Lung-specific exosomes for doxorubicin delivery in lung adenocarcinoma therapy.

Doxorubicin (DOX) could be utilized to treat lung adenocarcinoma (LUAD), while dose-limiting cardiotoxicity limits its clinical utilization. MDA-MB-231 cell-derived exosomes show lung-specific organotropism features. In this study, we aimed to explore the potential of MDA-MB-231 cell-derived exosomes in DOX specific delivery to the lung. MDA-MB-231 cell-derived exosomes were coincubated with to construct for the doxorubicin delivery system (D-EXO). Exosomes labeled with fluorescein isothiocyanate were incubated with A549 cells or 293T cells, and the engulf and the mean intensity of the fluorescence were detected with immunofluorescence and flow cytometry assay. Cell viability was detected with cell counting kit-8 (CCK-8), and cell migration was determined by scratch test. The protein expression was detected by Western blot assay. A549 cell line-derived xenograft mouse model was constructed to examine the treatment effect of D-EXO. MDA-MB-231 cell-derived exosomes could be specially taken up by A549 cells with diminished cell viability but not engulfed by 293T cells. D-EXO inhibited A549 cell migration, and upregulated the protein expression of caspase 3 and cleaved caspase 3 expression, while did not show any inhibition on 293T cells. In vivo orthotopic xenotransplantation model indicated that D-EXO inhibited tumor growth characterized by diminished tumor weight and improved survival rate. No significant change in body weight was observed after the D-EXO treatment. In conclusion, D-EXO proposed in this study could be utilized to treat LUAD with lung-specific delivery effects to improve the survival rate.

SiO2/hyaluronic acid nanoparticles carry CaO2, DOX and p53 plasmid to effectively achieve ion interference/chemical/gene multimodal therapy of lung cancer.

Monotherapy of lung cancer shows limited therapeutic effects due to its poorly targeted enrichment and low bioavailability. Using nanomaterials as carriers to form drug delivery systems has become a popular method to improve the targeting of anticancer drug therapy and patients' safety. However, the uniformity of the loaded drugs and the unsatisfactory effects are still the bottleneck in this field up to now. This study aims to construct a novel nanocomposite carrying 3 different types of anticancer drugs to enhance treatment efficacy. Herein, mesoporous silica (MSN) with high loading rate was constructed by dilute sulfuric acid thermal etching as the framework. Hyaluronic acid (HA) was loaded with CaO2, p53 and DOX to construct nanoparticle complexes-SiO2@CaO2@DOX@P53-HA. First, MSN was proved to be a porous sorbent with a mesoporous structure through BET analysis. The images obtained from the uptake experiment clearly show the gradual enrichment of the DOX and Ca2+ within the target cell. For in vitro experiments, the pro-apoptotic effects of SiO2@CaO2@DOX@P53-HA significantly increased compared to that of the single-agent group at different time points. Furthermore, in the tumor-bearing mouse experiment, the tumor volume was remarkably inhibited in the SiO2@CaO2@DOX@P53-HA group compared to that in the single-agent group. By observing the pathological sections of the euthanized mice, it is obvious that the tissues of the mice treated with the nanoparticles were more intact. Based on these beneficial results, it is believed that multimodal therapy is a meaningful treatment strategy for lung cancer.

Protein Tyrosine Phosphatase Receptor Type R (PTPRR) Reduces AChR Clustering by Dephosphorylating MuSK.

Neuromuscular junction (NMJ) formation and maintenance depend on the proper localization and concentration of various molecules at synaptic contact sites. Acetylcholine receptor (AChR) clustering on the postsynaptic membrane is a cardinal event in NMJ formation. Muscle-specific tyrosine kinase (MuSK), which functions depending on its phosphorylation, plays an essential role in AChR clustering. In the present study, we used plasmid-based biochemical screening and determined that protein tyrosine phosphatase receptor type R (PTPRR) is responsible for dephosphorylating MuSK on tyrosine residue 754. Furthermore, we showed that PTPRR significantly reduced MuSK-dependent AChR clustering in C2C12 myotubes. Collectively, these data illustrate a negative regulation function of PTPRR in AChR clustering.