The Nanoparticles Loading Docetaxel And The Inhibitor Of PI3K/Akt Pathway To Target The Breast Cancer And Overcome The Multidrug Resistant

Objective: DTX and GDC0941 loading nanoparticles(R7/PSD-Fol NPs),were constructed for targeting to tumor and achieving an effective antitumor effect.And further explore its possible mechanism of overcoming the multidrug resistance(MDR).Methods: PSD-Folate?PLGA-PEG-R7 were synthesized using the previous study method.DTX and GDC0941 loading nanoparticles(R7/PSD-Fol NPs),by using the polymer of PLGA-mPEG?pH sensitive block PSD-Folate and PLGA-PEG-R7,were prepared by improved emulsion solvent evaporation method.The solution of R7/PSD-Fol NPs was clear with light blue milk light.Particle size and distribution were measured by using a Particle Sizing System.The cellular uptake,intracellular distribution of R7/PSD-Fol NPs were carried out compararive studies on MCF-7 cells and MCF-7/Adr cells.The data was measured by confocal laser scanning microscope(CLSM)and flow cytometer.The data of mitochondrial membrane potential of MCF-7 cells and MCF-7/Adr cells treated with the R7/PSD-Fol NPs was measured by flow cytometer.The colonization of MCF-7 cells and MCF-7/Adr cells treated with the R7/PSD-Fol NPs was carried out.Preparing MCF-7/Adr tumor bearing mice,the tumor targeting ability of the multifunctional nanoparticles was investigated through in vivo imaging,and further evaluated antitumor effect.Results: the carrier material of PLGA-PEG-R7 and PSD-Folate was successfully synthesized.The formulation and process were optimized to prepared R7/PSD-Fol NPs,which showed typical spherical shapes.The particle size,PDI,zeta potential,drug encapsulation efficiency and drug loading of R7/PD-Fol NPs were 164.5±11.3nm,0.263±0.012,-6.47±1.62 mV,81.6%,(1.21±0.21)%,respectively.The R7/PSD-Fol NPs could significantly enhance cellular uptake and cytotoxicity in MCF-7 and MCF-7/Adr cells when compared to the nanoparticles solely modified by R7.The mitochondrial membrane potential in both MCF-7 and MCF-7/Adr cells treated with R7/PSD-Fol NPs decreased significantly compared with the group of R7 NPs.And the colonization of MCF-7 and MCF-7/Adr cells was inhibited by R7/PSD-Fol NPs,comparing with the R7 NPs and DTX+GDC0941.The In vivo in the breast cancer mice model,R7/PSD-Fol NPs could target to the tumor effectively and significantly inhibit the tumor growth.Conclusion: R7/PSD-Fol NPs targeted specifically to MCF 7/Adr tumor site via active targeting effect of folate,and then entered into tumor tissues and cells through the folate receptor-mediated endocytosis and cell penetrating effect,the targeting delivery of GDC0941 effectively inhibit the PI3K/Akt pathway to reverse the MDR.And the PSD contribute to the pH triggered drug release,and the antitumor effect of DTX cloud be enhanced.Therefore,R7/PSD-Fol NPs could be a potential carrier for antitumor drug such as DTX to reverse multidrug resistance(MDR)and improve the therapeutic effect.