Salmonella-mediated blood-brain barrier penetration,tumor homing and tumor microenvironment regulation for enhanced chemo/bacterial glioma therapy

Chemotherapy is an important adjuvant treatment of glioma,while the efficacy is far from satisfactory,due not only to the biological barriers of blood-brain barrier(BBB)and blood-tumor barrier(BTB)but also to the intrinsic resistance of glioma cells via multiple survival mechanisms such as upregulation of P-glycoprotein(P-gp).To address these limitations,we report a bacteria-based drug delivery strategy for BBB/BTB transportation,glioma targeting,and chemo-sensitization.Bacteria selectively colonized into hypoxic tumor region and modulated tumor microenvironment,including macrophages repolarization and neutrophils infiltration.Specifically,tumor migration of neutrophils was employed as hitchhiking delivery of doxorubicin(DOX)-loaded bacterial outer membrane vesicles(OMVs/DOX).By virtue of the surface pathogen-associated molecular patterns derived from native bacteria,OMVs/DOX could be selectively recognized by neutrophils,thus facilitating glioma targeted delivery of drug with significantly enhanced tumor accumulation by 18-fold as compared to the classical passive targeting effect.Moreover,the P-gp expression on tumor cells was silenced by bacteria typeⅢsecretion effector to sensitize the efficacy of DOX,resulting in complete tumor eradication with 100%survival of all treated mice.In addition,the colonized bacteria were finally cleared by anti-bacterial activity of DOX to minimize the potential infection risk,and cardiotoxicity of DOX was also avoided,achieving excellent compatibility.This work provides an efficient trans-BBB/BTB drug delivery strategy via cell hitchhiking for enhanced glioma therapy.

Extracellular Polysaccharide from Rhizopus nigricans Inhibits Hepatocellular Carcinoma via miR-494-3p/TRIM36 Axis and Cyclin E Ubiquitination

Background and Aims:This study was designed to uncov-er the mechanism for extracellular polysaccharide(EPS1-1)-mediated effects on hepatocellular carcinoma(HCC)devel-opment.Methods:HCC cells were treated with EPS1-1,miR-494-3p mimic,sh-TRIM36,and pcDNA3.1-TRIM36.The levels of miR-494-3p and TRIM36 were measured in nor-mal hepatocytes,THLE-2,and HepG2 and HuH7HCC cell lines,along with the protein expression of cyclin D/E and p21.The proliferation,cell cycle,and apoptosis of HCC cells were assayed.The interactions between miR-494-3p and TRIM36,and between TRIM36 and cyclin E were assessed.Finally,the expression and localization of TRIM36 and cyclin E were monitored,and tumor apoptosis was detected,in tumor xenograft model.Results:EPS1-1 suppressed HCC cell proliferation and cyclin D/E expression and promoted apoptosis and p21 expression.miR-494-3p was upregulated and TRIM36 was downregulated in HCC cells.Transfection with miR-494-3p mimic or sh-TRIM36 facilitated HCC cell proliferation and the expression of cyclin D/E protein but they inhibited apoptosis and p21 expression in the pres-ence of EPS1-1.Overexpression of TRIM36 further con-solidated EPS1-1-mediated inhibition of HCC proliferation,cyclin D/E,and the promotion of apoptosis and p21 expres-sion.Those effects were reversed by miR-494-3p overex-pression.TRIM36 was a target gene of miR-494-3p,and TRIM36 induced cyclin E ubiquitination.EPS1-1 suppressed cyclin E expression,promoted TRIM36 expression and tu-mor apoptosis,all of which were abrogated by increasing the expression of miR-494-3p in vivo.Conclusions:EPS1-1 protected against HCC by limiting its proliferation and sur-vival through the miR-494-3p/TRIM36 axis and by inducing cyclin E ubiquitination.