Study On PH - Sensitive Block Copolymer Micelles Of Docetaxel

Amphiphilic block copolymers Poly（2-ethyl-2-oxazoline）-Poly（D,L-lactide）（PEOz-PLA） with EOz/LA molar ratio ranging from 0.37 to 1.05 were synthesized by two-step ring-opening polymerization and characterized by FTIR and ¹HNMR.The number-average molar mass（Mn）of the three copolymers,determined by Gel permeation chromatography（GPC）,are 6491,8357,12504, respectively.The copolymer solubility test suggested that the copolymers had good solubility in most solvents but saturated hydrocarbon.The critical micellar concentrations（CMC）of the copolymers were measured by Pyrene Fluorescent Probe Technique.The results showed that the CMC of the three copolymers ranged from 0.9×10^-3to 3.3×10^-3g.L^-1,and decreased as the length of the hydrophobic block increased.Fill dispersion method was used here to prepare blank PEOz-PLA micelles.A Nicomp-380 laser particle sizing system was exploited to determine the particle size of the micelles.The results showed that the blank micelles had mean diameters of 20 to 46nm,depending on the type and dosis of the organic solvent and the length of hydrophobic segment of the copolymers.Transmission Electron Microscopy（TEM）showed that the micelles had a globular shape and well dispersed.The Zeta potential of the micelles was determined as 1.19 mV by a Zeta potential analyzer.In weak acid condition,the particle size and the CMC value of PEOz-PLA micelles increased,which proved the pH-sensitive self-assembly of the PEOz-PLA micelles.Docetaxel was chosen as the model drug,and its in vitro assay method was established.Film dispersion method and dialysis method were investigated by measuring entrapment efficiency and size of the micelles.The results indicated that the micelles which prepared by film dispersion method had higher entrapment efficiency and smaller particle size.By preparing micelles in different conditions,we investigated the influence of formula factors on drug loading.The result suggested that reducing the acetone dosis,as well as increasing the length of the hydrophobic block, helped to improve the drug loading of the micelles.Compared with blank micelles,drug-loaded mieelles showed no significant differences in its morphous,particle size and Zeta potential.The stability experiments showed better stability of the micelles stored in 4 ^C refrigerator than those stored under room temperature.By dialysis method,we studied the drug release behavior of doeetaxel PEOz-PLA micelles,and found that the increase of the drug loading content and the length of hydrophobic block would lead to a delay of docetaxel release.The pH value of the PBS solution was another important influential factor.In pH 7.4 surroundings,drug was released in a sustained manner from the micelles,while in pH 5.0 PBS,drug was released more rapidly,which suggested the pH-sensitive drug release behavior of the PEOz-PLA micelles.Finally,we established an assay method for docetaxel in plasma,and studied the pharmacokinetic properties of PEOz-PLA micelles.Compared with docetaxel solution,docetaxel PEOz-PLA micelles administrated by i.v.c could significantly extend the circulating time of Doctaxel in plasma,which indicated the excellent in vivo sustained-release and long-term circulating capability of PEOz-PLA micelles.Among the three block copolymerie micelles,the PEOz-PLA-0.37 micelles revealed the best long-circulation capability,then came the PEOz-PLA-0.67 micelle,and PEOz-PLA-1.05 was relatively the worst.According to this result,it can be concluded that the extension of the hydrophobic segment would depress the long-circulation capability of the micelles.