| In this study a series of amphiphilic polymers based onβ-CD (sPEL/CDs,sPEC/CDs) were synthesized by introducing the methoxyl poly(ethylene glycol)-polylactide (mPEL) or methoxyl poly(ethylene glycol)- poly(s-caprolactone) (mPEC) diblock copolymer to the primary hydroxyl group positions onβ-CD. By regulating the feed ratio of mPEG to PLA or PCL, the resultant sPEL/CDs with different PLA or sPEC/CD with different PCL content can be achieved. The chemical structures of these polymers were characterized by FTIR, ~1H NMR and size exclusion chromatograph (SEC). From the results of pyrene fluorescence measurement, it was confirmed that these amphiphilic polymers could self-assemble in aqueous media to form micelles. In addition, the critical micelle concentration (CMC) of the polymers can be regulated from 0.0092mg/ml to 0.01mg/ml by increasing the hydrophobic length to ensure the stability of micelles.Doxorubicin (DOX), as a model drug, was physically loaded into micelles by film dispersion method or o/w emulsion method. The effects of methods on drug loading content (LC) and entrapment efficiency (EE) were investigated. It was found that the LC and EE were both higher and the particle sizes were small when film dispersion method was employed. But this method is limited by the water solubility of the polymers. For o/w emulsion method, the LC and EE were both higher regardless of the property of the polymers. For o/w emulsion method, the effects of polymer/drug feed ratio and polymer composition were investigated. The LC was increased with increasing the length of hydrophobic segment. TEM image demonstrated that sPEL/CDs,sPEC/CDs polymeric micelles were regularly spherical with the mean diameters of 100-300nm. The in vitro release profiles indicated that DOX-release from micelles was accelerated by decreasing pH, which was quite suited to the physical microenvironment of tumor tissues. In addition, the release rate decreased as increasing length of hydrophobic segment and drug loading content. Compared to the sPEC/CDs with PCL as hydrophobic, the drug released faster from the sPEL/CDs polymeric micelles with PLA as hydrophobic.The MTT assay was used to test cellular cytotoxicity of sPEL/CDs and sPEC/CDs in vitro. It showed that the amphiphilic polymer based onβ-CD has good biocompatibility. The cytotoxicity of DOX-loaded micelles compared to that of free DOX was determined by MTT method combined with flow cytometry and confocal laser microscope. It showed that with the growth of hydrophobic chain, the cytotoxicity of drug loaded micelles was enhanced. Compared to free DOX, DOX-loaded micelles showed markedly improved the cytotoxicity to MCF-7/ADR cells, which indicated that it could reverse the drug resistance. Rhodamine-123 cellular uptake was determined to evaluate the polymer action on the inhibiting of P-gp. The results suggested that the polymeric micelles sPEL/CDs and sPEC/CDs exhibit comparative or greater inhibiting effect on P-gp as compared with CsA, an inhibitor of the P-gp.The in vivo pharmacokinetics in SD rats indicated that the DOX-loaded micelles can intended the half-life of DOX and raised the area under curve (AUC) obviously, suggesting that the polymeric micelles had the long circulation ability. The DOX-loaded micelles have great inhibiting effect to the B16 cell of the ICR mice.All these results suggest that the amphiphilic polymers based onβ-CD(sPEL/CDs,sPEC/CDs) exhibit potentials as carriers for anti-cancer drug delivery system, and it is worth in-depth study.
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