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Int. J. Mol. Sci. 2016, 17(12), 1998; doi:10.3390/ijms17121998

Enhancing Anticancer Effect of Gefitinib across the Blood–Brain Barrier Model Using Liposomes Modified with One α-Helical Cell-Penetrating Peptide or Glutathione and Tween 80

Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan
Faculty of Pharmacy, National Yang-Ming University, Taipei 112, Taiwan
Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan
Institute of Oncology, National Taiwan University, Taipei 106, Taiwan
Authors to whom correspondence should be addressed.
Academic Editor: Bing Yan
Received: 22 October 2016 / Revised: 22 November 2016 / Accepted: 22 November 2016 / Published: 29 November 2016
(This article belongs to the Section Biomaterial Sciences)
View Full-Text   |   Download PDF [6303 KB, uploaded 29 November 2016]   |  


Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib, have been demonstrated to effectively treat the patients of extracranial non-small cell lung cancer (NSCLC). However, these patients often develop brain metastasis (BM) during their disease course. The major obstacle to treat BM is the limited penetration of anticancer drugs across the blood–brain barrier (BBB). In the present study, we utilized gefitinib-loaded liposomes with different modifications to improve gefitinib delivery across the in vitro BBB model of bEnd.3 cells. Gefitinib was encapsulated in small unilamellar liposomes modified with glutathione (GSH) and Tween 80 (SUV-G+T; one ligand plus one surfactant) or RF (SUV-RF; one α-helical cell-penetrating peptide). GSH, Tween 80, and RF were tested by the sulforhodamine B (SRB) assay to find their non-cytotoxic concentrations on bEnd.3 cells. The enhancement on gefitinib across the BBB was evaluated by cytotoxicity assay on human lung adenocarcinoma PC9 cells under the bEnd.3 cells grown on the transwell inserts. Our findings showed that gefitinib incorporated in SUV-G+T or SUV-RF across the bEnd.3 cells significantly reduced the viability of PC9 cells more than that of free gefitinib. Furthermore, SUV-RF showed no cytotoxicity on bEnd.3 cells and did not affect the transendothelial electrical resistance (TEER) and transendothelial permeability of sodium fluorescein across the BBB model. Moreover, flow cytometry and confocal laser scanning microscopy were employed to evaluate the endocytosis pathways of SUV-RF. The results indicated that the uptake into bEnd.3 cells was mainly through adsorptive-mediated mechanism via electrostatic interaction and partially through clathrin-mediated endocytosis. In conclusion, cell penetrating peptide-conjugated SUV-RF shed light on improving drug transport across the BBB via modulating the transcytosis pathway(s). View Full-Text
Keywords: gefitinib; blood–brain barrier (BBB); liposomes; peptides; lung cancer gefitinib; blood–brain barrier (BBB); liposomes; peptides; lung cancer

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Lin, K.-H.; Hong, S.-T.; Wang, H.-T.; Lo, Y.-L.; Lin, A.M.-Y.; Yang, J.C.-H. Enhancing Anticancer Effect of Gefitinib across the Blood–Brain Barrier Model Using Liposomes Modified with One α-Helical Cell-Penetrating Peptide or Glutathione and Tween 80. Int. J. Mol. Sci. 2016, 17, 1998.

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