| Cancer has been one of the main diseases,which has seriously threatened human health. Chemotherapy is playing an important role in treatment of malignant tumors.However, the use of chemotherapeutic agents is frequently associated with severe negative-side effects,due to systemic distribution.Targeting a desired site of action would not only increase the therapeutic efficiency of the drug,but also allow a reducing in the amount of drug administered,thus minimizing side effects.Therefore,targeting anti-tumor drug delivery system is currently one of the most active areas in the field of cancer research.The magnetic drug targeting carrier mainly consists of three parts,magnetic nanoparticles,supplement material and the drug,itself which uses a magnetic field to direct and locate the cancer in order to target drug delivery.Biopolymer molecules such as albumin,starch,and chiston have been used as supplement of magnetic targeting anti-cancer drug carriers because of their biocompatibility and biodegradality. Cyclodextrins are cyclic oligosaccharides.The three-dimensional structure forms a truncated cone and provides a cavity,which presents a cavity with the appropriate size to accommodate another molecule,thus forming an inclusion compound through host-guest interactions.2-hydroxypropyl-β-cyclodextrin(HP-β-CD)is a derivation ofβ-cyclodextrin and has been already approved as oral medical supplement materials by the FDA and SFDA.The FDA also warrants HP-β-CD in intravenous administration.The properties of HP-β-CD on the capability of lower kidney toxicity,less sitmulation and hemolysicity indicate that it can be used in the supplement material of magnetic targeting anti-cancer drug delivery.It is significance to investigat the relative between HP-β-CD and anti-cancer drug to evaluate the application of HP-β-CD as a magnetic targeting drug cartier.The aim of this study is to investigate the theoretical question of doxorubicin/HP-β-CD inclusion complex,its anti-cancer activity in vitro and mechanism of anti-cancer activity.Synthesis of magnetic HP-β-CD composite nanoparticles and evaluate doxorubicin loaded efficiency and drug release in vitro.We also investigated the morphology of rats and the biological distribution of the doxorubicin-loaded composite nanoparticles in the rat bearing liver cancer.Herein,doxorubicin/HP-β-CD inclusion complex was prepared by lyophilizing aqueous solutions of the complexes.The physical-chemical methods(NMR,DSC,XRD,FTIR) were used to character the formation of the inclusion complex.A computer simulation method was applied to construct drug molecular and HP-β-CD molecular structure domain;structure energy was optimized through molecular mechanics,molecular dynamics and quantum chemistry of the different procedures(including PM3 and AM1). The result of fluorescence spectrum titration showed that the combinative ratio of doxorubicin and HP-β-CD was 1:1 and the inclusion constant was 2.08×104 M-1.The photostability of doxorubicin was examined in aqueous solutions in different HP-β-CD concentrations.The result showed that HP-β-CD delayed the photo-degradation of doxorubicin,the degradation constant of doxorubicin in the presence of HP-β-CD cavity (k0=0.0947 h-1)was more than 3 times lower than the degradation of doxorubicin in the absence of HP-β-CD(Kc=0.0344 h-1).The mechanism of anti-tumor activity of doxorubicin/HP-β-CD inclusion complex was investigated in vitro using MTT method,gene expression microarray and the morphology observation to detect the anti-tumor activity of doxorubicin/HP-β-CD inclusion complex on cancer cell line(Walker-256).The results showed that the activity of doxorubicin/HP-β-CD inclusion complex inhibited the growth and proliferation of cancer cells and more effective compared to doxorubicin after treated with doxorubicin/HP-β-CD inclusion complex and doxorubicin separetely,The gene expression profiling of Walker-256 cells were anaylized,Difference of gene expression profiling were revealed in cell cycle,apoptosis,DNA synthesis,as well as signal transduction aspects.The result indicated that HP-β-CD could increase doxorubicin-inducing Walker-256 into apoptosis; it's one of main reason that increases doxorubicin treatment effiency.HP-β-CD was introduced to the surface of magnetic nanoparticles(MNps)in the presence of NH3·H2O to synthesize magnetic HP-β-CD composite nanoparticles.The results showed that the iron content in the composite nanoparticles was 55.4%.The size of range of magnetic HP-β-CD composite nanoparticles was 10-20 nm.The magnetization was 59.9 emu/g.The capacity of composite nanoparticles for doxorubicin adsorption is 87.8μg/mg after incubated for 72 h.The cumulative percentage of released doxorubicin in 1 d,4 d,10 d were 35.5%,49.3%,76.5%,respectively.Thus,the magnetite HP-β-CD composite nanoparticles could be a potential carrier in the magnetic targeted drug delivery.Sprague-Dawley rats were injected with magnetic HP-β-CD composite nanoparticles by portal vein.The rats were killed at 24 h,14 d and 1 month after injection.Liver and lung were dissected and stained with hematoxylin and eosin for histopathological analysis. Light microscopy analysis revealed HP-β-CD composite nanoparticles were preferentially driven towards the liver,accompanying with inflammation.However,the inflammatory process reduces as a function of time,and it is a reversible process.And the concentration of doxorubicin in the liver of rat beating liver cancer was higher in concentration compared to lung,heart and kidney.In conclusion,the magnetic HP-β-CD composites nanoparticles is promising prospect of carrier for targeting drug delivery.
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