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Conclusion: Fas ligand (FasL) gene therapy may provide a new efficient therapeutic model for head and neck squamous cell cancer (HNSCC). Acid ceramidase (AC) may not play an important role in the sensitivity of HNSCC cell lines to Fas-induced apoptosis. Objectives: The aims of this study were to investigate the efficacy of FasL gene therapy for HNSCC in vitro and to determine whether the expression of AC in different kinds of HNSCC cell lines is related to the sensitivity of HNSCC cell lines to Fas-mediated apoptotic induction. Methods: Three HNSCC cell lines (Hep-2, MMSI, and SCCVII) were transfected with pEGFP-FasL, a plasmid containing a modified human FasL gene fused to enhanced green fluorescent protein (GFP). pEGFP-C1, a plasmid containing the GFP gene alone, was used as a control. Cell death was observed by fluorescence imaging and quantified using a tetrazolium-based (MTS) assay. SCCVII cells were analyzed by flow cytometry to determine the presence of apoptotic induction. Hep-2 and MMSI cells were evaluated by quantitative real-time PCR to evaluate the expression of AC. Results: Transfection of pEGFP-FasL plasmid was shown to be able to induce cell death, the sensitivity of Fas-mediated apoptosis in HNSCC was different, and the level of AC did not correlate with the sensitivity of HNSCC cells to Fas-induced apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: Combination of gene therapy and chemotherapy is a promising approach for glioma therapy. In this study, a co-delivery system of plasmid encoding human tumor necrosis factor-related apoptosis-inducing ligand (pORF-hTRAIL, Trail) and doxorubicin (DOX) has been simply constructed in two steps. Firstly, DOX was intercalated into Trail to form a stable complex. Secondly, DOX-Trail complex was condensed by Dendrigraft poly-l-lysine (DGL) to form a nanoscaled co-delivery system. Choline transporters are both expressed on blood–brain barrier (BBB) and glioma, Herein, a choline derivate with high choline transporter affinity was chosen as BBB and glioma dual targeting ligand. Choline-derivate modified co-delivery system showed higher cellular uptake efficiency and cytotoxicity than unmodified co-delivery system in U87 MG cells. In comparison with single medication or unmodified delivery system, Choline-derivate modified co-delivery system induced more apoptosis both in vitro and in vivo. The therapeutic efficacy on U87 MG bearing xenografts further confirmed the predominance of this dual targeting and co-delivery system. [Copyright &y& Elsevier]

Abstract: Among all the malignant brain tumors, glioma is the deadliest and most common form with poor prognosis. Gene therapy is regarded as a promising way to halt the progress of the disease or even cure the tumor and RNA interference (RNAi) stands out. However, the existence of the blood–brain barrier (BBB) and blood tumor barrier (BTB) limits the delivery of these therapeutic genes. In this work, the delivery system targeting to the transferrin (Tf) receptor highly expressed on both BBB and glioma was successfully synthesized and would not compete with endogenous Tf. U87 cells stably express luciferase were employed here to simulate tumor and the RNAi experiments in vitro and in vivo validated that the gene silencing activity was 2.17-fold higher with the targeting ligand modification. The dual-targeting gene delivery system exhibits a series of advantages, such as high efficiency, low toxicity, stability and high transaction efficiency, which may provide new opportunities in RNAi therapeutics and nanomedicine of brain tumors. [Copyright &y& Elsevier]

Abstract: A tumor targeting nanoparticle system has been successfully developed to response to the lowered tumor extracellular pH (pHe) and upregulated matrix metalloproteinase 2 (MMP2) in the tumor microenvironment. The nanoparticles are modified with activatable cell-penetrating peptide (designated as dtACPP) that's dual-triggered by the lowered pHe and MMP2. In dtACPP, the internalization function of cell-penetrating peptide (CPP) is quenched by a pH-sensitive masking peptide, linking by a MMP2 substrate. The masking peptide is negatively charged to quench the cationic CPP well after systemic administration. Hence, dtACPP-modified nanoparticles possesses passive tumor targetability via the enhanced permeability and retention (EPR) effect. Once reaching the tumor microenvironment, the pre-existing attraction would be eliminated due to the lowered pHe, accompanying the linker cleaved by MMP2, dtACPP would be activated to expose CPP to drive the nanoparticles' internalization into the intratumoral cells. The studies of plasmid DNA loading, toxicity assessment, cellular uptake, tumor targeting delivery, and gene transfection demonstrate that dtACPP-modified nanoparticle system is a potential candidate for tumor targeting gene delivery. [Copyright &y& Elsevier]

Abstract: Gene therapy offers great potential for brain glioma. However, therapeutic genes could not reach glioma spontaneously. A glioma-targeting gene delivery system is highly desired to transfer exogenous genes throughout the tumor focus. In this study, the nanoscopic high-branching dendrimer, polyamidoamine (PAMAM), was selected as the main vector. Chlorotoxin (CTX), which has been demonstrated to bind specifically to receptor expressed in glioma, was exploited as the targeting ligand to conjugate PAMAM via bifunctional polyethyleneglycol (PEG), yielding PAMAM–PEG–CTX. The cellular uptake of CTX itself was observed apparently in C6 glioma cells, almost not in 293 cells. The modification of CTX could significantly increase the cellular uptake of vectors and the DNA-loaded nanoparticles (NPs) in C6 cells. The in vivo distribution of PAMAM–PEG–CTX/DNA NPs in the brain was higher than that of PAMAM/DNA NPs and PAMAM–PEG/DNA NPs. Furthermore, the gene expression of PAMAM–PEG–CTX/DNA NPs was higher and broader in glioma than that of unmodified and PEG-modified counterparts. The TUNEL analysis showed a more wide-extended apoptosis in the CTX-modified group, compared to other groups including commercial temozolomide group. The median survival time of CTX-modified group and temozolomide group was 59.5 and 49 days, respectively, significantly longer than that of other groups. The results suggested that CTX could be exploited as a special glioma-targeting ligand, and PAMAM–PEG–CTX/DNA NPs is a potential non-viral delivery system for gene therapy of glioma via intravenous administration. [ABSTRACT FROM AUTHOR]