Aerobic glycolysis is the primary energy supply mode for glioblastoma (GBM) cells to maintain growth and proliferation. However, due to the metabolic reprogramming of tumor cells, GBM can still produce energy through fatty acid oxidation (FAO) and amino acid metabolism after blocking this metabolic pathway. In addition, GBM can provide a steady stream of nutrients through high-density neovascularization, which puts the block energy metabolism therapy for glioma in the situation of “internal and external problems”. Herein, based on the abundant reactive oxygen species (ROS) and glutathione (GSH) in the tumor microenvironment and cytoplasm, we successfully designed and developed a cascade-responsive 2-DG nanocapsule delivery system. This nanocapsule contains a conjugate of anti-VEGFR2 monoclonal antibody (aV) and CPT1C siRNA (siCPT1C) linked by a disulfide cross-linker (aV-siCPT1C). The surface of this nanocapsule (2-DG/aV-siCPT1C NC) is loaded with the glycolysis inhibitor 2-DG, and it utilizes GLUT1, which is highly expressed on the blood–brain barrier (BBB) and GBM cells, to effectively penetrate the BBB and target GBM. The nanocapsule realizes multidrug codelivery, jointly blocks glycolysis and FAO of GBM, and reduces angiogenesis. Meanwhile, it also solves the problems of low delivery efficiency of mAb in the central nervous system (CNS) and easy degradation of siRNA. In general, this drug joint delivery strategy could open up a new avenue for the treatment of GBM.
Temozolomide (TMZ) is a conventional chemotherapeutic drug for glioma, however, its clinical application and efficacy is severely restricted by its drug resistance properties. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme, which can repair the DNA damage caused by TMZ. A large number of clinical data show that reducing the expression of MGMT can enhance the chemotherapeutic efficacy of TMZ. Therefore, in order to improve the resistance of glioma to TMZ, an angiopep-2 (A2) modified nanoprodrug of polytemozolomide (P(TMZ)n) that combines with MGMT siRNA (siMGMT) targeting MGMT was developed (A2/T/D/siMGMT). It not only increased the amount of TMZ within tumor lesion site, but also reduced MGMT expression in glioma. The in vitro experiments indicated that the A2/T/D/siMGMT effectively enhanced the cellular uptake of TMZ and siMGMT, and resulted in a significant cell apoptosis and cytotoxicity in the glioma cells. The in vivo experiments showed that glioma growth was inhibited and the survival time of animals were prolonged remarkably after A2/T/D/siMGMT was injected via tail vein. The results showed that the therapeutic effect of A2/T/D/siMGMT in the treatment of glioma was significantly improved.
Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. The predictive role of SH2D4A has been shown to be closely related to various cancers progression,but there is no comprehensive analysis of the clinical significance in glioblastoma. Hence, this study aimed to explore the relationship between the prognosis of GBM and SH2D4A expression. Methods: The expression of SH2D4A in GBM was analyzed using TIMER2.0 and GEPIA, and validated by qRT-PCR experiments. The CGGA database analyzed the differential expression of SH2D4A in glioma and evaluated the impact of SH2D4A on the survival of glioma patients.LinkedOmics database and GeneMANIA database were studied for SH2D4A co-expression network. A lasso regression model and nomogram were constructed to assess the prognosis of GBM. TCGA database was used to do a GSEA to find functional differences. The relationship between SH2D4A expression and tumor-infiltrating immune cells was analyzed using xCELL, the CIBERSORT algorithm and the TIMER database. Results: In GBM patients, we found that the expression of SH2D4A was upregulated, and the elevated expression of SH2D4A was strongly associated with the grade of the tumor. High SH2D4A expression was found to be a significant independent predictor of poor overall survival (OS) in GBM patients by survival curve analysis and multivariate cox regression analysis. GSEA revealed that SH2D4A was mainly enriched in extracellular matrix tissues, and the expression level of SH2D4A was inversely correlated with the level of infiltration of CD8+T cells, CD4+T cells, B cells, neutrophils and macrophages in GBM, but was positively correlated with the level of dendritic cell infiltration. Immunoassays suggest that altered SH2D4A expression may affect the immune infiltration of GBM tissues and thus affect the survival outcome of GBM. Conclusion: In addition to being a possible prognostic marker and therapeutic target for GBM, SH2D4A may also accelerate the progression of GBM.
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