| Recently, the long-circulating liposomes mediated by folate receptor have attracted considerable attention as drug targeting delivery. In present study, Docetaxel (DTX) was used as a model drug and used to prepare DTX loaded long-circulating liposomes and DTX loaded long-circulating solid lipid nanoparticles. The effect of some factors on the formulations and preparation of these two long-circulating nanocarries was investigated. Furthermore, the response surface methodology was used to optimize these two long-circulating nanocarriers. The long-circulating liposomes mediated by folate receptor were also prepared. The targetability and growth inhibition of immunoliposomes on MCF-7 cells in vitro and Balb/c nude mice in vivo was also studied.The long-circulating liposomes were prepared with DTX and the effect of some factors on the encapsulation efficiency was investigated. Then the formulation was optimized by the response surface methodology. Finally, the long-circulating liposomes were prepared by SPC: DTX (20:10,SPC:Chol(3:1),3% of SPC in water and 5% molar ratio of SPC with the encapsulation efficiency of 90.42±3.25% and the particle distribution of 117.6±5.34 nm. The liposomes were single unilamellar vesicles and spherical under TEM. The cumulative release within 24 h was 62.3±3.12%, and the release rate of liposomes raised in rat plasma. To store for long time, the long-circulating liposomes were freeze-drying.The long-circulating solid lipid nanoparticles were prepared with DTX and the effect of some factors on the encapsulation efficiency and particle size was investigated. Then the formulation was optimized by the response surface methodology. Finally, the long-circulating SLN were prepared by 5% in water,,5% of emulsifier in water (SPC:F68 1:1),lipid/DTX (20:1),7% of DOPE-PEG with the encapsulation efficiency of 93.1±4.3% and the particle distribution of 136.4±11.2 nm。The SLNs were spherical under TEM. In water with Tween-80 (0.5%),30% of DTX was released within the first 2h, however, DTX didn't release completely at the 24th h.Chol-PEG-Folic acid (Chol-PEG-Fol) was synthesized and analyzed with IR, NMR. Using Chol-PEG-Fol, the long-circulating liposome mediated by folate receptor (Fol-PEG-DTXL) was prepared and investigated.Results of flow cytometer and fluorescence microscopy, suggested the liposome internalized in cells mediated by folic acid. Fool-PEG-DTXL was more catatonic on MCF-7cells than PEG-DTXL (P<0.01), when cytotoxicties were compared for Hela cells, no significant differences were observed between Fol-PEG-DTXL and PEG-DTXL (P>0.05), suggesting that Fol-PEG-DTXL showed relative selective cytotoxicity on MCF-7 cells. The additional folic acid reduced the cytotoxicity on MCF-7 cells, but no effect on Hela cells. Using Balb/c nude mice bearing MCF-7 cells, we compared the antitumor efficacy of liposomal DTX and DTX. The treatment with DTX, liposomal DTX inhibited primary tumor growth of MCF-7cells compared with the control group. Furthermore, five injections of Fol-PEG-DTXL resulted in substantial tumor regressions, and tumor regressions in the Fol-PEG-DTXL group were significantly greater than in the non-targeted groups (P<0.05) and far superior to the control PBS treatment (P<0.01). The antitumor efficacy of Fol-PEG-DTXL was 67.6%.The pharmacokinetic parameters of Fol-PEG-DTXL were studied in Wister rat. The t1/2 of DTX, DTXL and Fol-PEG-DTXL were 1.157 h,3.08 h, and 7.795 h, respectively. The t1/2 of Fol-PEG-DTXL was 6.74-fold to DTX, and 2.66-fold to DTXL. MRT0-t and MRT0-∞of Fol-PEG-DTXL were 5.5-fold and 5.26-fold to DTX,3.32-fold and 3.10-fold to DTXL These results suggested Fol-PEG-DTXL reduced the toxicity of DTX. The results of biodistribution in mouse suggested docetaxel solution distributed rapidly and extensively, could somehow penetrate the blood brain barrier, and cause acute and chronic cardiac toxicity. Compared to DTX and DTXL, Fol-PEG-DTXL enhanced the time in blood. DTX distribution in heart,brain and kidney were decreased, which could depress DTX side effects on these organs.
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