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Angiopep-2-conjugated liposomes encapsulating γ-secretase inhibitor for targeting glioblastoma stem cells

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Abstract

CD133+ cell subpopulation in U87 MG cells displays glioblastoma stem cell (GSC) like properties. Notch, a key regulator of stem cells, is also over-activated in GSCs. It was previously reported that γ-secretase inhibitors inhibit the Notch pathway by targeting the γ-secretase complex. To examine the GSCs, CD133+ cells were separated from the U87 MG cells by magnetic activated cell sorting and only cell populations with nearly 90 % CD133+ cells were used as GSCs. The sorted U87-CD133+ cells indeed display enhanced chemoresistance and high Notch activity. For targeting studies, Angiopep-2 (An2)-conjugated YO-01027 (YO) encapsulating liposomes (PEG-lipo-YO-An2) were prepared by lipid film hydration method. An2 is an effective ligand of low density lipoprotein receptor-related protein which is over-expressed in the blood–brain barrier and GSCs. The mean diameter, zeta potential and encapsulation efficiency of PEG-lipo-YO-An2 was around 180 nm, −10.0 mV and 56.6 %, respectively. In in vitro studies, we confirmed that PEG-lipo-YO-An2 showed enhanced anti-GSC properties such as enhanced stability, anti-proliferation and anti-tumor sphere formation abilities towards than free drug. This study demonstrates that An2 conjugation and liposomal encapsulation of YO enhance the cytotoxicity of YO against GSCs, and this formulation could be used as a promising candidate for the treatment of glioblastoma multiforme by targeting GSCs.

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Acknowledgments

This article does not contain any studies with human and animal subjects performed by any of the authors. All authors (S. Xuan, D. H. Shin and J. S. Kim) declare that they have no conflict of interest. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (no. 2011-0030074) and by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (2014R1A2A2A01004353).

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Correspondence to Jin-Seok Kim.

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Shuhua Xuan and Dae Hwan Shin equally contributed as first-authors to this study.

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Xuan, S., Shin, D.H. & Kim, JS. Angiopep-2-conjugated liposomes encapsulating γ-secretase inhibitor for targeting glioblastoma stem cells. Journal of Pharmaceutical Investigation 44, 473–483 (2014). https://doi.org/10.1007/s40005-014-0151-2

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