effect. Meanwhile, the Mn2+ ions released from acid microenvironment-responsive MnO2 enable in vivo monitoring of the therapeutic process with magnetic resonance imaging (MRI). Our study shows great promise with this MRI-visible MOF-based nanomedicine for treating TNBC by inhibition of glycolysis via the RNA interference.
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