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A dual-mediated liposomal drug delivery system targeting the brain: rational construction, integrity evaluation across the blood-brain barrier, and the transporting mechanism to glioma cells.

ABSTRACT: As the global population ages, cancer rates increase worldwide, and degenerative diseases of the central nervous system (CNS), brain tumors, and inflammation threaten human health more frequently. We designed a dual-mediated (receptor-mediated and adsorption-mediated) liposome, named transferrin-cell penetrating peptide-sterically stabilized liposome (TF-CPP-SSL), to improve therapy for gliomas through combining molecular recognition of transferrin receptors (TF-Rs) on the blood-brain barrier (BBB) and glioma cells with the internalization and lysosomal escaping ability of CPP. Based on the systematic investigation of structure-activity relations on the cellular level, we constructed TF-CPP-SSL rationally by conjugating TF and CPP moieties to the liposomes via PEG_3.4K and PEG_2.0K, respectively, and found the optimum densities of TF and CPP were 1.8% and 4%, respectively. These liposomes had the highest targeting efficacy for brain microvascular endothelial cell and C6 cell uptake but avoided capture by normal cells. Fluorescence resonance energy transfer technology and coculture models of BBB and glioma C6 cells indicated that TF-CPP-SSL was transported across the BBB without drug leakage, liposome breakup, or cleavage of ligand. TF-CPP-SSL offered advantages for crossing the BBB and entering into glioma C6 cells. Real-time confocal viewing revealed that TF-CPP-SSL was entrapped in endosomes of glioma C6 cells and then escaped from lysosomes successfully to release the liposomal contents into the cytosol. Entrapped contents, such as doxorubicin, could then enter the nucleus to exert pharmacological effects.

SUBMITTER: Liu C

PROVIDER: S-EPMC5378461 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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A dual-mediated liposomal drug delivery system targeting the brain: rational construction, integrity evaluation across the blood-brain barrier, and the transporting mechanism to glioma cells.

Liu Chang C Liu Xiao-Na XN Wang Gui-Ling GL Hei Yu Y Meng Shuai S Yang Ling-Fei LF Yuan Lan L Xie Ying Y

International journal of nanomedicine 20170328

As the global population ages, cancer rates increase worldwide, and degenerative diseases of the central nervous system (CNS), brain tumors, and inflammation threaten human health more frequently. We designed a dual-mediated (receptor-mediated and adsorption-mediated) liposome, named transferrin-cell penetrating peptide-sterically stabilized liposome (TF-CPP-SSL), to improve therapy for gliomas through combining molecular recognition of transferrin receptors (TF-Rs) on the blood-brain barrier (B ...[more]

PMID: 28405164

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Project description: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.

Project description:In malignant glioma, cytotoxic drugs are often inhibited from accessing the tumor site due to the blood-tumor barrier (BTB). Ibrutinib, FDA-approved lymphoma agent, inhibits Bruton tyrosine kinase (BTK) and has previously been shown to independently impair aortic endothelial adhesion and increase rodent glioma model survival in combination with cytotoxic therapy. Yet additional research is required to understand ibrutinib's effect on BTB function. In this study, we detail baseline BTK expression in glioma cells and its surrounding vasculature, then measure endothelial junctional expression/function changes with varied ibrutinib doses in vitro. Rat glioma cells and rodent glioma models were treated with ibrutinib alone (1-10 µM and 25 mg/kg) and in combination with doxil (10-100 µM and 3 mg/kg) to assess additive effects on viability, drug concentrations, tumor volume, endothelial junctional expression and survival. We found that ibrutinib, in a dose-dependent manner, decreased brain endothelial cell-cell adhesion over 24 h, without affecting endothelial cell viability (p < 0.005). Expression of tight junction gene and protein expression was decreased maximally 4 h after administration, along with inhibition of efflux transporter, ABCB1, activity. We demonstrated an additive effect of ibrutinib with doxil on rat glioma cells, as seen by a significant reduction in cell viability (p < 0.001) and increased CNS doxil concentration in the brain (56 ng/mL doxil alone vs. 74.6 ng/mL combination, p < 0.05). Finally, Ibrutinib, combined with doxil, prolonged median survival in rodent glioma models (27 vs. 16 days, p < 0.0001) with brain imaging showing a - 53% versus - 75% volume change with doxil alone versus combination therapy (p < 0.05). These findings indicate ibrutinib's ability to increase brain endothelial permeability via junctional disruption and efflux inhibition, to increase BTB drug entry and prolong rodent glioma model survival. Our results motivate the need to identify other BTB modifiers, all with the intent of improving survival and reducing systemic toxicities.

Dataset Information

A dual-mediated liposomal drug delivery system targeting the brain: rational construction, integrity evaluation across the blood-brain barrier, and the transporting mechanism to glioma cells.

Publications

A dual-mediated liposomal drug delivery system targeting the brain: rational construction, integrity evaluation across the blood-brain barrier, and the transporting mechanism to glioma cells.

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