Construction And Brain Targeting Research Of Solid Lipid Nanoparticles Comodified With Borneol And PEG

In recent years,the rate of central nervous system disease is increasing,but the drug therapy is less effective for that blood brain barrier(blood brain-barrier BBB)limites drug transport into the brain.Development of brain targeting drug delivery system is becoming a hot topic in pharmaceutical research.Studies show that multiple modified nano-drug delivery system is an effective way to target the brain.Bomeol is an aromatic resuscitation compounds with relatively small molecular weight and stronglipid solubility.Bomeol is a kind of excellent blood-brain barrier penetration enhancer.It is reported that drug can be promoted upward across the blood brain barrier and transported into the brain when it is combined with Bomeol.We prepared bpSLN with appropriate ratio of borneol modified oleoyl phosphatidyl ethanolamine(BO-DOPE)and PEGylated stearic acid as the basic carrier materials.It is designed to be used for drug delivery through the blood-brain barrier.Construction of blank bpSLN:BO-DOPE were synthesized by esterification and amidation reaction with Ding two anhydride linker,the structures of BO-DOPE were confirmed by MS,1H-NMR and 13C-NMR.bpSLN were prepared by resolvent-solvent volatility with BO-DOPE and PEG-SA as lipid material.The particle size and stability were made as the indexes of the process and prescription screening.The grain size of the blank bpSLN was 75.8+ 7.5 nm,Zete potential was-26.92 + 1.95 mV.BBB model in vitro:HBMEC cell was used to develop the BBB model.The evaluation of the model were made by light microscopy,electron microscopy,transendothelial resistance TEER and permeability coefficient of 14C-sucrose.HBMEC cells were spindle shaped under light microscope.TEM showed that cells formed a close connection,the value of TEER was 277.57±2.77Ω· cm2,14C-sucrose permeability coefficient was 1.85 X 10-3cm/min.Evaluation of BpSLN in vitro:the group were devided as bpSLN,bSLN,SLN,and coumarin-6 was used as a fluorescent probe.The cell toxicity experiment showed that the toxicity among the three groups was not significant when the drug was in a low dose.The toxicity was significantly reduced in bSLN and bpSLN in a high dose when compared with SLN.In the dye uptake experiment,bSLN was the strongest.In the transition experiment,the apparent across membrane permeability Papp reached a maximum at98.3×10-6 and 95×10-6 cm/s for bpSLN and bSLN,respectively.The Papp of SLN was increased with time and reached a maximum of 51.3×10-6 cm/s at 4 h.The Pappmax of bSLN and bpSLN were 1.91 and 1.85 times of that of SLN.In the mechanism study,the BBB were incubated with bpSLN,and soon it was able to open up tight junctions between cells,which is consistent with the TEER value.After removal of bpSLN,the tight junction began to recover 1h later,and after 4h the tight j unction was restored.The prompt of bpSLN is reversible for the open action of a tight junction.bpSLN brain targeting evaluation:Using Cy7 as the tracer,the SLN,bSLN and bpSLN were prepared respectively.And after the injection by the tail vein in the mouse,the fluorescence distribution of 0.5,2,4 h was observed under the living fluorescence imager.As a result,the bSLN group and the bpSLN group quickly developed a strong fluorescence in the brain and quickly reached the peak,then the fluorescence in the brain gradually decreased over time.Conclusion:The results suggested that solid lipid nanoparticles has a good role in passing the blood-brain barrier after chemical modification of borneol,which provided a good interpretation system for drugs to treat diseases of the central nervous system.