Design And Synthesis Of Functional Hyperbranched Polyethers And Their Bio-applications

Hyperbranched polymer is one novel kind of three dimensional topological macromolecules possessing highyly branched architectures, many inner cavities and aboundant terminal functional groups. It has gained much more attention due to its unique molecular structure and properties. Up to now, many reaction methods were used to prepare hyperbranched polymer, such as polycondensation, self condensing vinyl polymerization (SCVP), ring-opening multibranching polymerization (ROMBP), all of which facilitated the development of hyperbranched polymers. And also, great progress has been made in the characterization,modification, functionalization of hyperbranched polymers, especially in its bio-application, including drug delivery, gene transfection. In this dissertation,hyperbranched polyethers with great biocompatibility are well-considered, and modified via various synthetic routes to achieve the polyfunctionality of hyperbranched polyether in biology. The details and main results are shown as follows:1. Fabrication and Application of Tumor pH-Responsive Polymer-Platinum(?)Complex from Carboxyl-Modified Hyperbranched Polyether and Cis-Dichlorodiammineplatinum(?)A hydrophobic hyperbranched polyether (HPMHP) was synthesized by the cation ring-opening polymerization. To realize the pH-targeting delivery of antitumor drug cis-dichlorodiammineplatinum(?) (cisplatin, CDDP), a tumor pH-responsive polymer-platinum(?) complex (Suc-HPMHO-CDDP) from carboxyl-modified hyperbranched polyether (Suc-HPMHO) and cisplatin was designed and prepared.Because of the existence of hydrophobic core and ionization of surface carboxylic acid, Suc-HPMHO showed reversible pH-response in aqueous solution, and its responding pH value could be readily adjusted by only changing the degree of carboxylation of Suc-HPMHO. With plenty of terminal carboxyl groups,Suc-HPMHO could form the complex with CDDP by substituting the chloride ions with carboxyls. Methyl tetrazolium (MTT) assay showed Suc-HPMHO had low cytotoxicity, while Suc-HPMHO-CDDP complex presented a similar antitumor effect with the free CDDP. Under the tumor acidic pH (pHe), Suc-HPMHO-CDDP complex deposited around/in cells because of its pH-response. Therefore, the pH-targeting of Suc-HPMHO-CDDP complex to tumor tissue was realized. All of these results show that the tumor pH-responsive Suc-HPMHO-CDDP complex is a potential pH-targeting drug delivery system in cancer therapy.2. Cationic amphiphilic hyperbranched polyether for gene deliveryHydrophobic hyperbranched polyether (HPMHO) was modified into Amine-HPMHOs with N,N,-carbonyldiimidazole (CDI) and ethylene diamine (EDA)successively. The structure and properties of Amine-HPMHO was characterized by NMR, FTIR, UV-vis. Due to the existence of hydrophobic core and protonation of surface amine groups, Amine-HPMHO is amphiphilic and can show reversible pH-response in aqueous solution. Its biocompatibility was tested by MTT and showed much less cytotoxicity than HPEI which is widely used in gene delivery system.Moreover, as a polycation, its DNA condensation ability was examined by agarose gel electrophoresis (GE), transmission electron microscope (TEM). Amine-HPMHO displayed high transfection efficiency in COS-7 cells.3. Backbone-Thermoresponsive Hyperbranched Polyglycerol by Random Copolymerization of Glycidol and 3-MethyI-3-(hydroxymethyl)oxetaneHyperbranched polyglycerol analog, hyperbranched poly[glycerol-co-3-methyl-3-(hydroxymethyl)oxetane] [HP(G-co-M)], was synthesized in one-step by random copolymerization of glycidol and 3-methyl-3-(hydroxymethyl)oxetane (MHO). The obtained polymer exhibited a thermo-responsive behavior in an aqueous solution, and the correspondent lower critical solution temperature (LCST) could be readily adjusted by changing the feed ratio of glycidol to MHO. The MTT assay against COS-7 cells demonstrated that HP(G-co-M) had low cytotoxicity. Moreover, the existence of numerous hydroxyl terminals of HP(G-co-M) facilitated their further modification and functionalization.All of these characteristics suggest that this novel backbone-thermoresponsive hyperbranched polyglycerol is a promising functional material for biomedical applications.4. Hyperbranched polyether for protein deliveryAs a novel kind of three dimensional topological macromolecules with highly branched architectures and great biocompatibility, hyperbranched polyethers have become gained much potential in protein delivery, such as protection and elongation of activity. In this research, hyperbranched polyglycerol was modified into NHS-HPG with succinic anhydride and N-hydroxysuccinimide, and conjugated with a variety of enzymes to form HPG-Enzyme complexes, which have minus zeta potentials and maintain 70-80% catalytic activity compared with the native enzymes. Native Alcohol oxidase (AOx) is an enzyme which can oxidize alcohol but shows poor alcohol detoxifying effect in vivo experiment. After conjugating with HPG, the HPG-AOx performed as alcohol antidotes very well both orally and intravenously, and the blood alcohol concentration (BAC) of mice reduced dramatically showing great alcohol detoxifying effect. Even 48 hour later after HPG-AOx uptake, the mice still showed resistant to alcohol.