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Liposomes with peptide motifs have been successfully used in glioma-targeted delivery of various general chemotherapy agents. However, their use for the encapsulation of low-toxicity molecularly targeted anticancer agents has been limited. In the present study, we aimed to assess the efficacy and safety of a novel low-toxicity mTORC1/mTORC2 inhibitor (MTI-31) as a treatment for glioma when encapsulated in appropriate liposomes. Since some of the peptide-modified liposomes have been determined to be immunogenic and may have life-threatening consequences in mice, an immunogenicity-based investigation with candidate liposomal carriers was conducted. Following this study, D VAP ( D P D A D V D R D T D N D S) modified liposomes ( D VAP-liposomes) were identified as an immunologically safe carrier and therefore utilized for MTI-31 encapsulation. D VAP is a tumor homing peptide exhibiting high binding affinity to glucose regulated protein 78 (GRP78) overexpressed in glioma, glioma stem cells, vasculogenic mimicry and neovasculature. Modification of liposomes with D VAP imparts a glioma-directing property. In vitro, the developed D VAP-liposomes/MTI-31 were efficiently internalized by U87 cells and consequently showed a potent antiproliferation effect. In vivo, the safety and anti-glioma efficiency of D VAP-liposomes/MTI-31 were validated in intracranial glioma bearing BALB/c nude mice. While showing both systemic and immunological safety, D VAP-liposome/MTI-31 treatment resulted in a significant improvement in the median survival time (24.5 days for saline, 26 days for free MTI-31, 25 days for liposomes/MTI-31 and 36 days for D VAP-liposome/MTI-31). The results highlight MTI-31 as an effective anti-glioma agent when encapsulated in non-immunogenic glioma-targeted liposomes, which may contribute to the development of better anti-glioma treatment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Nanosized lipodisks with flat circular phospholipid bilayers surrounded by PEGylated edges have demonstrated promise in drug delivery. In the present work, a lipodisk-based paclitaxel and melittin co-delivery system functionalized with glycopeptide 9G-A7R (9G-A7R-Disk/PTX/melittin) was successfully constructed, in which melittin which was fully protected from proteolysis and hemolysis was effectively reduced. The ratio of paclitaxel to melittin in lipodisks could be accurately controlled through a film hydration-adsorption method. Paclitaxel combined with melittin showed synergism against U87 cells in vitro, and 9G-A7R-Disk/PTX/melittin demonstrated an enhanced anti-glioma effect in vivo, significantly prolonging the survival time of glioma-bearing mice. The results suggested a promising formulation for the co-delivery of paclitaxel/melittin and glioma-targeted therapy.

Background: Epithelial cell transformation sequence 2 (ECT2) is upregulated in glioma and promotes glioma cell proliferation. A preliminary experiment showed a positive correlation between ECT2 and pituitary tumor-transforming gene 1 (PTTG1). The aim of this study was to explore how ECT2 affects PTTG1 to influence the proliferation of glioma cells., Methods: The expression of ECT2 in glioma was detected by western blot and reverse transcription PCR. The effect of ECT2 on glioma proliferation was examined using cell proliferation-related assays and in vivo experiments. The effect of ECT2 on the stability of E2F transcription factor 1 (E2F1) and the expression of PTTG1 were examined by western blot, co-immunoprecipitation, and in vivo ubiquitination assays., Results: ECT2 was upregulated in gliomas and was negatively correlated with prognosis; its downregulation inhibited glioma cell proliferation. Furthermore, ECT2 regulated PTTG1 expression by affecting the stability of E2F1, thereby affecting the glioma cell proliferation. In addition, the deubiquitinating enzyme proteasome 26S subunit, non-ATPase 14 (PSMD14) affected the degradation of E2F1 and regulated the stability of E2F1. Interestingly, ECT2 regulated the expression of PSMD14., Conclusion: In this study, we clarify a new mechanism by which ECT2 regulates the expression of PTTG1 and thus affects the proliferation of glioma cells: ECT2 influences the stability of E2F1 by regulating the expression of the deubiquitinating enzyme PSMD14, thereby affecting the expression of PTTG1. Intensive and extensive understanding of the mechanism of ECT2 in glioma proliferation may provide an opportunity for the development of new molecular therapeutic targets for glioma treatment., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Application of liposomes-based drug delivery in treatment of glioma has been hampered by the poor permeability of blood-brain barrier and the low uptake efficiency by glioma tissues. Moreover, many chemotherapy drugs promote the activation of the NF-κB, which plays a role in the development and progression of cancer and chemoresistance. In this report, CB5005 peptide, designed for its dual function in cell membrane penetration and NF-κB inhibition, was conjugated to PEGylated liposomes loaded with doxorubicin (CB5005-LS/DOX) or a fluorescent dye (CB5005-LS/dye). These CB5005-modified liposomes were utilized for targeting and penetrating glioma. Both qualitative and quantitative evaluations of CB5005-LS/dye showed that modification by CB5005 significantly increased cellular uptake of the liposomes by glioma cells, and substantially improved permeability of the liposomes into tumor spheroids. Intracellular localization studies demonstrated that CB5005-modified liposomes could not only penetrate into glioma cells but also deliver DOX into the nucleus. Cytotoxicity assay indicated that compared with the unmodified DOX liposomes (LS/DOX), CB5005-LS/DOX increased the efficiency of killing glioma cells by more than fivefold. In vivo imaging illustrated that CB5005-modified liposomes, via intravenous injection, distributed fluorescence into the brain and accumulated at tumor xenograft and intracranial glioblastoma in different animal models. More importantly, CB5005-LS/DOX treatment significantly prolonged the survival time of nude mice bearing intracranial glioblastoma. In summary, CB5005-modified liposomes represent a promising drug delivery system for cancer treatment attributing to its unique ability not only to transfer drugs to the tumor sites but also to function as a synergist for chemotherapy of glioma and other human tumors., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Heptapeptide ATWLPPR (A7R) binds specifically to vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) overexpressed in glioma cells, exhibiting high potential to achieve glioma targeted drug delivery. However, in vivo application of A7R peptide remains challenging due to the poor proteolytic stability and inaccessibility of A7R to the brain. To tackle these problems, we identified a glycosylated A7R derivative to enhance in vivo stability and brain transport efficacy. Our results showed that glycosylation of peptide could efficiently improve stability in serum, traverse the blood-brain barrier (BBB) and be uptaken by glioma cells. Furthermore, a novel glioma-targeted drug delivery system was constructed successfully employing glycopeptide as the targeting moiety and nanodisk as the carrier of paclitaxel (PTX). Physicochemical characterization showed that the nanodisk presented suitable size of 50 nm and adequate loading capacity of PTX. Compared to non-glycosylated nanodisk, glycopeptide modification could significantly enhance the uptake of disks by brain capillary endothelial cells through glucose transporter 1 (GLUT1). In vivo imaging and glioma fluorescence section results also indicated that nanodisks modified with glycopeptide showed a higher accumulation in glioma. The glycopeptide-enabled PTX delivery system exhibited superior anti-glioma efficacy in intracranial glioma xenograft model. These results suggested that glycosylation of peptides provided an efficient pathway to design multifunctional and stable brain targeting ligands., (Copyright © 2018. Published by Elsevier B.V.)

Background: MIR155 host gene (MIR155HG) is a long noncoding RNA that has been considered as the primary micro (mi)RNA of miR-155. MIR155HG plays an essential role in hematopoiesis, inflammation, and tumorigenesis. Our study investigated the clinical significance, biological function, mechanisms, and small-molecule inhibitors of the MIR155HG/miR-155 axis in glioma., Methods: We analyzed the expression of the MIR155HG/miR-155 axis and the correlation with glioma grade and patient survival using 2 different glioma gene expression datasets. Biological significance was elucidated through a series of in vitro and in vivo experiments. Furthermore, we conducted a high-throughput screening for small molecules to identify a potential inhibitor of the MIR155HG/miR-155 axis., Results: Increased MIR155HG was associated with glioma grade, mesenchymal transition, and poor prognosis. Functionally, MIR155HG reduction by small interfering RNA inhibited cell proliferation, migration, invasion, and orthotopic glioma growth by repressing the generation of its derivatives miR-155-5p and miR-155-3p. Bioinformatics and luciferase reporter assays revealed that protocadherin 9 and protocadherin 7, which act as tumor suppressors by inhibiting the Wnt/β-catenin pathway, were direct targets of miR-155-5p and miR-155-3p, respectively. Finally, we identified NSC141562 as a potent small-molecule inhibitor of the MIR155HG/miR-155 axis., Conclusions: Our results demonstrate that the MIR155HG/miR-155 axis plays a critical role in facilitating glioma progression and serves as a prognostic factor for patient survival in glioblastoma. High-throughput screening indicated that the MIR155HG/miR-155 axis inhibitor NSC141562 may be a useful candidate anti-glioma drug., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Gliomas result in the highest morbidity and mortality rates of intracranial primary central nervous system tumors because of their aggressive growth characteristics and high postoperative recurrence. They are characterized by genetic instability, intratumoral histopathological variability and unpredictable clinical behavior in patients. Proliferation is a key aspect of the clinical progression of malignant gliomas, complicating complete surgical resection and enabling tumor regrowth and further proliferation of the surviving tumor cells., Methods: The expression of Fstl1 was detected by western blotting and qRT-PCR. We used cell proliferation and colony formation assays to measure proliferation. Then, flow cytometry was used to analyze cell cycle progression. The expression of Fstl1, p-Smad1/5/8 and p21 in GBM tissue sections was evaluated using immunohistochemical staining. Furthermore, we used coimmunoprecipitation (Co-IP) and immunoprecipitation to validate the relationship between Fstl1, BMP4 and BMPR2. Finally, we used orthotopic xenograft studies to measure the growth of tumors in vivo., Results: We found that follistatin-like 1 (Fstl1) was upregulated in high-grade glioma specimens and that its levels correlated with poor prognosis. Fstl1 upregulation increased cell proliferation, colony formation and cell cycle progression, while its knockdown inhibited these processes. Moreover, Fstl1 interacted with bone morphogenetic protein (BMP) 4, but not BMP receptor (BMPR) 2, and competitively inhibited their association. Furthermore, Fstl1 overexpression suppressed the activation of the BMP4/Smad1/5/8 signaling pathway, while BMP4 overexpression reversed this effect., Conclusion: Our study demonstrated that Fstl1 promoted glioma growth through the BMP4/Smad1/5/8 signaling pathway, and these findings suggest potential new glioblastoma treatment strategies., (© 2017 The Author(s). Published by S. Karger AG, Basel.)

Unlabelled: Clinical application of cell-penetrating peptides (CPPs) in cancer therapy is greatly restricted due to lack of tissue selectivity and tumor-targeting ability. CB5005, a rationally designed CPP that targets and inhibits intracellular NF-κB activation, is constituted by a unique membrane-permeable sequence (CB5005M) cascading to a NF-κB nuclear localization sequence (CB5005N). In vitro cellular evaluation confirmed that CB5005 was effectively taken up by brain capillary endothelial cell bEnd.3 and glioma cells U87. The intracellular localization analysis further demonstrated that CB5005 could not only penetrate into the cells but also enter into their nuclei. More interestingly, CB5005 permeated deeply into the tumor spheroids of U87 cell. In vivo imaging illustrated that the fluorescence-labeled CB5005 distributed itself into the brain and accumulated at the tumor site after intravenous injection. Given the important role of over expressed NF-κB in tumor growth and development, we further investigated CB5005 for its potential in treatment of glioma. When combined administration in vitro with doxorubicin (DOX), CB5005 exhibited a synergistic effect in killing U87 cells. In a nude mice xenograft model, CB5005 inhibited the growth of tumor when applied alone, and displayed a synergistic anti-tumor effect with DOX. In conclusion, CB5005 functioned simultaneously as a cell penetrating peptide and a tumor growth inhibitor, therefore can work as a potential synergist for chemotherapy of human tumor., Statement of Significance: Clinical application of cell-penetrating peptides in cancer therapy is restricted due to lack of tissue selectivity and tumor-targeting ability. In this manuscript, we reported a rationally designed peptide, named CB5005, which had an attractive capability of translocation into the cell nucleus and blocking nuclear translocation of endogenous NF-κB protein. CB5005 had unique affinity with brain and glioma, and could rapidly accumulate in these tissues after intravenous injection. Furthermore, CB5005 showed a synergistic effect on inhibiting gliomas when administrated with doxorubicin. This is the first literature report on this multi-functionalized peptide, which can work as a potential synergist for chemotherapy of tumor. This work should be of general interest to scientists in the fields of biomaterials, biology, pharmacy, and oncology., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)