LY294002 (LY, 2-嗎啉-4-基-8-苯基-4H-色烯-4-酮）是一種有效抑制磷脂醯肌醇3-激酶(phosphatidylinositol 3-kinases, PI3Ks)的小分子抑制劑，但是，微水溶性與低劣的藥物代謝動力學特性則是侷限LY在生物體上的應用。聚乳酸聚乙醇酸共聚物（poly(lactic-co-glycolic acid), PLGA）是一種可生物降解的奈米材料，可以用來作為載體用於藥物傳遞。 因此，我們發展出LY294002包覆於無表面活性劑的PLGA奈米粒子(LY294002-loaded surfactant-free PLGA nanoparticles, SF-LY NPs)並研究是否該奈米粒子可以改善LY的療效。 SF-LY NPs，相較於LY294002包覆於表面活性劑聚乙烯醇(polyvinyl alcohol, PVA) 的奈米粒子(LY294002-loaded PVA -containing PLGA nanoparticles, PVA-LY NPs) 以及 LY，則表現出優越的抑制細胞生長效果、持續抑制絲氨酸/蘇氨酸激酶 (蛋白激酶B) (protein kinase B, AKT)的活性以及增加LY在細胞內的含量。此外，我們觀察到SF-LY NPs傾向於積累在內質網 (endoplasmic reticulum, ER)，並誘發顯著的內質網壓力(ER stress)反應所衍生的細胞死亡機制。將SF-LY NPs注射到腫瘤後也表現抗腫瘤的作用。在SF-LY NPs誘導的細胞死亡機制，我們建立了能定位在不同胞器中的PLGA奈米粒子，並發現到位於內質網中的SF-LY NPs能促使細胞死亡。此外，我們也觀察到諸多現象，如，內質網衍生空泡化 (ER-derived vacuolization) 和泛素高度聚集的聚集小體 (aggresomes)。接下來，我們發現含纈酪肽蛋白（Valosin-containing protein, VCP）是重要的因子，其能減緩SF-LY NPs誘導的諸多細胞現象和細胞死亡。這些研究結果表明，SF-LY NPs通過PI3K/AKT和VCP相關機制導致細胞死亡並具有發展成抗癌藥物的潛力。

LY294002 (LY) is a potent inhibitor of phosphatidylinositol 3-kinases (PI3Ks); however, bio-applications of LY are limited by its poor solubility and pharmacokinetic profile. Poly (lactic-co-glycolic acid) (PLGA) is a biodegradable nanomaterial that can be used as a carrier for drug delivery. LY294002-loaded surfactant-free PLGA nanoparticles (SF-LY NPs) were developed to improve the therapeutic efficacy of LY. SF-LY NPs showed a stronger growth inhibitory effect, sustained suppression of the serine/threonine kinase AKT activation, and increased intracellular uptake of LY compared with LY294002-loaded PVA (polyvinyl alcohol) -containing PLGA nanoparticles (PVA-LY NPs) or free LY. In addition, we observed that SF-LY NPs tend to accumulate in the endoplasmic reticulum (ER), subsequently induced pronounced ER stress-derived cell death. After injection into tumors, SF-LY NPs exhibited a stronger antitumor effect than free LY. In cell death mechanisms of SF-LY NPs, we developed different organelle-targeting PLGA NPs with LY entrapment and found that SF-LY NPs preferentially located at ER to determine cell fate, rather than the properties of PLGA NPs. Furthermore, PLGA NPs with LY loading, located at ER, exhibited multiple cellular phenomena, such as, ER-derived vacuolization and ubiquitin-concentrated aggresomes. Next, we identified that vasolin-containing protein (VCP) rescued SF-LY NPs -induced multiple cellular phenomena and was critical for SF-LY NPs -mediated cell death. These findings indicated that the surfactant-free formulation of PLGA is an ideal vector to carry LY and that SF-LY NPs possess promising anticancer activity via both PI3K/AKT and VCP -related mechanisms.

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