| Docetaxel,belonging to the second generation of taxane drugs,has a good effect on breast cancer,lung cancer,gastric cancer,prostate cancer,ovarian cancer and soft tissue sarcoma.But it is not been widely used due to its low water solubility.Only docetaxel injection is used in clinical currently,which needs polysorbate 80 and 13% ethanol as solvent.But most patients have a serious allergic reaction.So that the clinical application of docetaxel injection is limited.The object of this paper was to prepare a kind of docetaxel albumin nanoparticles(DTX-BSA-NPs)with certain targeting function,then improved the water solubility of drugs and reduced the toxicity and side effects.Firstly,we prepared DTX-BSA-NPs with high pressure homogenization technology,and then optimized the preparation process.Secondly,we characterized the nanoparticles under process optimization,investigated the stability and the release in vitro.Finally,this paperstudied pharmacokinetics,phannacodynamic in vitro,mechanism of cellular uptake and tissue distribution studies in tumor-bearing mice.Then the parameters of process were invastigated,the optimized parameters were as follows: homogenization pressure(1500 bar),homogenization cycles(15 times),water phase / oil phase(50:1,v/v),DTS1 / DTS2(15:1,v/v),albumin(1%),drug/BSA(1:7.5,g/g),the pH of water phase was 6.8.The reproducibility of nanoparticles prepared under optimized conditions was better.The parameters were as follows: partlcle size(187.0 ± 2.0)nm,Zeta potential(-19.61 ± 0.84)mv,encapsulation efficiency(91.79 ± 0.75)%,drug loading efficiency(10.31 ± 0.16)%.The results of DSC and SEM demonstrated that nanoparticles had uniform size,smooth surface,amorphous form.Stability study demonstrated that DTX-BSA-NPs can remain stable within 36 hours and the freeze-dried powder can remain stable in 4℃ refrigerator within 3 months.In vitro release study,DTX-BSA-NPs released slowly,the cumulative release amount was 53.87% within 36 h.The results of pharmacokinetic study showed that the plasma drug concentration of both preparations reached a peak after 5 min for administration,the nanoparticle group was lower in the maximum plasma concentration,and nanoparticle group was higher than the injection group in total clearance rate.The results of phannacodynamic in vitro demonstrated that the cytotoxicity of nanoparticles group was slightly stronger than the injection group.InA549 and MCF-7 cells,cell uptake of the two preparations were concentration dependent,through the comparison between nanoparticle group and injection group,it was found that the uptake of DTX by A549cells(for nanoparticle group)increased by 31%,and the uptake of DTX by MCF-7 cells(for nanoparticle group)increased by 28%.The mechanism of uptake by tumor cells indicated that DTX-BSA-NPs can interacted with SPARC protein on the surface of tumor cells,which mediated the cellular uptake of nanoparticles,then entered the cell by caveolae-1,this process required energy consumption.The results of tissue distribution showed that drug in liver,spleen,lung and tumor increased significantly,so DTX-BSA-NPs have tumor targeting function. |
