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Pronounced induction of endoplasmic reticulum stress and tumor suppression by surfactant-free poly (lactic-co-glycolic acid) nanoparticles via modulation of the PI3K signaling pathway

Authors Hou CC, Tsai TL, Su WP, Hsieh HP, Yeh CS, Shieh DB, Su WC

Received 25 April 2013

Accepted for publication 24 May 2013

Published 25 July 2013 Volume 2013:8(1) Pages 2689—2707

DOI https://doi.org/10.2147/IJN.S47208

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 4

Chia-Cheng Hou,1,6 Tsung-Lin Tsai,1,6 Wen-Pin Su,6 Hsing-Pang Hsieh,7 Chen-Sheng Yeh,4,5 Dar-Bin Shieh,1–4 Wu-Chou Su1,6

1Institute of Basic Medical Sciences, 2Institute of Oral Medicine and Department of Stomatology, 3Advanced Optoelectronic Technology Center, 4Center for Micro/Nano Science and Technology, 5Department of Chemistry, 6Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 7Division of Biotechnology and Pharmaceutical Research, NHRI, Miaoli, Taiwan

Background: LY294002 (LY) is a potent inhibitor of phosphatidylinositol 3-kinases (PI3Ks); however, biological applications of LY are limited by its poor solubility and pharmacokinetic profile. This study aimed at developing LY-loaded surfactant-free poly(lactic-co-glycolic acid) (PLGA) nanoparticles (SF-LY NPs) to improve the therapeutic efficacy of LY.
Materials and methods: Cellular viability was measured by MTT assay. The subcellular distribution of NPs was studied using an ultraviolet-visible spectrophotometer and confocal microscope. The expression of cell-death-associated proteins was determined using Western blotting and the in vivo activity of SF-LY NPs was tested in a xenograft animal model.
Results: SF-LY NPs enhanced the intracellular level of LY, induced sustained suppression of AKT, and induced marked cancer cell death. In addition, SF-LY NPs tended to accumulate in the endoplasmic reticulum (ER) and induce pronounced ER stress. Finally, SF-LY NPs exhibited a prominent antitumor effect in vivo.
Conclusion: The surfactant-free formulation of PLGA is critical to the promising anticancer activity of SF-LY NPs.

Keywords: LY294002, AKT, surfactant-free poly(lactic-co-glycolic acid), endoplasmic reticulum stress

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