Synthesis And Application On Drug Delivery Of An Amphiphilic Dendrimer-like Copolymer

There have been a lot researches on making polymeric materials as a potential drug carrier. The drugs physically encapsulated or chemical conjugated by polymeric materials can overcome the disadvantages such as low solubility in water, instability under physiological conditions, high systemic toxicity, which may greatly enhance therapeutic efficacy of modified drugs. Vesicles and micelles formed by amphiphilic block copolymer self-assembly were used to encapsulate and transport drugs, which can avoid the influence of biological enzyme and other environment on the drug transport. In theory, the drugs can be slowly released in target zone. However, the micelles can be formed into solution only above the critical micelle concentration (CMC). Once the micelles are injected into the body, they are subjected to dilution and may lead to unexpected dissociation of micelles. Furthermore, the size of micelles ranges from50to500nm those are disfavored by the transport channel in vivo. To make micelles and vesicles with less size and good control on dissociation is key points to apply amphiphilic copolymers on drug release.Recently, it has found that the unimolecular micelle formed by amphiphilic copolymer can form small size micelle and the degradation of micelle can be effectively controlled. In contrast with conventional amphiphilic linear diblock copolymer that formed polymeric micelles, the unimolecular micelle has an average size of30nm and shows excellent stability in aqueous solution, which is independent of solution concentration and temperature. Therefore, it is more suitable for the application on drug release system.In this thesis, we synthesized an amphiphilic layered dendrimer-like copolymer using ethylene oxide (EO) and2,3-epoxy-1-(1-ethoxyethoxy)propane (EEGE) as monomers via the method of living anionic ring-opening polymerization (AROP). We studied the polymerization conditions and the drug release in vitro by encapsulating an anticancer drug DOX. The details are as follows:1. Synthesis of amphiphilic dendrimer-like copolymer. A three-arm dendrimer-like polymer was firstly prepared based on the AROP of EEGE from1,1,1-tris(hydroxymethyl)ethane which was deprotonated using DPMK and DMSO/THF(v/v:3/2) as mixed solvent. Aforementioned intermediate was end-modified with a branching agent carrying double bonds and oxidized to get a star polymer, which has six hydroxyls at the end, two hydroxyls of each branching chain. Following the same procedures based on the AROP of EEGE, the second generation dendrimer-like PEEGE was synthesized. Finally, we obtained an amphiphilic dendrimer-like copolymer which possessed two generation of hydrophobic PEEGE core and one generation of hydrophilic PEO shell. By controlling polymerization conditions, we synthesized a dendrimer-like copolymer with well-controlled molecular structure and molecular weight. These samples were characterized by Elemental Analysis (EA), Infra-Red (IR) Spectrum, Nuclear Magnetic Resonance (NMR) Spectroscopy and Gel Permeation Chromatography (GPC).2. The preparation of micelle and drug delivery study. The micelles of dendrimer-like polymeric formed in solution were characterized by dynamic light scattering (DLS) and transmission electron microscope (TEM). To study the drug delivery capability of micelles, we prepared DOX-loaded micelles by dialysis and rotary evaporation method. The properties of drug delivery in different environments were studied by UV-Vis and X-ray fluorescence spectrometer.