L-Carnitine-conjugated nanoparticles to promote permeation across blood-brain barrier and to target glioma cells for drug delivery via the novel organic cation/carnitine transporter OCTN2.

Abstract

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.

• Authors: Longfa Kou, Yanxian Hou, Qing Yao, Weiling Guo, Gang Wang, Menglin Wang, Qiang Fu, Zhonggui He, Vadivel Ganapathy, Jin Sun
• Journal: Artificial cells, nanomedicine, and biotechnology (Artif Cells Nanomed Biotechnol) Vol. 46 Issue 8 Pg. 1605-1616 (Dec 2018) ISSN: 2169-141X [Electronic] England
• PMID: 28974108 (Publication Type: Journal Article)

Chemical References

• Neoplasm Proteins
• SLC22A5 protein, human
• Solute Carrier Family 22 Member 5
• Paclitaxel
• Carnitine

Topics

• Blood-Brain Barrier (metabolism, pathology)
• Caco-2 Cells
• Carnitine (chemistry, pharmacokinetics, pharmacology)
• Drug Delivery Systems (methods)
• Glioblastoma (drug therapy, metabolism, pathology)
• Humans
• Nanoparticles (chemistry, therapeutic use)
• Neoplasm Proteins (metabolism)
• Paclitaxel (chemistry, pharmacokinetics, pharmacology)
• Permeability
• Solute Carrier Family 22 Member 5 (metabolism)