期刊
ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY
卷 46, 期 8, 页码 1605-1616出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/21691401.2017.1384385
关键词
L-Carnitine; OCTN2; nanoparticles; blood-brain barrier; glioma cells; transporter-mediated endocytosis
资金
- National Nature Science Foundation of China [81473164, U1608283]
- National Basic Research Program of China (973 Program) [2015CB932100]
- Welch Endowed Chair in Biochemistry at the Texas Tech University Health Sciences Center [BI-0028]
- China Scholarship Council [201508210200]
Overcoming blood-brain barrier (BBB) and targeting tumor cells are two key steps for glioma chemotherapy. By taking advantage of the specific expression of Na+-coupled carnitine transporter 2 (OCTN2) on both brain capillary endothelial cells and glioma cells, L-carnitine conjugated poly(lactic-co-glycolic acid) nanoparticles (LC-PLGA NPs) were prepared to enable enhanced BBB permeation and glioma-cell targeting. Conjugation of L-carnitine significantly enhanced the uptake of PLGA nanoparticles in the BBB endothelial cell line hCMEC/D3 and the glioma cell line T98G. The uptake was dependent on Na+ and inhibited by the excessive free L-carnitine, suggesting involvement of OCTN2 in the process. In vivo mouse studies showed that LC-PLGA NPs resulted in high accumulation in the brain as indicated by the biodistribution and imaging assays. Furthermore, compared to Taxol and paclitaxel-loaded unmodified PLGA NPs, the drug-loaded LC-PLGA NPs showed improved anti-glioma efficacy in both 2D-cell and 3D-spheroid models. The PEG spacer length of the ligand attached to the nanoparticles was optimized, and the formulation with PEG1000 (LC-1000-PLGA NPs) showed the maximum targeting efficiency. We conclude that L-carnitine-mediated cellular recognition and internalization via OCTN2 significantly facilitate the transcytosis of nanoparticles across BBB and the uptake of nanoparticles in glioma cells, resulting in improved anti-glioma efficacy. [GRAPHICS]
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