Artificial exosomes mediated spatiotemporal-resolved and targeted delivery of epigenetic inhibitors.

BACKGROUND: Malignant 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. METHODS: The 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. RESULTS: This 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 α4ß1 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. CONCLUSION: This novel style of spatiotemporal-resolved nanoparticles can be used as a theranostic platform for lung cancer therapy.

Hybrid artificial cell-mediated epigenetic inhibition in metastatic lung cancer.

HYPOTHESIS: Histone deacetylase inhibitors (HDACIs), such as vorinostat (suberoylanilide hydroxamic acid, SAHA), has become a promising approach for the treatment of metastatic lung cancer. However, HDACIs usually showed a short circulation lifetime, low specificity, and low bioavailability, which limited their therapeutic effect in this field. We supposed that the use of biomimetic nanoparticles enabled to overcome the disadvantages of HDACIs, and improved the inhibition of metastatic lung cancer. EXPERIMENTS: SAHA was encapsulated into a pH-sensitive core constructed with Poly(lactic-co-glycolic acid) (PLAG) and 1,2-dioleoyloxy-3-(trimethylammonium) propane (DOTAP), followed by the camouflage with hybrid membranes derived from red blood cells and metastatic NCI-H1299 lung cancer cells (HRPDS). The physical and chemical properties were characterized with Transmission electron microscope (TEM), Size & Zeta potential analyzer. The cellular uptake was analyzed with Confocal laser scanning microscope (CLSM) and Flow cytometry (FACS). The biological effect analysis was performed with Western blotting (WB), RNA-Sequencing (RNA-Seq), and ChIP-Sequencing (ChIP-Seq). FINDINGS: HRPDS exhibited enhanced circulation lifetime in vivo and homotypic targeting to metastatic cells in the metastatic foci, which induced significant suppression of lung cancer liver metastasis. Our work opens a new avenue for the treatment of metastatic lung cancer by epigenetic inhibition based on this style of biomimetic nanovehicle.