Hyperbranched Polyglycerol Derivatives For Drug And Gene Delivery

Now gene and drug carriers are one of important research fields in biomedical application, which can delivery drug and gene into lesion location for treating the disease of human. We have got some significant achievement. However, there are still a lot of issues, such as the drug burst release and instability of traditional micelles, high toxicity and side effect, the low transfection of cationic polymer gene delivery, the unsatisfied efficacy of individual gene therapy. On the other hand, when gene and drug carriers enter the human body by the intravenous injection, they will interact with blood tissue more or less, but there are few reports on the evaluation of blood compatibility about them, which is a big difficulty in clinical application.Hyperbranched polyglycerol is a highly and randomly branched polymer, which is characterized by the combination of a loose and stable polyether scaffold, a large number of end hydroxyl groups. Moreover, they are synthesized easily, and they are also promising biomaterials owing to their high water solubility, high chemical reactivity, high biocompatibility(similar or even much better than linear PEG), especially the better blood compatibility, and thermal and oxidative stability(more stable than linear PEG). In view of this, various functional hyperbranched polymers based on HPG have been constructed by modifying the terminal hydroxyl group of HPG, so that they can efficiently delivery drug or gene into cells and play an important role in solving the scientific problems. Specific studies of this thesis mainly consist of two parts and are given as follows: 1. Amphiphilic hyperbranched polyglycerol derivatize for drug delivery of docetaxel toanti-tumourAn amphiphilic hyperbranched polyglycerol derivative(HPG-C18) of trimethylolpropane as the core characterized by 1,2-epoxyloctadecane is synthesized through the anionic ring-opening copolymerization, and its physical and chemical properties are well analyzed by 1H NMR, gel permeation chromatography(GPC), dynamic light scattering(particle size and ζ-potential), TEM and so on. The obtained HPG-C18 can form the large size complex micelles aggregating from many 5-30 nm unimolecular micelles. The complex micelles show a good stability in aqueous solution. Due to its amphiphilic property, HPG-C18 is used to load hydrophobic docetaxel, a clinical antitumor drug, to inhibit MCF-7 cells proliferation. Moreover, its blood compatibility is also studied by hemolysis analysis, red blood cells observarion, thromboelastography, APTT and PT assay. These results indicate that HPG-C18 can inhibit MCF-7 cells effectively, meanwhile has good blood compatibility, suggesting a potential application in tumor therapy. 2. Based on amphiphilic hyperbranched polyglycerol derivatize characterized bydendritic poly(L-lysine) for drug and gene co-deliveryThe well-defined hyperbranched polyglycerol derivatives based on HPG-C18, named as HPG-C18-G3 and HPG-C18-G4, are synthesized by the modification of dendritic poly(L-lysine)(generation = 3) and dendritic poly(L-lysine)(generation = 4), and their physical and chemical properties are well characterized by 1H NMR, fourier transform infrared(FTIR), gel permeation chromatography(GPC), dynamic light scattering(particle size and ζ-potential), TEM and so on. The obtained products are studied for DNA binding and transfection. It is found that, HPG-C18-G3 and HPG-C18-G4 both exhibit strong DNA condensation. In vitro transfection analyses, the transfected cell numbers of HPG-C18-G3 are approximately similar to PEI, and the transfected cell numbers of HPG-C18-G4 are much more than PEI. HPG-C18-G3 and HPG-C18-G4 are also explored to load the hydrophobic docetaxel, which can inhibit MCF-7 cells proliferation. In vitro cytotoxicity of HPG-C18-G3 and HPG-C18-G4 on MCF-7 cells are both lower than PEI. Moreover, their blood compatibility is also studied by hemolysis analysis, red blood cells observarion, and thromboelastography assay. These results indicate that HPG-C18-G3 and HPG-C18-G4 have good blood compatibility at a low concentration, but they are unsafe at a high concentration, which provides a very important guiding significance for clinical research application in the future.