Studies On The DTX-loaded Polymeric Micelles

Docetaxel (DTX) is an antineoplastic agent belonging to the second generation taxane derived from the needles of the European yew tree, Taxus baccata. The synthesis of DTX starts from10-deacetylbaccarin III, an inactive precursor compound isolated from the needles of European yew tree. It shows2-to4-fold higher than paclitaxel as an inhibitor of microtubule depolymerisation in vitro. It is one of the most active chemotherapeutic agents for treating various human malignancies including ovarian cancer, advanced and metastatic breast cancer, non-small cell lung cancer and prostatic carcinoma. In addition, combination of DTX with certain cytotoxic drugs has a synergistic antitumor effect.As DTX is poorly water soluble (3μg/mL), DTX is dissolved in the non-ionic surfactant Tween80. Presently, the only available commercial formulation (Taxotere(?) or Duopafei(?)) for clinical use contains40mg/mL docetaxel and1040mg/mL Tween80and requires further dilution with13%ethanol before addition to the intravenous infusion solution. However, this system has been associated with serious adverse reactions due to either the agent itself or to the solvent system and it is necessary to receive premedication with antihistamines and glucocorticoid. What’s more, it interferes with the normal binding of DTX to serum proteins in a concentration dependent-manner and can change the pharmacokinetics of DTX in vivo. The drawbacks associated with the presence of Tween80in the formulation of DTX encouraged researchers to develope a formulation that could increase the drug solubility while avoiding the use of Tween80. Thus, the development of Tween80-free formulation has become the hot-spot of research. Since polymeric micelles were first proposed as drug carriers by Bader et al. in1984, they have been the object of growing scientific attention. Polymeric micelles are characterized by a core-shell structure self-assembled from amphiphilic polymers in aqueous media and typically have diameters ranging from10to100nm. They can solubilize poorly water-soluble drugs into their hydrophobic inner core and improve the bioavailability of hydrophobic drugs. Moreover, the use of polymeric micelles often allows for achieving extended circulation time, favorable biodistribution and lower toxicity of the drug. In some cases, passive targeting is achieved via the enhanced permeability and retention (EPR) effect.In this paper, we firstly describe the preparation of DTX-loaded pluronic F68micelles. The micelles were prepared by nano-precipitation methods. Based on the results of single factor experiments, the formulation was optimized by the orthogonal design. The encapsulation efficacy (EE%) and drug loading (DL%) were determined by RP-HPLC method. The physicochemical characteristics were evaluated, including the surface morphology, particle size and size distribution as well as zeta potential. The in vitro release behaviors of the micelles were carried out by the dynamic membrane dialysis technique. The results showed that before freeze-dried the drug-loading rate and entrapment rate were0.060±0.003%and89.10±1.50%, respectively. The micelles were spherical or approximately spherical with the mean particle size of135.1±3.42nm and the zeta potential of-10.56±3.52mV. After freeze-dried, the drug-loading rate and entrapment rate were0.052±0.006%and83.23±2.34%, respectively. The micelles were spherical or approximately spherical with the mean particle size of183.69±5.23nm and the zeta potential of-15.34±2.12mV. The in vitro release behaviors followed the Weibull equation: lnln(1/(1-Q/100))=0.65881nt-1.6394(r=0.9795).After some experiments before, and found that the drug of F68perlong Nick is too small, and can’t meet the body dynamics experimental and clinical requirements, so in the search for a large number of documents and do a lot of after the experiment you, and finally determined that choose vitamin E TPGS do increase solvent, preparation of polymer mixed glue. The results show that, to join TPGS, average seaied rate was93.24%, and the average drug loadings is0.923%, micellar drug loadings increased significantly, and better stability. For experimental animals with rabbit, determination of blood drug concentration, pharmacokinetic studies. The body dynamics experimental results show that the polymer micelle can delay the west more than his metabolism, a long time to maintain the high concentration, and accord with2rooms model.To sum up, the subject was successfully achieved much west he "micelle, preparation technology was simple and feasible, spherical shape or form of spherical, small size and distribution is uniform. Before and after freeze-drying micelle physical and chemical properties of no change, can improve the stability of freeze preparation, beneficial to the long-term storage. The body dynamics that can delay the release of glue, side effects of small.