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
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 Su<sup>1,6

1</sup>Institute 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