Synthesis And Properties Of Targeted Nano Drug Delivery Based Ursolic Acid

Ursolic acid(UA)is a pentacyclic triterpenoid compound,which is widely found in plants such as Prunella vulgaris and T.ilex.Its main drug effects are anti-inflammatory,liver protection,anti-tumor,and so on.Due to its poor solubility and lack of targeting,clinical application of UA was restricted.In order to ameliorate the problems and give better play to the medicinal functions,two kinds of nano drug carrier materials were designed and prepared in this thesis.Natural polymer carboxylated cellulose nanocrystals(CCNs)and carboxymethyl chitosan(CMCS)were chosen as polymer chains,and they are modified with targeting molecule folic acid(FA).The nano drug carrier particles were prepared to deliver UA,and the thesis evaluated in vitro release,cell cytotoxicity,in vivo drug efficacy and other properties in details.The specific works were carried out in the thesis as follows:1.Based on the ring-opening polymerization of CCNs and lactide,a carboxylated nanocellulose-poly-L-lactic acid(CCNs-g-PLLA)graft copolymer was prepared as a drug carrier.The CCNs chain was modified with FA,and nanoparticles(FA-CCNs-g-PLLA / UA NPs)were made by self-assembly wrapping of the drug molecule UA.The analysis of infrared spectrum and nuclear magnetic spectrum showed the chain structure of the synthesized polymer.Scanning electron microscopy and transmission electron microscopy observed that the nanoparticles were uniformly dispersed and spherical before and after drug loading,with particle sizes of 164 nm and 179 nm,respectively.The drug release in vitro showed that the sustained release of UA could be achieved.After 120 h,the release rate at p H 7.4 was 85.7%,while the release rate at p H 5.5 reached 91.4%.In vitro cytotoxicity showed that FA-CCNs-g-PLLA/UA NPs was slightly superior to UA in antitumor activity.2.Carboxymethyl chitosan-ursolic acid nano drug carrier which modifies FA on the surface was designed and preparated,and another anti-tumor drug 10-hydroxycamptothecin(HCPT)was self-assembled to make nano particles(FPCU/HCPT NPs).The analysis of infrared spectrum and nuclear magnetic spectrum showed the chain structure of the polymer.The transmission electron microscope and the scanning electron microscope observed that the particle size of the nanoparticles was uniform and spherical,and the particle size was 183 nm.The drug loading efficiency of nanoparticles reached 6.4%(UA)and 14.1%(HCPT),respectively.3.Further pharmacodynamics analysis of FPCU/HCPT NPs was conducted in vitro and in vivo.In vitro drug release studies showed the properties of the p H response of nanoparticles.In the cell cytotoxicity trial,FPCU/HCPT NPs had the most significant efficacy.of which the cell survival rates after 72 h were 10.0%(4T1)and 9.1%(MCF-7),respectively.The experiments demonstrated that the 4T-1 cells could better uptake FPCU/HCPT NPs compared with the free HCPT.Mouse experiments indicates that the antitumor activity was ranked from strong to weak: FPCU / HCPT NPs> FPCU NPs> UA and HCPT.