Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 572, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ijpharm.2019.118762
Keywords
Gefitinib; Extracellular vesicles; Exosomes; EGFR; Non-small cell lung cancer
Categories
Funding
- JSPS KAKENHI [JP16H02612, JP19H05553]
- JST CREST [J19ZZ00066]
- Leading University as a Base for Human Resource Development in Nanoscience and Nanotechnology, Osaka Prefecture University
- National Institutes of Health [R21CA178301, R01CA169259]
- American Cancer Society [RSG-13-047]
- Harvard Stem Cell Institute Blood Program [DP-0110-12-00]
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Extracellular vesicles (exosomes, EVs) are cell membrane particles (30-200 nm) secreted by virtually all cells. During intercellular communication in the body, secreted EVs play crucial roles by carrying functional biomolecules (e.g., microRNAs and enzymes) into other cells to affect cellular function, including disease progression. We previously reported that the macropinocytosis pathway contributes greatly to the efficient cellular uptake of EVs. The activation of growth factor receptors, such as epidermal growth factor receptor (EGFR), induces macropinocytosis. In this study, we demonstrated the effects of gefitinib, a tyrosine kinase inhibitor of EGFR, on the cellular uptake of EVs. In EGFR-mutant HCC827 non-small cell lung cancer (NSCLC) cells, which are sensitive to gefitinib, macropinocytosis was suppressed by gefitinib treatment. However, the cellular uptake of EVs was increased by gefitinib treatment, whereas that of liposomes was reduced. In accordance with the results of the cellular uptake studies, the anti-cancer activity of doxorubicin (DOX)-loaded EVs in HCC827 cells was significantly increased in the presence of gefitinib, whereas the activity of DOX-loaded liposomes was reduced. The digestion of EV proteins by trypsin did not affect uptake, suggesting that the cellular uptake of EVs might not be mediated by EV proteins. These results suggest that gefitinib can enhance cell-to-cell communication via EVs within the tumor microenvironment. In addition, EVs show potential as drug delivery vehicles in combination with gefitinib for the treatment of patients harboring EGFR-mutant NSCLC tumors.
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