Abstract
The objectives of the present study were to develop functional targeting epirubicin liposomes for transferring drugs across the blood-brain barrier (BBB), treating glioblastoma, and disabling neovascularization. The studies were performed on glioblastoma cells in vitro and on glioblastoma-bearing mice. The results showed that the constructed liposomes had a high encapsulation efficiency for drugs (>95%), suitable particle size (109 nm), and less leakage in the blood component-containing system; were significantly able to be transported across the BBB; and exhibited efficacies in killing glioblastoma cells and in destroying glioblastoma neovasculature in vitro and in glioblastoma-bearing mice. The action mechanisms of functional targeting epirubicin liposomes correlated with the following features: the long circulation in the blood system, the ability to be transported across the BBB via glucose transporter-1, and the targeting effects on glioblastoma cells and on the endothelial cells of the glioblastoma neovasculature via the integrin β3 receptor. In conclusion, functional targeting epirubicin liposomes could be used as a potential therapy for treating brain glioblastoma and disabling neovascularization in brain glioblastomas.
Highlights
Glioblastoma is a high-grade malignant brain glioma with rich vasculature that support the growth of glioblastoma [1, 2]
The results showed that the Glu-targeting coumarin liposomes or the functional coumarin liposomes were bound with the Glucose transporter 1 (Glut-1) on the brain microvascular endothelial cells (BMVECs), in contrast to the coumarin liposomes or cRGD-targeting coumarin liposomes (Fig. 3A), and that the cRGD-targeting coumarin liposomes or the functional targeting coumarin liposomes were bound to the integrin β3 receptors on the glioblastoma U251 cells, in contrast to the coumarin liposomes or Glu-targeting coumarin liposomes (Fig. 3B)
The results demonstrate that the binding with Glut-1 facilitates the active targeting of functional targeting coumarin liposomes or Glu-targeting coumarin www.impactjournals.com/oncotarget liposomes to the BMVECs, while binding with integrin β3 receptors promotes the internalization of functional targeting epirubicin liposomes or cRGD-targeting epirubicin liposomes into glioblastoma cells
Summary
Glioblastoma is a high-grade malignant brain glioma with rich vasculature that support the growth of glioblastoma [1, 2]. Glioblastoma vascularization involves an early co-option of normal brain blood vessels, and the angiogenesis in the tumor region [3, 4]. The treatment of glioblastoma is a comprehensive strategy that mainly uses surgical therapy and is supplemented by radiation therapy and chemotherapy [8, 9]. The combined treatment strategy is not able to eliminate all of the glioblastoma cells and cannot destroy the aberrant vasculatures around the glioblastoma tissue. These residual malignant cells and vasculature result in glioblastoma recurrence [10]
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