Study On The Adhesive Polymorphism Of Adriamycin Temperature / PH Unsensitive Self - Assembled Block Copolymer

A novel temperature and pH sensitive polyhistidine-co-DL-lactide-co-glycolide-polyethylene glycol-polyDL-lactide-co-glycolide-co-histidine block copolymers were synthesized and characterized by FT-IR and 1H-NMR. The number-average molar mass (Mn) of the two kinds of copolymers determined by Gel Permeation Chromatography (GPC) were 16634 and 20227, respectively. The number-average molar mass (Mn) of PLGA-b-PEG-b-PLGA segment in the two copolymers was 10734. The critical micellar concentrations (CMC) of the copolymer at different temperatures were measured by Pyrene Fluorescent Probe Technique. The CMC values of the copolymer ranged from 0.0224 to 0.0017μg·ml-1. The CMC values decreased as the temperature going up, which indicated that the self-assembly behavior of the copolymer in water was temperature sensitive.Dialysis method was employed to prepare blank micelles of OLH-PLGA-PEG-PLGA-OLH, and the Nicomp-380 laser particle sizing system was exploited to determine the particle size and the distribution of the micelles. The results showed that the blank micelles had mean diameter of 23.1±3.2 nm. Transmission Electron Microscopy (TEM) revealed that the micelles had a regular globular shape, the similar size and good dispersion. The Zeta potential of the micelles measured by Zeta potential analyzer was-9.88 mv.Ddialysis method, film dispersion method and the dissolution method were investigated to prepare adriamycin loaded micelles, and the best method was dialysis method due to its highest entrapment efficiency. Single factor test results indicated that the type of organic solvent and drug feeding amount were main factors which greatly affecting the drug loading into the copolymer micelles. Compared with the blank micelles, drug-loaded micelles showed no significant differences in its morphous, particle size and Zeta potential. The results of drug dissolution test showed that drug release profiles from micelles exhibited obvious sustained-release characteristics, and drug release rate increased with the pH of release medium decreasing, prominently at pH5.0. These results indicated that drug release behavior from micelles was pH responded.The determination method of adriamycin in plasma was developed and applied to study the pharmacokinetic behavior of adriamycin-loaded OLH-PLGA-PEG-PLGA-OLH micelles. The T1/2 of the adriamycin injection was 12.508 h,while the corresponding data of the micelles was 20.545 h, adriamycin-loaded micelles distributed more quickly and eliminated more slowly, which indicated the excellent sustained-release behavior in vivo. A fluorescence photometry method was developed for the determination of adriamycin in mice’s biological samples. The tissue distribution of adriamycin injection and adriamycin-loaded copolymer micelles in mice after i.v.c administration were studied. The results revealed that the adriamycin-loaded micelles could significantly enhance the liver distribution, decrease the adriamycin’s distribution in heart and kidney and increase the adriamycin’s concentration in brain.