Exosomes (Exos) are endogenous nanocarriers that have utility as novel delivery systems for the treatment of brain cancers. However, in general, natural Exos show limited BBB-crossing capacity and lack specific targeting. Further modifications including targeting peptides and genetic engineering approaches can circumvent these issues, but the process is time-consuming. Focused ultrasound (FUS) has been approved by the Food and Drug Administration for the diagnosis and treatment of brain diseases due to its noninvasive nature, reversibility, and instantaneous local opening of the BBB. In this study, we developed a natural and safe transportation system using FUS to increase the targeted delivery of Exos for glioma therapy. We also compared the advantages of macrophage-derived Exos (R-Exos) and blood serum-derived Exos (B-Exos) to screen for an improved platform with scope for clinical transformation. In vitro, both R-Exos and B-Exos were transported through BBB models and accumulated in glioma cells with the assistance of ultrasound exposure. R-Exos and B-Exos displayed no obvious differences in physical characteristics, drug release, tumor targeting, and cytotoxicity when combined with FUS. In vivo animal imaging studies suggested that the fluorescence intensity of B-Exos plus single FUS in brains was 4.45-fold higher than that of B-Exos alone. Furthermore, B-Exos plus twice FUS treatment efficiently suppressed glioma growth with no obvious side effects. We therefore demonstrate that the combination of FUS and naturally abundant B-Exos is a potent strategy for brain cancer therapeutics.
This study aimed to identify key functional modules and genes in functional module involved in hepatocellular carcinoma (HCC) development. The microarray data set GSE54236 was obtained from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between HCC, and normal samples were identified by Limma. DAVID was used to identify the gene ontology terms these genes enriched. The co-expression network was constructed based on Pearson correlation coefficient between gene expression values, and the functional modules these DEGs obviously enriched in were recognized through GraphWeb. Then, based on the genes related to the development of HCC, the DEGs interacting with HCC-associated genes were spotted. Finally, survival analysis and real-time quantitative polymerase chain reaction were performed. Totally, 427 upregulated (e.g., cell division cycle associated 5 [CDCA5], kinesin family member 4A [KIF4A], TPX2 microtubule nucleation factor [TPX2]) and 313 downregulated (e.g., metallothionein 1E [MT1E]) DEGs were identified in HCC. Besides, CDCA5, KIF4A, and TPX2 had interacting relationship and played important roles in HCC development by interrelating with HCC-related gene, forkhead box M1 (FOXM1). Furthermore, CDCA5, KIF4A, TPX2, and FOXM1 obviously enriched in cell cycle-related functional module, whereas MT1E enriched in mineral absorption module in Kyoto Encyclopedia of Genes and Genomes. CDCA5, KIF4A, and TPX2 expression were increased in HCC cells, and their high expressions were related to poor prognosis. Overexpression of CDCA5, KIF4A, TPX2, and FOXM1 coregulated cell cycle and thereby promoted the development of HCC. The finding provided potential targets for the study and treatment of HCC.
C-myb is a member of the myb transcription factor family and involved in cell proliferation and differentiation. It activates specific target genes to regulate specific program through certain channel, and it takes signal transduction to regulate function and expression of protein. In this paper, c-myb, by binding to Wnt signaling pathway, makes Lgr5 start to promote cell proliferation and differentiation, and it can serve as a new therapeutic target to provide the basis of early diagnosis and treatment for colorectal cancer.
Key words:
Colorectal cancer; c-myb; Apoptosis
Sonodynamic therapy (SDT), wherein focused ultrasound is used to guide the site-specific delivery of nano-sonosensitizers and trigger profound sono-damage, has great potential in cancer theranostics. The development of nanosensitizers with high sono-activatable efficiency and good biosafety is however challenging. Methods: In this study, we designed a functionalized smart nanosonosensitizer (EXO-DVDMS) by loading sinoporphyrin sodium (DVDMS), an excellent porphyrin sensitizer with both potential therapeutic and imaging applications, onto homotypic tumor cell-derived exosomes. Because of the high binding-affinity between DVDMS and proteins, coincubation of DVDMS and exosome would result in DVDMS attached on the surface or loaded in the core of exosomes. The prepared EXO-DVDMS was applied for ultrasound-responsive controlled release and enhanced SDT. Results: Tumor cell-derived exosomes exhibited high stability and specificity towards the homotypic tumors, along with highly controlled ultrasound-responsive drug release, and boosted reactive oxygen species (ROS) generation to augment SDT. Intriguingly, EXO-DVDMS was endocytosed by lysosomes, and the low pH in the latter triggered DVDMS relocation synergistically with the ultrasound, thereby initiating multiple cell death-signaling pathways. Furthermore, the exosomal formulation served as a functionalized nanostructure, and facilitated simultaneous imaging and tumor metastasis inhibition, that were respectively 3-folds and 10-folds higher than that of free form. Conclusions: Taken together, our findings suggest that an extracorporeal ultrasound device can non-invasively enhance homogenous tumor targeting and SDT toxicity of EXO-DVDMS, and the developed endogenous nano-sonosensitizer is a promising nanoplatform for activated cancer theranostics.
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