Preparation And Evaluation Of Paclitaxel Polymeric Micelles

Paclitaxel is a widely used chemotherapy drug which has an extremely low solubility in water, approximately 1mg·L^-1. At present, Paclitaxel injection （Taxol） is the main formulation of paclitaxel clinically, yet its component Cremophor EL could trigger the release of histamine and cause acute allergic effect which may lead to death when severe. To solve the problem of insoluble drug administration and to increase the drug effect, a formulation named Paclitaxel Polymeric Micelles （PPM） with comparative stability was developed. As a bio-compatible carrier, this preparation can not only increase the solubility of insoluble drugs but also improve the curative effect.In this thesis, the new paclitaxel nano micelle system composed of phospholipid and a novel adjuvant Solutol HS15 as mixed drug carrier was developed. After diluted by physiological saline, the particle size of the micelle drug system was measured by DLS, and formulation with effective particle size of the range from 110nm to 120nm was selected to perform the following experiments. TEM pictures demonstrated that the nano particles were spherical. The result of high-temperature acceleration experiment displayed that the preparation had a satisfactory stability and inferred a two-year shelf life.In this thesis, we used in vivo optical imaging technique to inspect the anti-tumor effect of PPM, and at the same time, we also studied the drug effect in traditional method so as to contrast these two methods. The two methods had similar results which displayed that PPM preparation had a better anti-tumor effect which was 72.56% than Taxol （58.28%）. In the survival time test of bearing B16 melanoma cell C57 mice, group PPM had a mean survival time 31.7d, which was longer than group Taxol （27.4d）. The acute sensitivity test displayed that the mice in group PPM had slighter anaphylactic reaction and quicker recovery than group Taxol. In acute toxicity tests (testing the evaluation of LD₅₀), LD₅₀ of PPM preparation was 43.2 mg·kg^-1, higher than Taxol which was 33mg·kg^-1, and this result meant that the safety of PPM preparation had been improved.HPLC was applied to measure the body distribution of paclitaxel in the bearing cancer mice. As a result, in heart, liver, kidney and tumor, the paclitaxel distribution value of group PPM had significant difference contrast to the group Taxol. However in spleen and lung, there were no significant differences. In hearts, the paclitaxel distribution value of group Taxol was higher than group PPM, however in tumors, the paclitaxel distribution value of group PPM was higher than group Taxol. In addition, in vivo imaging technique was applied to test the distribution of the drug delivery systems in the mice, using two preparations marked by DiR, a lipid soluble dye. The result showed that PPM preparation had some drug carrier enrichment in tumor, and reduced the heart distribution so as to reduce the toxicity of heart.