Folate Targeting Capecitabine Loaded Sustained-release Nanoparticles Preparation And Research

This thesis aimed at developing capeicitabine(CAP) loaded antitumor nanocarriers withtargeting and sustained delivery, so as to expand nano drug carrier application and providenew ways for CAP in the treatment of colorectal cancer. PEG-PLGA compound withpolyethylene glycol (PEG) as hydrophilic block and poly (lactic co glycolic acid)(PLGA) ashydrophobic block was synthesized. Antitumor drug CAP and tumor targeting ligand folate(FA) were chemically bonded at PEG-PLGA, these two molecules being carrier materialswere thus obtained. By emulsion solvent evaporation and nano precipitation and dialysismethods, the carrier materials, CAP and tetramethoxysilane (TMOS) were used to preparedrug loaded nanoparticles(NPs) and nano micelles under emulsifying and self assemblyimpetus. CAP connected with hydrophobic end condensed in the core while FA bonded onhydrophilic end exposure to outside, the hydrolysis of TMOS while emulsifying formedhydrogen bonds with PEG, a layer of silica shell was thus formed between hydrophobic andhydrophilic segment.The materials synthesis, drug loaded NPs preparation and characteristics were analyzed，the kinetics of micelles formation, in vitro release behavior and its mathematical modelexpression were also discussed in this thesis. Details are as follows:(1) PEG had been modified to mono carboxyl terminated functional polymerHO-PEG-COOH, the optimum synthetic condition of HO-PEG-COOH were as follows: themolecular ratio of PEG: succinic anhydride=1∶2.2, the concentration of catalyst4-dimethylamino pyridine (DMAP) was0.4%wt.(mass faction, similarly hereinafter),triethylamine (TEA) was0.1%wt; amphiphilic compounds PEG-PLGA, FA-PEG-PLGA andPEG-PLGA-CAP were successfully synthesized on the basis of HO-PEG-COOH, the CMC ofFA-PEG-PLGA/PEG-PLGA-CAP was about1.2ug/ml, showing that these two amphiphiliccompounds were easy to form mocrospheres and micelles;(2) The prepared drug loaded silica cross-linked nanoparticles (SSCL NPs) and nonesilica crosslinked drug loaded nanoparticles (NSSCL NPs) were about230nm. Xphotoelectron spectroscopy detected the nitrogen element of FA on SSCL NPs surface. NSSCL NPs surface potential was-15.9mV, while that of NSSCL NPs was slightlyhigher as the silica shell hinded the contribution of nuclear to negative charge of shell. X-raydiffraction analysis and differential scanning calorimetry indicated that CAP encapusulatedwithin the NPs was in molecular state and uniformly distributed, which provided a theoreticalbasis for the study on drug release;(3) For NPs prepared by emulsion solvent evaporation, three important factors relatedwith NPs preparation were selected for the Lg(33) orthogonal test. Reduce the stirring speedand water/oil phase volume ratio, improve the carrier concentration were effctive onenhancing loading and the interaction of any two factors is not significant for enhancingdrug loading. The best conditions for achieving maximum loading amount were obtained asfollows: the carrier concentration was20mg/ml, water/oil phase volume ratio was70andstirring speed was626.72rpm;(4) For nanomicelles prepared by nano precipitation and dialysis, the UV-vis absorbanceof PEG-PLGA-CAP/FA-PEG-PLGA micellar was platform between PH1.2-12.8, whichshowed turbidity stability with PH changes. Below50℃, CMC decreased with the increase oftemperature. The addition of NaCl had little effect on CMC values as FA-PEG-PLGA andPEG-PLGA-CAP are non ionpolymer, thus the ion created by NaCl ionization didn’t play role.Composite micelles in the presence of salt could still keep a low CMC, which was veryimportant for drug loaded micelles used in intravenous injection;(5) In vitro release results showed that SSCL NPs and NSSCL NPs had good slowrelease effect for drugs.The optimal formulation was when polymer/drug being10:1. The drugrelease went through two stages, from30h to70h, the release followed diffusion mechanism;from70h to180h, since complex changes took place in this stages, the chemical bondhydrolysis and the molecular chain broke gradually; molecules became small and the channelsof NPs became bigger, the release followed the degradation–diffusion mechanism. Moreover,the hydrogen bonding between PEG and the silica shell fractured. Besides, it was concludedthat the hindrance of silica shell on the first stage release is larger than the second stage.