Journal
BIOMATERIALS
Volume 35, Issue 1, Pages 518-529Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2013.09.094
Keywords
Glioma; Dual-targeted drug delivery system; Glucose transporter; Endocytic mechanism; Avascular glioma spheroids
Funding
- National Key Basic Research Program of China [2013CB932502]
- National Natural Science Foundation of China [81302716, 81302710]
- National Science and Technology Major Project [2012ZX09304004]
- Natural Science Foundation of Jiangsu Province [BK2012445]
- Ordinary University Natural Science Research Project of Jiangsu Province [13KJB350004]
- Advanced Talent Foundation of Jiangsu University [13JDG013]
- School of-Pharmacy, Fudan University & the Open Project Program of Key Lab of Smart Drug Delivery (Fudan University), Ministry of Education, China [SDD2012-4]
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Based on the facilitative glucose transporter (GLUT) over-expression on both blood-brain barrier (BBB) and glioma cells, 2-deoxy-D-glucose modified poly(ethylene glycol)-co-poly(trimethylene carbonate) nanoparticles (DGlu-NP) were developed as a potential dual-targeted drug delivery system for enhancing the BBB penetration via GLUT-mediated transcytosis and improving the drug accumulation in the glioma via GLUT-mediated endocytosis. In vitro physicochemical characterization of the dual-targeted nanoparticulate system presented satisfactory size of 71 nm with uniform distribution, high encapsulation efficiency and adequate loading capacity of paclitaxel (PTX). Compared with non-glucosylated nanoparticles (NP), a significantly higher amount of DGlu-NP was internalized by RG-2 glioma cells through caveolae-mediated and clathrin-mediated endocytosis. Both of the transport ratios across the in vitro BBB model and the cytotoxicity of RG-2 cells after crossing the BBB were significantly greater of DGlu-NP/PTX than that of NP/PTX. In vivo fluorescent image indicated that DGlu-NP had high specificity and efficiency in intracranial tumor accumulation. The anti-glioblastoma efficacy of DGlu-NP/PTX was significantly enhanced in comparison with that of Taxol and NP/PTX. Preliminary safety tests showed no acute toxicity to hematological system, liver, kidney, heart, lung and spleen in mice after intravenous administration at a dose of 100 mg/kg blank DGlu-NP per day for a week. Therefore, these results indicated that DGlu-NP developed in this study could be a potential dual-targeted vehicle for brain glioma therapy. (C) 2013 Elsevier Ltd. All rights reserved.
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