PLGA Nanoparticle-based Docetaxel/LY294002 Drug Delivery System Enhances Antitumor Activities Against Gastric Cancer

Background:Gastric cancer(GC)is one of the most common malignancies in the world.Its incidence ranks the fifth,and mortality ranks the third worldwide.In China,the incidence of GC is the second in males and the third in females,and its mortality is the second among all cancers.Docetaxel(TXT)is acknowledged as one of the most important chemotherapy agents for GC,but the hydrophobicity of TXT limits its clinical application.PI3K/AKT signaling pathway is involved in cell growth,proliferation,differentiation,apoptosis,and glucose transportation.Abnormal activation of PI3K/AKT signaling promotes GC cell proliferation and invasion,and inhibits GC cell apoptosis.It has been reported that PI3 K inhibitor is a promising target for cancer therapy.LY294002 is a PI3 K inhibitor that inactivates the PI3K/AKT signaling pathway,thereby suppressing cell proliferation and increase cell apoptosis.LY294002 exhibits potential antitumor effects.PI3 K inhibitor could promote the cell apoptosis induced by taxanes.However,the hydrophobicity of TXT and the poor solubility and low bioavailability of LY294002 limit their clinical application.Objective:To overcome the hydrophobicity of TXT and the poor solubility and low bioavailability of LY294002,we designed poly(lactic acid/glycolic)(PLGA)nanoparticles loaded with TXT and LY294002,and evaluated its antitumor effects on GC.Methods:TXT/LY294002-loaded PLGA NPs were formed by the emulsion-solvent evaporation method.We then evaluated the characterization,in vitro stability,and cellular uptake of PLGA(TXT+LY294002).The effects of PLGA NPs on cell apoptosis and cell cycle were assessed.We further investigated the in vivo distribution of PLGA NPs.Using xenograft mouse models and orthotopic mouse models,we assessed the effects of PLGA(TXT+LY294002)on GC growth in vivo antitumor efficacy and toxicity.Immunohistochemistry was used to evaluate the effects of PLGA NPs on GC cell proliferation and apoptosis.Results:We developed PLGA(TXT+LY294002)NPs with an average diameter of155.30 nm.The PLGA(TXT+LY294002)NPs dispersed uniformly with no aggregation according to the transmission electron micrograph.The PLGA NPs were stable and provides controlled release.In vitro experiments showed that PLGA(TXT+LY294002)NPs could be absorbed by MKN45 cells and promoted cell apoptosis and affected cell cycle,exerting anti-proliferation effects.In vivo experiments showed that PLGA facilitated the accumulation of TXT and LY294002 at the tumor sites,and had antitumor effects with no toxicity to major organs.Conclusion:We constructed a novel PLGA-based TXT/LY294002 drug delivery system in this study.The PLGA(TXT+LY294002)provides controlled release and tumor targeting and potent anti-GC effects.In vitro and in vivo studies confirmed that PLGA(TXT+LY294002)could inhibit GC growth,and this drug delivery system was safe in vivo and had low side effects.