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OX26/CTX-conjugated PEGylated liposome as a dual-targeting gene delivery system for brain glioma.

ABSTRACT: BACKGROUND: The successful gene delivery into the brain is a major challenge due to the presence of the blood-brain barrier (BBB). In order to transport plasmid DNA across the BBB and target the brain glioma, the PEGylated liposomes (PLs) modified with OX26 and chlorotoxin (CTX) were developed as a dual-targeting gene delivery system, and the therapeutic efficacy of OX26/CTX-PL/pC27 against glioma was evaluated using in vitro and in vivo experimental models. METHODS: The PEGylated liposome complexes were prepared by the reverse phase evaporation method, and their physicochemical properties were examined. The transfection efficiency, intracellular distribution, in vitro effects of OX26/CTX-PL/pC27 were determined on C6, F98 and HEK293T cell lines. The dual-targeting therapeutic efficacy of OX26/CTX-PL/pC27 against glioma were assessed using the BMVECs/C6 cells co-culture model and the rat orthotopic glioma model. RESULTS: The OX26/CTX-PL/pDNA complexes exhibited a subglobose shape, and possessed notably low toxicities to HEK293T and C6 cells post 4 h incubation. In the in vitro transfection experiment, gene expressions of hTERTC27 from C6 and F98 cells were significantly improved by OX26 and CTX modification. Our in vitro results also showed that OX26 endowed the PLs with the transport ability across the BBB. Using the BMVECs/C6 cells co-culture model, the viability of C6 cells was decreased to 46.0% after OX26/CTX-PL/pC27 transfection. The OX26/CTX-PL/pC27 complexes exhibited enhanced therapeutic effects on C6 cells. Moreover, the dual-targeting therapeutic effects were further conformed with diminished tumor volumes (18.81?±?6.15 mm³) and extended median survival time (46 days) in C6 glioma-bearing rats. Immunohistochemical analysis revealed the therapeutic effects derived from enhanced hTERTC27 expression in the tumor site. CONCLUSIONS: The PEGylated liposomes modified with OX26 and CTX are able to significantly promote cell transfection, increase the transport of plasmid DNA across the BBB and afterwards target the brain glioma cells in vitro and in vivo, exhibit the most significant therapeutic efficacy. The ligand OX26 plays a critical role in transporting the lipoplexes across the BBB, and CTX acts as a major role in targeting brain glioma cells. The results would encourage further developments for non-invasive targeting therapy of brain gliomas by intravenous injection.

SUBMITTER: Yue PJ

PROVIDER: S-EPMC4137094 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Project description:Alzheimer’s disease (AD) is the most common cause of late-life dementia characterized by progressive neurodegeneration and brain deposition of amyloid-β (Aβ) and phosphorylated tau. The APOE ε2 encoding apolipoprotein E (APOE2) is a protective allele against AD among the three genotypes (APOE ε2, ε3, ε4), while APOE4 is the strongest genetic factor substantially increasing AD risk. APOE regulates brain lipid homeostasis and maintaining synaptic plasticity and neuronal function, where APOE2 has a superior function compared to APOE3 and APOE4. Gene therapy that increases APOE2 levels in the brain is, therefore, a promising therapeutic strategy for AD treatment. We previously reported that PEGylated liposomes conjugated with transferrin and a cell-penetrating peptide Penetratin sufficiently deliver chitosan-APOE2 cDNA plasmid complex into the brain of wild-type mice. Here, we investigated how brain-targeting liposome-based APOE2 gene delivery influences Aβ)-related pathologies in amyloid model AppNL-G-F knockin mice at 12-month-old. We found a trend of reductions of insoluble Aβ levels in the mouse cortices 1 month after APOE2 gene therapy. Furthermore, in the AppNL-G-F knockin mice that received the APOE2 gene therapy, brain transcriptome analysis through RNA-sequencing identified the upregulation of genes/pathways related to neuronal development. This was supported by increases of Dlg4 and Syp mRNAs coding synaptic proteins in the experimental group. On the other hand, we found that APOE2 gene delivery increased soluble Aβ levels, including oligomers, as well as exacerbated neurite dystrophy and decreased synaptophysin. Together, our results suggest that brain-targeting liposome-based APOE2 gene therapy is potentially beneficial for synaptic formation at the transcriptional level. Forced APOE2 expressions, however, may exacerbate Aβ toxicity by increasing the dissociation of Aβ oligomers from aggregates in the presence of considerable amyloid burden.

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OX26/CTX-conjugated PEGylated liposome as a dual-targeting gene delivery system for brain glioma.

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