The Study Of Long-circulating Thermo-sensitive Liposome Containing Paclitaxel

Objective: At present, cancer is still one of the diseases that have the highest fatality, which threaten the life of human beings seriously. There is a great deal of studies on anti-tumor drugs. In the recent years, scientist paid close attention to liposome, as it has the advantages of increasing the therapeutic effect, reducing toxicity, no toxic and having no immunosuppression. However, the common liposome did not have the ideal targeting effect, it was instability in vivo and there existed some questions upon the store. These disadvantages limited its industrialization and application in clinical. Long-circulating thermo-sensitive liposome was a new kind of liposome that has a targeting for heat. When aiti-neoplastic agents were encapsulated in liposome, as the tumor site was heating, not only the circulating time was prolonged, but also the drug release was increased at the tumor site, so the anti-tumor effect was improved.Paclitaxel is thus far one of the most effective anticancer drugs available on the market. It has shown substantial clinical efficacy for ovarian, breast, colon, head and neck and non-small cell lung cancers. However, paclitaxel is poor soluble in water and therefore, clinical administration is currently formulated in a 1:1 mixture of Cremophor EL, a polyethoxylated castor oil, and ethanol. This formulation is associated with a series of significant vehicle related toxicity in the clinic. This give the patients much painful and limite its application in clinical. In this study, we selected the anti-tumor agent paclitaxel as the model drug, and prepared the paclitaxel long-circulating thermo-sensitive liposome (PLTL). Expect of changing the release characteristic of liposome in vivo, increasing the therapeutic effect, reducing the toxic and side effects in the whole body, so as to ease the pain that the cancer patients are suffered in a certain extent.Methods: The liposome was prepared by the thin film evaporation and poly- carbonate membrane extrusion method. We read some references and did the preliminary experiment, and then the formulation and prepare process were studied. The encapsulation efficiency, the vesicle size and the lyophilization of the liposome were investigated among the experiment. We studied the characteristics of the liposome, including the physical and chemical properties, the stability, pharmacodynamics and pharmacokinetics.Results: In this study, we determined the formulation and technology through selecting the kind and ratio of phospholipids, lipid-to-drug molar ratio, the kind and concentration of lyophilization, and the lyophilization process. The encapsulation efficiency of the liposome was above 90%, and the mean particle size of the liposome was about 100 nm. The stability research revealed that the liposome remain stable for at least 72 h at room temperature. The research of pharmacodynamics demonstrated that PLTL has a significant difference compared to the control groups (p<0.05). The tumor inhibition of the PLTL was 74.07%.The pharmacokinetics results revealed that, the vivo behavior of the PLTL in the SD rat complied with the three compartment model. From differences of the main parameters of PLTL and Paclitaxel injection (IJ), we can see that there are significant differences of pharmacokinetic behavior in vivo of two preparations. The t1/2α,t1/2β,t1/2pi and AUC of PLTL are 5.77,5.42,1.96 and 4.04 times, respectively, than IJ. This demonstrated that, when given the same dosage, the elimination of PLTL is much slower than IJ. The long-circulating liposome can maintain a longer time in vivo, so that have much more chances to get the target site and achieve the target effect. The Vd and Cl of IJ are 1.36 and 4.07 times than IJ, demonstrated that the elimination of IJ is much faster than PLTL. The pharmacokinetics results revealed that, compared to the paclitaxel injection, PLTL can significantly prolong the circulation time in vivo, demonstrated that PLTL has an significant long-circulating effect.Conclusion: The prepare technology in this study was stable and repeatable, and the liposome we prepared had a satisfactory characteristic. The study in vivo demonstrated that PLTL can prolong the circulation time and can improve the tumor inhibition efficacy.