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.
BACKGROUND
Y294002 (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.


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.


CONCLUSIONS
The surfactant-free formulation of PLGA is critical to the promising anticancer activity of SF-LY NPs.
Institute of Basic Medical Sciences, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Chia-Cheng
CC
Hou
Tsung-Lin
TL
Tsai
Wen-Pin
WP
Su
Hsing-Pang
HP
Hsieh
Chen-Sheng
CS
Yeh
Dar-Bin
DB
Shieh
Wu-Chou
WC
Su
D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D053758:Nanoparticles / Q000737:chemistry*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
D002867:Chromones; D009025:Morpholines; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019344:Lactic Acid; D019869:Phosphatidylinositol 3-Kinases
AKT; LY294002; endoplasmic reticulum stress; surfactant-free poly(lactic-co-glycolic acid)