Study On Preparation And Pharmacokinetics Of Arsenic Trioxide-loaded PH-responsive Mesoporous Silica Nanoparticles

Objective To prepare arsenic trioxide-loaded pH-responsive mesoporous silica nanoparticles(PAA-ATO-MSNs)and to investigate their physicochemical properties,in vitro release behavior and pharmacokinetics in rats.Methods PAA was covalently attached to the exterior surface of amino group functionalized MSNs prepared by co-condensation method and ATO was loaded into them by electrostatic adsorption.The formation was optimized in terms of orthogonal design based on single factor analysis including reaction temperature,reaction pH,CTAB concentration,volume of TEOS,volume ration of TEOS and APTES.Morphology was observed by transmission electron microscope(TEM)and scanning electron microscope(SEM).Small angle X-ray diffraction(SAXRD)was used to determine the mesoporous structure;nitrogen adsorption was used to calculate the surface area,pore diameter and pore volume;fourier transform infrared(FT-IR)spectra was to determine function of the amino and PAA;thermogravimetric analysis(TGA)was to calculate the grating ratio and laser particle size analyzer were used to determine the size and Zeta potential.The Entrapment efficiency and drug loading of PAA-ATO-MSNs were investigated with the method of high speed centrifugation combined with inductively coupled plasma emission spectrum(ICP).The drug release behavior of PAA-ATO-MSNs was studied using dynamic dialysis method,PBS(pH 5.0,6.0 and 7.4)chosen as release medium.Pharmacokinetics behavior of PAA-ATO-MSNs after intravenous injection in rats was studied.Femoral artery and jugular vein catheterization technology were used to collect blood samples;plasma concentration was determined by inductively coupled plasma mass spectrometry(ICP-MS).Results The ICP method was established to evaluate the content of ATO in vitro and the calibration curve showed a good linear relationship in the concentration range of 0.25～8.0 mg/L.MSNs were prepared by the optimum formulation:reaction temperature was 80℃,reaction pH was 11.5,CTAB concentration was 0.2%,0.6 mL TEOS,volume ration of TEOS and APTES was 2:1.Morphology of PAA-ATO-MSNs was spherical and the mean particle size,Zeta potential,EE and DL of PAA-ATO-MSNs were(158.6± 1.32)nm,(-28.40±10.34)mV,(40.95±3.21)%,(11.42±1.75)%,respectively.In vitro release behavior of PAA-ATO-MSNs showed significant pH-responsive and some sustained characteristic and the cumulative release amount was increased with the decrease of pH.The profiles of in vitrio were expressed well by Webull equation.Compared with ATO-Sol and ATO-MSNs group,t1/2β was significantly prolonged and AUC was significantly increased(P<0.01).Conclusion In vitro and vivo analysis methods were established successfully,PAA-ATO-MSNs were successfully prepared with small size,higher EE and DL.Release of ATO from PAA-ATO-MSNs showed the obvious pH-responsive characteristic and sustained-release in vitro and PAA-ATO-MSNs had improved the pharmacokinetics behavior in rats.PAA-MSNs might be promising carrier to load ATO for cancer therapy.