| In this paper, an inclusion-interaction assembly strategy was used to construct novel p H/redox responsive micelles for controlled release of 6-MP. At first, a hydrophilic ?-CD grafted carboxymethyl chitosan(CMCS-g-?-CD) and a dimer of 6-MP(DMP) was synthesized. After that, a novel amphiphilic inclusion complex(CMCS-g-?-CD·DMP) was prepared with the dimer being partially embedded into the cavity of ?-CD moiety. At last, it self-assembled into micelles in distilled water. Their structure and morphology were observed by transmission electron microscopy(TEM). The stability, p H-sensitivity and reduction-response of the micelles were investigated by dynamic light scattering(DLS). Their stimuli-responsive release properties and anti-tumor activity were also investigated. The main results of this paper were shown as follows:(1) CMCS-g-?-CD·DMP was synthesized and characterized by FT-IR, DSC and 1H-NMR.At first, CS and ?-CD were modified with chloroacetic acid to obtain CMCS and CM-?-CD. Then CMCS-g-?-CD was obtained via the formation of amide bonds between the carboxyl groups of CM-?-CD and the amino groups of CMCS. 6-MP was oxidized to obtain DMP. At last, CMCS-g-?-CD·DMP was synthesized with DMP partially embedding into the cavity of ?-CD moiety. The structure of CMCS-g-?-CD·DMP was confirmed by FT-IR, DSC and 1H-NMR analysis.(2) The amphiphilic inclusion complex self-assembled into core-shell micelles, with dimer as the core and polymer as the shell. Their structure and morphology were observed by TEM and their stability, p H-sensitivity and reduction-response were investigated by DLS.The amphiphilic inclusion complex self-assembled into p H/redox responsive micelles in distilled water. The TEM showed that these micelles had a core-shell structure with an average diameter of about 160 nm. DLS showed that the micelles were stable in water. The particle size changed with p H values and GSH concentrations, and reached a maximum diameter at p H 6.0 and 20 m M GSH respectively, exhibiting an obvious p H/redox responsibility.(3) Three kinds of buffer solutions were used to mimic extracellular fluids, intracellular environments of normal cells and tumor cells, respectively. The in vitro drug release behaviors of the micelles were investigated in these buffer solutions.Release profiles of 6-MP form the micelles showed a release rate of 27.3 wt% in p H 7.4 buffer containing 10 ?M GSH, and 88 wt% in p H 5.0 buffer containing 20 m M GSH, indicating that the micelle might be stable in bloodstream and rapidly release 6-MP when it entered into the intracellular environment of tumor cells. These results showed the micelles may be used for tumor-specific drug release. The release behaviors of micelles with different DMP contents were also investigated. The results indicated that the cumulative release rate of the micelles increased with the DMP content.(4) The anti-cancer activity of the micelles was investigated with He La cells using MTT method.In vitro test showed that CMCS-g-?-CD had little toxicity for He La cells, indicating a good biocompatibility, however, the micelles had a dose-dependent toxicity for He La cells, indicating that the micelles could be used for tumor-specific drug release. |
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