| It is well known that when amphiphilic block copolymers are dissolved in asolvent selective for one of the blocks, micelles are usually formed with a rather densecore of the insoluble blocks, surrounded by the diffuse outer corona formed from thesoluble blocks. Its good prospects for controlled drug delivery applications havecaused a wide attention from pharmaceutical investigator. The polymer micelle has avariety of advantages, including nanoscale particle size （10-100nm in diameter）,solubilization of insoluble drugs, controlled drug release, prolong the circulation timein vivo, escaping recognition and uptake of the reticuloendothelial system （RES）,passive targeting by the enhanced permeability and retention （EPR） effect, and activetargeting after modified. Drug molecules can be loaded into the polymeric micelles bymeans of physical entrapment, chemical bonding or electrostatic interactions.The key of the micelle preparation is amphiphilic block polymer. Thecyclodextrin ring has outer hydrophilic and hydrophobic inner cavity. Due to thisparticular structure, it has ability to form inclusion complexes with numerousmolecules, and is widely used in a variety of areas such as food and pharmaceutical.Because of a plurality of reaction activity hydroxyl group, cyclodextrin can bemodified to gain novel compound. In this work a series of amphiphilic polymersbased on β-CD （β-CD[P（AA-co-MMA）-b-PVP]） were synthesized by introducing thepoly（acrylic acid）-co-poly（methyl methacrylate）-b-poly（vinyl pyrrolidone） blockcopolymer to the primary hydroxyl group positions on β-CD. We discuss the molecular structure and micellization behavior of the polymer, and explore the drugloading characteristics of the model drug, drug release in vitro and drug tissuedistribution in vivo. The main contents are as follows:1. Dithiophosphate ester structure was introduced to the primary hydroxyl groupon β-CD using a simple one step reaction between carboxylic acid and alcohol in thepresence of P4S10. A series of macromolecular chain transfer agents with differentnumber of dithioester group on β-CD （three, four, five and six groups） were preparedby adjusting the number of the introduction of the dithioester groups. Through the"core-first" reversible addition-fragmentation chain transfer （RAFT） polymerizationapproach and the azobisisobutyronitrile as an initiator, the macroRAFT agents wereused to induce the RAFT polymerization of acrylic acid, methyl methacrylate andN-vinyl pyrrolidone, respectively, to obtain the multi-arm star copolymerβ-CD[P（AA-co-MMA）-b-PVP]. The chemical structures of RAFT agents andpolymers were characterized by FT-IR. From the results of pyrene fluorescence andTEM measurement, it was confirmed that these amphiphilic polymers couldself-assemble in aqueous media to form micelles. In addition, the critical micelleconcentration （CMC） of the polymers can be regulated from0.98×10-35.24×10-2g/L,indicating that the series polymer has good drug-loaded stability.2. Vinpocetine （VP）, as a model drug, was physically loaded into micelles byfilm dispersion method, solvent evaporation method and dialysis method. The effectsof methods on drug loading content and entrapment efficiency were investigated. Itwas found that the solvent evaporation method was the most suitable for thepreparation of VP-loaded micelles, with higher drug loading and entrapmentefficiency than the other two methods. For solvent evaporation method, the effects oftype of polymer, type of organic solvent, organic solvent to water ratio, dosage,polymer concentration, mixing temperature, stirring speed, stirring time and solventevaporation temperature were investigated. After that, the AM-PK111-4P1was choseto orthogonal optimization test with the factors of dosage, the amount of polymer,stirring time and stirring speed. A L16（45） orthogonal design was done to get the bestVP-loaded micelles process of drug dosage of25mg, amount of polymer of50mg, stirred for2h and stirring speed of1400rpm. Through the program drug loading andencapsulation efficiency of VP-loaded micelle were （21.44±0.14）%and （49.05±0.36）%, respectively.3. VP-loaded micelles were characterized by FT-IR, DLS and TEM. It wasconfirmed that VP package set out in the formation of polymer micelle nuclear. Theaverage particle size of the VP-loaded micelles was about65nm and the particle sizedistribution was narrow, and the micelles showed a good round on TEM. It wasshown that in certain sustained-release ability and pH-sensitive characteristics ofVP-loaded micelles having a faster release rate in the conditions of low pH （pH4.5） inin vitro release studies. Differences in the release rate of the VP micelles prepared bydifferent polymers were presented.4. Two kinds of polymer were selected to studies of in vivo pharmacokinetics andtissue distribution in rats, and commercially available VP injection was as control.The results showed that, compared with the commercial VP injection, VP-loadedmicelles have obvious lung targeting, and other organizations within the drugconcentration in the injection group at the same level.Overall, the series of multi-arm star copolymers based on the β-CD has a certainapplication prospect which worthy of in-depth study. |
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