Preparation And Characterization Of Deoxycholic Acid/Folic Acid Modified Oleanolic Acid Nanoparticles

Oleanolic acid(OA)is a pentacyclic triterpenoid widely distributed in various plants,which shows potential hepatoprotective,anti-inflammatory,hypoglycemic and anti-tumor activities.However,poor aqueous solubility and low bioavailability limites its application in the fields of food,medicine and cosmetics.Previous studies indicate that structure modification or nano-embedding technique can address these problems,but polymer-or liposome-based nanoparticles have low drug encapsulation efficiency,poor stability and targeting.Self-assemble technology is a simple and efficient method to construct nanoparticles with no need to introduce complex polymers.In this paper,two strategies were used to obtain deoxycholic acid(DOCA)/folic acid(FA)modified OA deviatives and DOCA/FA surface modified nanoparticles,followed by the comparison of their characterization,stability,encapsulation efficiency and release behaviors.Main results are listed as follows:(1)The nano-emulsion processing parameters for the preparation of O A self-assembled nanoparticles(OANPs)were optimized by single factor and orthogonal test,and the optimum parameter were as follows:ethyl acetate as the organic solvent,the concentration of PVA 2.5%,emulsification time 30 s,oleanolic acid concentration 10 mg/mL.The average particle size of OA NPs obtained was 251.3±2.2 nm,the dispersity index was 0.07±0.01,and the yield was 81.04±1.03%.(2)By using polyethylene glycol dicarboxylic acid(PEG-DCM)as a linker,DOCA/FA modified OA derivatives were obtained,followed by structure confirmation using fourier infrared absorption spectroscopy(FT-IR)and nuclear magnetic resonance spectroscopy(1H-NMR)determination.The OA-PEG-DOCA dereviative can form uniform spherical nanoparticles with an average particle size of 302.4±2.5 nm by nono-emulsion.However,FA modification(OA-PEG-FA)improved the aqueous solubility,and cannot self-assemble to form nanoparticles.(3)DOCA/FA graft modification of OA NPs surface was performed by using PEG-DCM as a linker to obtain DOCA-PEG/OA NPs and FA-PEG/OA NPs.The average particle size of DOCA-PEG/OA NPs and FA-PEG/OA NPs was 273.1±2.4 nm and 288.6±3.4 nm,with an increase of 22 nm and 37 nm compared with OA NPs,respectively.(4)The thermostability,encapsulation capability and release behavior of OA NPs,OA-PEG-DOCA NPs and surface graft modified DOCA-PEG/OA NPs and FA-PEG/OA NPs were characterized and compared.Results showed that nanoemulsion of OA NPs was stable when the temperature was no higher than 60℃,but was destroyed when the temperature was higher than 80℃.No significant difference of thermostability was observed between OA NPs and FA graft modified OA NPs.However,both OA-PEG-DOCA NPs and DOCA-PEG/OA NPs showed significantly improved thermostabiliy than OA NPs.Particularly,OA-PEG-DOCA NPs was much better,and kept stable even when heated at 100℃ for 1 hour.All these particles kept stable when shaked at 37 0C for 5 days or incubated at 4℃ for 1 month,and the particle size kept uniform.Also,all the NPs showed good encapsulation capacity with an encapsulation efficiency for paclitaxel about 50%.These data indicated that DOCA modified OA derivative OA-PEG-DOCA NPs has the potentiality to form self-assembled nanoparticles and could be used as poteintial stable and efficient nano-carriers.