Study On The Modification Of Hyperbranched Polyethers, Drug Delivery And Properties

Hyperbranched polymers have attracted a great deal attention during the past two decades. The main interest in the early period of studies focused on synthesis of a large number of hyperbranched polymers with different molecular structures to study the branched structure and the related material properties especially. Many reactions including polycondensation, self condensing vinyl polymerization (SCVP), ring-opening multibranching polymerization (ROMBP) and other polymerization methods have been used to prepare hyperbranched polymers. Hyperbranched polymers contain a large number of teminal functional groups in their molecular structures. By modification of these end-groups, the properties of hyperbranched polymers such as glass transition temperature, solubility, melt viscosity and surface properties are significantly modulated to define mainly possible applications. Even though several application aspects of hyperbranched polymers, such as additives, catalyts, rheology modifiers, and coating resins have been explored successfully, the extensive applications of hyperbranched polymers are still blind in more fields. So it is essential to understand the properties of the highly branched and three-dimension globular molecular structure to obtain special applications. The application of hyperbranched polymer as durg delivery material is a novel and meaningful subject to study. In this paper, the hyperbranched polyether(HP) with low toxicity and biocompatibility is selected as drug carrier . The model drugs are hydrophobic Probucol(PRO), hydrophilic Aspirin(ASP) and gas drug Nitric Oxide(NO) with various characters. In addition, the degradation properties of this hyperbranched polyether and its derivatives bearing different end-groups are studied initially as they are basic for their further applications. The main contents including the following five parts: 1. The amphiphilic hyperbranched polyethers (HP-g-PEO) consisting of hydrophobic hyperbranched polyethers core and hydrophilic poly(ethylene glycol) arms was prepared by the cation ring-opening polymerization. A series of HP-g-PEO samples with different degree of branching (DB) were synthesized under various reaction temperatures. The structure of resulting HP-g-PEO was characterized by IR, 13CNMR and GPC. Nanoparticles were obtained by self-assembly of HP-g-PEO in aqueous media. Using hydrophobic drug Probucol (PRO) as model drug, the mean diameters of nanoparticles were less than 100nm, and exhibited uniform spherical formations and narrow size distributions. The drug loading efficiency (LE) and incorporation efficiency (IE) of PRO were achieved to 35% and 89%, respectively. The in vitro release of PRO from the nanoparticles exhibited a sustained release and the cumulative drugs released for more than 600h. With the DB of HP-g-PEO increasing, the size and size distribution of nanoparticles decreased as well as the release rate. Nanoparticle size and size distribution, LE, IE and drug release rate were slightly affected by the initial solution concentration of polyethers. Using hydrophilic Aspirin (ASP) as model drug,the results of TEM demonstrated the size of these drug loaded nanoparticles was in the range of 75¹30nm, and the size distribution exhibited a narrow pattern as characterized by dynamic light scattering (DLS). The maximum incorporation efficiency of ASP was about 25%. With the increase of DB, the mean diameters and distributions of nanoparticles decreased, and the size and size distribution of ASP loaded nanoparticles increased with increasing the initial solution concentration. The releasing behaviors of ASP could be modulated by the variation of the DB value and initial solution concentration. The results of in vitro drug release suggested that the nanoparticles self-assembly by HP-g-PEO performed good controlled release behaviors with potential practice as novelty drug delivery vehicles.2. The amphiphilic hyperbranched polyethers(HP-mPEG) were prepared through modified hydroxyl end groups by hydrophilic methoxy polyethylene glycol (mPEG) . The molecular structure of HP-mPEG was identified by IR, 1H-NMR and 13C NMR. The drug loading and releasing properties of these prepared nanoparticles for PRO and ASP were investigated. As for the loading of PRO, the drug loaded nanoparticles showed a narrow monodisperse size distribution and average diameter less than 200 nm. The drug loading efficiency (LE) and incorporation efficiency (IE) of these nanoparticles were achieved to 18 % and 90%, respectively. The in vitro release of PRO from the nanoparticles exhibited a sustained release and the cumulative drugs released for more than 450h. With the increase of mPEG chain length and modification degree, the mean diameter, polydispersity index and IE of drug loaded nanoparticles increased. In the case of ASP, the drug loaded nanoparticles had uniform spherical formation as determined by AFM . The best incorporation efficiency of ASP can achieve to 40%. ASP can release from the drug loaded nanoparticles for more than 100h. With the increase of chain length (molecular weight) and modification degree of mPEG, the mean diameters, distributions and incorporation efficiencies (IE) of nanoparticles increased, and meanwhile the loading efficiencies (LE) and the drug release rates decreased.3. Nitric oxide (NO) releasing hyperbranched polyethers (HP-g-DACA/N₂O₂) were prepared through a two-step procedure. The alkyltrimethoxysilane containing secondary amino groups(DACA) was reacted with the hydroxyl end groups of hyperbranched polyethers(HP) to obtain the precursor hyperbranched diamine (HP-g-DACA). Then HP-g-DACA was reacted with NO at 80psi pressure to be converted into nitric oxide (NO) releasing N-diazeniumdiolates. Using HP-g-DACA/N₂O₂ as NO donors, Ethylcellulose (EC) and chitosan (CS) as polymer matrix, polymer films were prepared. The NO releasing properties of N-diazeniumdiolate and the polymer films were also investigated. The release medium pH and temperature appeared to be the major driving force for the dissociation of HP-g-DACA/N₂O₂. The total amount of NO released from this diazeniumdiolate could achieve to 0.43μmol/mg and was proportional to the modified degree of HP by DACA. The total NO released from double films was greater than those of single films, but the release rate was slower. The NO flux on the surface of EC double films could maintain more than 1 mol-10*cm-2*min-1 for one week. The results of NO release profiles for HP-g-DACA/N₂O₂ doped polymer films indicated that the NO release properties could be controlled by the layers of films, composition of polymer matrix and the percentage of NO diazeniumdiolate doped into the films.4. Using Epichlorohydrin(ECH) and Diethylene triamine (DETA) as modifiers, secondary amines were covalently attached to the molecular of hyperbranched polyethers(HP) to synthesis the precursor for the further reaction with NO(HP-ECH-DETA). Then HP-ECH-DETA reacted with NO at 80psi pressure to be converted into the novel N-diazeniumdiolates HP-ECH-DETA/N₂O₂. The molecular structures of precursor and diazeniumdiolates were characterized by the means of FT-IR, 13C NMR and UV-vis spectroscopy. In UV-vis spectrum, the intensity of absorption at the characteristic wavelengh of -N₂O₂ decreased with time, illustrating the spontaneous decomposition of this new NO donor in aqueous solution. The total amount of NO released from HP-ECH-DETA/N₂O₂ was able to achieve to 0.75μmol/mg and increased with increasing the modification degree. With the addition of NaOMe in the reaction procedure of NO, the NO loading efficiency could be improved but the NO releasing rate corresponding increased. In addition, the NO releasing properties of EC films mixed with HP-ECH-DETA/N₂O₂ were studied. The results showed that the uniform mixture of NO donors and polymer matrix, the increase of film thickness and the decrease of NO donors'concentration can slow down the release rate of NO from the polymeric films.5. The degradation properties of a series of hyperbranched polyethers (HP) and their derivers (HP-HMDI-mPEG and HP-SA-mPEG) through modification of end groups were investigated initially. The HP can be oxidative degraded in the chlorine solution which was confirmed by the results of DSC. The influence of DB, concentration of chlorine solution and degradation time on the degradation properties of HP was studied. It demonstrated that the degradation rate could reach maximum at a certain DB value and could be modulated by DB. As the concentration of chlorine solution increased from 50ppm to 400ppm. And the degradation procedure involves three steps according to the degradation time. The hydrolysis properties of modified products HP-HMDI-mPEG and HP-SA-mPEG, which has urethane bonds and ester groups in the molecular structure respectively, were also investigated. It demonstrated that the hydrolysis of these two kinds of polymer exhibited similar principles as that of oxidative degradation of HP. The degradation properties of hyperbranched polyether were much different with that of linear polymers and can be used in the special fields.