| Thermosensitive hydrogel, due to its special temperture-sensitive, has a wide applications in drug controlled and release, biomaterial and pharmaceutical systems. Chitosan thermosensitive hrdrogel is a hotspot in thermo-sensitive gel studies. Because of insoluble in water, the applications of chitosan has been limited. HTCC, quaternized chitosan salt (QCS)is a derivate of chitosan, synthesized with the aid of a substituent containing a quaternary ammonium group. Compared with chitosan, QCS shows better solubility, moisture retentiveness, antimicrobial ativity, absorptive property, and cell proliferative capacity than CS. Therefore, preparing a hydrogel based on HTCC and glycerophosphate (GP) was potential as an intelligent drug delivery carriersFirstly, we investigated the preparation and characteristics of thermosensitive hydrogel based on quaternized chitosan. The effect of quaternized chitosan concentration, relative amount and incubation temperature on the gelating time was investigated by tube reverse method, the kinetics of phase change was determined by optical density assay during incubation, and the drug release in vitro was carried out via dialysis method. When the ratio of56%GPS/2%HTCC was0.2, and the temperature was37℃, a good gelating time was3.53minutes.Secondly, we studied on different preparations and influencing factors of doxorubicin liposomes, and the drug encapsulation efficiency was determined via cationic exchange resin. Doxorubicin liposomes were prepared by (NH4)2S04-gradiend method. When the concentration of ammonium sulfate was0.3mol/mL, the rate of drug and lipid was0.1, the incubation time was20min, and the incubation temperture was40℃, drug encapsulation efficiency higher was more than90%;Thermosensitive hydrogel containing drug-loaded liposome delivery system offered the possibility of reduced dosing frequency and sustained drug action. In the study, a soluble chitosan derivative, N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride (HTCC), was used and interacted with glycerophosphate (GP) to produce a thermosensitive hydrogel as the matrix of doxorubicin-loaded liposomes. The formulation could retain the liquid state with good fluidity below or at room temperature for long time but turned into a non-flowing gel after placed in body temperature in several minutes. The entrapment efficiency of doxorubicin in liposomes was not discounted by the hydrogels, which was over90%. In vitro drug release using membrane-less method showed that the erosion of doxorubicin gels was faster than liposomal gles while the drug release was slower than liposomal gels, suggesting liposomes could increase the gels strength and the interaction between GP and doxorubicin could delay the drug release. The in vitro release experiment performed with a dialysis membrane model showed that the liposomal gels exhibited the longest drug-release period compared with the liposome, general gels and the mixture of doxorubicin-HTCC. The initial burst release was disappeared in liposomal gels and it only released less than30%loaded drug in9days. The liposomal hydrogel in rats cannot be eliminated more than28days. In vivo antitumor activity was evaluated by the survival time of H22-bearing mice treated with various doxorubicin formulation, which showed that the hydrogels enhanced the antitumor activity and reduce the system toxicity. Thus, all these results showed that the thermosensitive hydrogel with embedded liposomes is a promising antitumor drug carrier for topical cancer therapy. |
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