Abstract
BackgroundMalignant tumor is usually associated with epigenetic dysregulation, such as overexpression of histone deacetylase (HDAC), thus HDAC has emerged as a therapeutic target for cancer. Histone deacetylase inhibitor has been approved for clinical use to treat hematological cancers. However, the low solubility, short circulation lifetime, and high cytotoxicity partially limited their applications in solid tumor.MethodsThe upconversion nanoparticles (UC) modified with mesoporous silica (SUC) was used to load an HDACI, suberoylanilide hydroxamic acid (SAHA), and further camouflaged with M1 macrophage-derived exosome membranes (EMS). EMS was characterized in size and compositions. We also analyzed the epigenetic regulation induced by EMS. Furthermore, we evaluate the biodistribution and in vivo tumor inhibition after the systemic administration of EMS.ResultsThis novel style spatiotemporal-resolved drug delivery system, EMS showed a high loading efficiency of SAHA. EMS could be taken up by lung cancer cells and lead to efficient epigenetic inhibition. We found that the integrin α4β1 on M1-EM, was crucial for the homing of EMS to tumor tissues for the first time. In tumor-bearing mice, EMS showed spatiotemporal-resolved properties and facilitated the drug accumulation in the tumors, which induced superior anti-tumor effects.ConclusionThis novel style of spatiotemporal-resolved nanoparticles can be used as a theranostic platform for lung cancer therapy.Graphical
Highlights
Malignant tumor is usually associated with epigenetic dysregulation, such as overexpression of histone deacetylase (HDAC), HDAC has emerged as a therapeutic target for cancer
Characterizations of upconversion nanoparticles (UCs)‐based nanoparticles The commercial UCs were coated by mesoporous silica (SUC), and the synthesized SUC showed fluorescence with typical peaks at 550 and 650 nm (Additional file 4: Fig. S1)
Transmission electron microscope (TEM) analysis and nanoparticle tracking analysis indicated that the diameter of exosomes was ~ 100 nm (Additional file 4: Fig. S6), which was similar to the ones derived from untreated RAW264.7 cells
Summary
Malignant tumor is usually associated with epigenetic dysregulation, such as overexpression of histone deacetylase (HDAC), HDAC has emerged as a therapeutic target for cancer. Histone deacetylase inhibitor has been approved for clinical use to treat hematological cancers. The low solubility, short circulation lifetime, and high cytotoxicity partially limited their applications in solid tumor. It has been well recognized that malignant tumor is associated with epigenetic dysregulation such as overexpression of histone deacetylase (HDAC) [1]. HDAC has been developed into a therapeutic target for cancer [2,3,4]. Several HDAC inhibitors have been applied in human to treat hematologic cancers. SAHA has low solubility in water, short circulation lifetime, and high cytotoxicity, which may partially account for its failure to treat solid tumors [5]. Previous reports indicated that the fabrication of SAHA prodrug or encapsulation of SAHA into nanoparticles might enhance its therapeutic effect on solid tumors [5]
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